Peri-conception human papillomavirus vaccination exposure and risk of birth defects: a population-based retrospective cohort study

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Previous studies have clarified the association between Peri-conception HPV vaccination and several adverse pregnancy outcomes (e.g., spontaneous abortion). However, the risk for birth defects remains controversial due to limited large-scale studies. This study aims to investigate whether peri-conception HPV vaccination is associated with an increased risk of birth defects. Methods This population-based retrospective cohort study included 177,574 pregnancies conceived between March 2018 and December 2021 in Xiamen, China. Peri-conception HPV exposure was defined as vaccination occurring from 90 days before the LMP to the end of the first trimester (i.e.,13 + 6 gestational weeks, approximately 97 days after the LMP). Propensity score matching (PSM) based Poisson regression was used to estimate the adjusted relative risk (aRR) of HPV vaccine exposure for total birth defects, excluding chromosomal abnormalities and 10 organ system-specific birth defects. Two subgroup analyses, including different exposure windows (pre-30 days [30 days preceding the LMP to 97 days after the LMP] vs. first trimester) and vaccine valences (quadrivalent vs. 9-valent), six sensitivity analyses, and a negative control analysis were performed. Results A total of 177,574 pregnancies were included, of which 566 were exposed to the HPV vaccine during the Peri-conception period. The rate of Peri-conception vaccine exposure increased from 0.10% in 2018 to 0.58% in 2021. After 1:4 PSM, Peri-conception HPV vaccination was not associated with an increased risk of total birth defects (2.22% vs. 2.88%; aRR 0.77, 95% confidence interval [CI] 0.42–1.42). Similarly, no significant association was found between HPV vaccination and the risk of 10 organ system-specific birth defects. In subgroup analyses, exposure during pre-30 days (aRR 0.59, 95% CI 0.23–1.48) and the first trimester (aRR 0.61, 95% CI 0.14–2.69) and exposure to the 4vHPV (aRR 1.25, 95% CI 0.62–2.51) and 9vHPV (aRR 0.57, 95% CI 0.13–2.49) vaccines were not associated with a higher risk of total birth defects. All sensitivity and negative control analyses demonstrated the robustness of the results. Conclusions Our evidence suggests that exposure to the HPV vaccine before and during early pregnancy does not increase the risk of birth defects. This conclusion helps increase the willingness of women of childbearing age to receive HPV vaccination. Trial registration: This population-based retrospective cohort study was registered at ClinicalTrials.gov (NCT06180447, December 21, 2023). HPV vaccine Birth defects Peri-conception Pregnancy Population-based cohort Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Persistent infection with high-risk human papillomavirus (HPV) is the main cause of cervical cancer 1 , with an estimated 604,127 cases worldwide in 2020 2 . HPV vaccines, including bivalent (2vHPV), quadrivalent (4vHPV), and 9-valent (9vHPV) 1 , 3 , are currently the most effective ways to prevent cervical cancer 4 , 5 . The Advisory Committee on Immunization Practices (ACIP) recommends HPV vaccination for women aged 11–26 years, with vaccination extended to the age of 45 years based on clinical conditions 6 . In 2017, the HPV vaccination rate reached 51% among American women aged 22–26 7 , and the coverage rate of the HPV vaccine has been on the rise in recent years, with a global rate of approximately 21% in 2022 8,9 . Although HPV vaccination is not recommended during pregnancy 6 , previous studies have shown that the rate of HPV vaccination during the Peri-conception period (from 90 days before the last menstrual period [LMP] to the end of the first trimester) ranges from 1.0–1.5% 10–12 . As the target population of the HPV vaccine includes women of childbearing age, there is a critical risk of Peri-conception HPV vaccination exposure, especially among women with unplanned pregnancies 10 , 13 , 14 . Several studies have investigated the association between Peri-conceptional HPV vaccination and adverse pregnancy outcomes 15 , 16 . For example, a meta-analysis of randomized controlled trials (RCTs) published in 2023 indicated that HPV vaccine exposures during the Peri-conception period or during pregnancy did not increase the risks of spontaneous abortion (pooled relative risk [RR] 1.15, 95% confidence interval [CI] 0.91–1.46) and preterm birth (pooled RR 0.94, 95% CI 0.67–1.32) 17 . However, as one of the most concerning adverse pregnancy outcomes, whether Peri-conception exposure to the HPV vaccine increases the risk of birth defects remains determined 6 , 15 , 17 – 20 .Owing to the low rate of HPV vaccination during pregnancy and the very-low incidence of birth defects, only large-sample studies can evaluate this association; however, such studies are still relatively rare. Additionally, previous studies have mostly focused on total birth defects, neglected specific types, and mainly considered only a single type of HPV vaccine. 15 , 21 . Some studies have also relied on patients’ self-reported vaccination data instead of rigorous registry-collected data 22 . Furthermore, due to variations in HPV infection and vaccination rates across ethnic groups 23 , 24 , the relationship between Peri-conception HPV vaccination and birth defects in Asian populations remains unclear. To provide further safety evidence for HPV vaccination, we conducted this population-based cohort study involving 177,574 pregnancies, including subgroup analyses for the pre-30 days (from 30 days preceding the LMP to 97 days after the LMP), the first trimester, 4vHPV vaccine, and 9vHPV vaccine, along with seven sensitivity analyses, to comprehensively evaluate the risk of Peri-conception HPV vaccination for birth defects. 2 Methods This population-based retrospective cohort study was registered at ClinicalTrials.gov (NCT06180447, December 21, 2023). 2.1 Data source To assess HPV vaccine exposure in pregnant women, we developed a population-based pregnancy vaccine database using a unique ID (i.e., citizen health identification number) to link two population-based databases in Xiamen, China: an established pregnancy registry database (REPRESENT) 25 and a vaccine prescription database. First, REPRESENT, described in detail elsewhere 25 , is a population-based, large-scale, longitudinal pregnancy registry database that collects healthcare data (e.g., sociodemographics, laboratory test results, and maternal and neonatal outcomes) from pregnant women and their offspring across all medical institutions in Xiamen City, China. As of December 2021, REPRESENT included 920,236 delivery pregnancies. Second, the vaccine prescription database was established by collecting vaccination information registered and collected by all hospitals and primary healthcare facilities in Xiamen City (i.e., 15 tertiary hospitals, 39 primary healthcare facilities, and 272 health stations) from January 2013 to December 2021, including the generic and trade name of vaccine, vaccination dates, and so on. The vaccination and information recording processes in all medical institutions in Xiamen were conducted in strict accordance with the requirements and standards set forth by the Chinese Center for Disease Control and Prevention 26 . In this pregnancy vaccine database, HPV vaccination can be accurately located at a specific period of the pregnancy life course by calculating the time difference between the date of vaccine administration and the LMP. 2.2 Inclusion exclusion criteria Because there has been a persistent discrepancy between HPV vaccine supply and demand since the HPV vaccine was approved in mainland China (the 2vHPV, 4vHPV, and 9vHPV vaccines were approved in July 2016, May 2017, and April 2018, respectively) 27 – 29 , we included HPV vaccinations administered between January 2018 and December 2021. To obtain information on HPV vaccine exposure during the Peri-conception period (from 90 days preceding to 97 days after the LMP), we included only pregnancies with LMP between March 2018 and December 2021. These pregnancies were excluded from this study: (1) pregnancies had not delivered by December 31, 2021; (2) pregnancies that resulted in miscarriage or stillbirth; (3) pregnancies that exposed to known risk factors for birth defects, including smoking, syphilis infection, exposure to radiation, epilepsy, insulin-dependent diabetes mellitus, adverse pregnancy history of Edward’s disease and Down syndrome, and family history of neural tube defect; and (4) pregnancies using medications known to increase the risk of birth defects during Peri-conception, including diazepam, flunitrazepam, midazolam, alprazolam, lorazepam, fluoxetine, olanzapine, oxycodone. 2.3 Exposure and control In this study, HPV vaccine exposure was defined as at least one dose of vaccine (2vHPV, 4vHPV, or 9vHPV) administered during the Peri-conception period, spanning from 90 days preceding the LMP to 97 days after the LMP (i.e., 13 + 6 gestational weeks) 30 – 32 . We further delineated the HPV vaccine exposure window into two specific periods (Fig. 1 ): (1) pre-30 days, from 30 days preceding the LMP to 97 days after the LMP, and (2) the first trimester, from the LMP to 97 days after the LMP. The control group included pregnancies that were not exposed to the HPV vaccine during the Peri-conception period. 2.4 Outcomes Following the National Health Standard Criteria 33 , a standardized questionnaire was employed to uniformly collect data on birth defects in REPRESENT. Birth defects are identified through prenatal ultrasound examinations or genetic testing, which detects malformations encompassing structural, functional, and metabolic disorders. Furthermore, diagnoses made by clinicians within the first 42 days post-birth, based on physical examinations or further tests, were included. The primary outcome of this study was total birth defects, excluding chromosomal abnormalities (ICD-10 code: Q00-Q89). The secondary outcomes were 10 organ system-specific birth defects, namely, congenital malformations of the nervous system (Q00-Q07), congenital malformations of eye, ear, face and neck (Q10-Q18), congenital malformations of the circulatory system (Q20-Q28), congenital malformations of the respiratory system (Q30-Q34), cleft lip and cleft palate (Q35-Q37), other congenital malformations of the digestive system (Q38-Q45), congenital malformations of genital organ (Q50-Q56), congenital malformations of the urinary system (Q60-Q64), congenital malformations and deformations of the musculoskeletal system (Q65-Q79), and other congenital malformations (Q80-Q89). For multiple pregnancies, we defined a pregnancy as having a birth defect if one of the births had a birth defect. 2.5 Covariates To minimize confounding, we incorporated an extensive range of covariates, including demographic characteristics (such as maternal age, pre-pregnancy body mass index [BMI], marital status, and education level), obstetrical characteristics (such as parity, multiple gestations, adverse pregnancy, and childbirth history), disease status (such as hepatitis B virus positivity, pre-existing diabetes, and chronic hypertension), and laboratory test results (such as total bilirubin, serum creatinine, and systolic blood pressure) (detailed in Table S1). 2.6 Statistical analyses The HPV vaccination rate was calculated by dividing the number of pregnancies in which the HPV vaccine was administered during the Peri-conception period by the total number of pregnancies within a specific period. Propensity score matching (PSM)-based Poisson regression was used to estimate the adjusted relative risk (aRR) and 95% CIs for the risk of HPV vaccination for birth defects. Propensity scores were calculated based on logistic regression models that estimated the probability of HPV vaccine administration based on all the covariates listed above. After propensity scores were calculated, nearest neighbor 1:4 PSM with a caliper width of 0.02 was used to match exposure and control 34 . After PSM, the balance in covariates was assessed using standardized mean difference (SMD) of < 0.1 35 . Given the low rate of missing data in this study, the full dataset was used in the primary analysis, after excluding missing data. Subgroup analyses were conducted, stratified by (1) HPV vaccine type: 4vHPV and 9vHPV, and (2) different exposure windows: pre-30 and first trimester. We performed six sensitivity analyses (Fig. 2 ), namely, (1) exposure group restricted to pregnancies administered two or more doses of the HPV vaccine during the Peri-conception period; (2) using propensity score overlap weighting approach (OW) to estimate aRR 36 ; (3) using 1:10 PSM with a caliper width of 0.02; (4) excluding pregnancies with previous HPV vaccination (i.e., exposure to the HPV vaccine preceding 90 days before the LMP); (5) using 1:4 PSM with a caliper width of 0.02 based on imputed dataset by using multiple imputation by chained equations (MICE) 37 ; and (6) using propensity score OW based on imputed dataset. Furthermore, a negative control exposure analysis was implemented to identify potential biases comprising pregnancies exposed to the HPV vaccine between 365 and 90 days preceding the LMP. It was hypothesized that vaccination during this period will not result in an increased incidence of birth defects. Continuous variables are presented as mean and standard deviation (SD) if normally distributed, otherwise as median and interquartile range (IQR). Categorical variables are expressed as frequencies and proportions. Differences between groups for continuous variables were assessed using the t-test or Mann-Whitney U test, as appropriate, and differences between categorical variables were evaluated using the chi-square test. All analyses were conducted using R software (version 4.2.3; R Project for Statistical Computing, Vienna, Austria). The significance level for the tests was established at a two-tailed P -value of < 0.05. The overall level of significance was not adjusted for multiple testing because all analyses were exploratory. 3 Results 3.1 Characteristics of the population This study included 177,574 pregnancies with live births between March 2018 and December 2021 (Figure S1). Among these pregnancies, the mean maternal age was 29.21 ± 4.54 years, 2.77% were obese (BMI ≥ 28.00), 57.47% had more than 12 years of education, and 43.38% were nulliparous. A total of 566 pregnancies (0.32%) were exposed to the HPV vaccine during the Peri-conception period, whereas 177,008 pregnancies (99.68%) were not. Among the exposed pregnancies, 338 (59.72%) were exposed to the 4vHPV vaccine, 157 (27.74%) to the 9vHPV vaccine, 71 (12.54%) to the 2vHPV vaccine, and 105 (18.55%) to two doses of the HPV vaccine. Compared with the unexposed group, pregnancies exposed to the HPV vaccine during the Peri-conception period were characterized by lower age, a lower prevalence of obesity, and a higher proportion of individuals with higher education levels. The baseline characteristics of the patients are presented in Table 1 . Table 1 Characteristics of pregnant women included in this study (n, %) Characteristic Overall (N = 177574) Exposed a (N = 566) Non-exposed (N = 177008) P value Maternal age (years) 35 22370 (12.60) 55 (9.72) 22315 (12.61) Missing 10 (0.01) 0 (0.00) 10 (0.01) Pre-pregnancy body mass index (kg/m 2 ) < 18.50 31604 (17.80) 107 (18.90) 31497 (17.79) 0.07 18.50-23.99 98445 (55.44) 338 (59.72) 98107 (55.43) 24.00-27.99 42588 (23.98) 110 (19.43) 42478 (24.00) ≥ 28.00 4923 (2.77) 11 (1.94) 4912 (2.78) Missing 14 (0.01) 0 (0.00) 14 (0.01) Transient population No 135485 (76.30) 499 (88.16) 134986 (76.26) < 0.001 Yes 41955 (23.63) 67 (11.84) 41888 (23.66) Missing 134 (0.08) 0 (0.00) 134 (0.08) Region Town 158594 (89.31) 503 (88.87) 158091 (89.31) 0.92 Countryside 18968 (10.68) 63 (11.13) 18905 (10.68) Missing 12 (0.01) 0 (0.00) 12 (0.01) Marital status Married 160482 (90.37) 522 (92.23) 159960 (90.37) 0.30 Other 16852 (9.49) 43 (7.60) 16809 (9.50) Missing 240 (0.14) 1 (0.18) 239 (0.14) Education level (years) 1–6 3049 (1.72) 1 (0.18) 3048 (1.72) 12 102047 (57.47) 464 (81.98) 101583 (57.39) Other 578 (0.33) 2 (0.35) 576 (0.33) Parity Multipara 100385 (56.53) 295 (52.12) 100090 (56.55) 0.08 Nullipara 77040 (43.38) 271 (47.88) 76769 (43.37) Missing 149 (0.08) 0 (0.00) 149 (0.08) Multiple gestations Singletons 175881 (99.05) 564 (99.65) 175317 (99.04) 0.54 Twins 10 (0.01) 0 (0.00) 10 (0.01) Triplets 1680 (0.95) 2 (0.35) 1678 (0.95) Missing 3 (0.00) 0 (0.00) 3 (0.00) Thalassemia No 172902 (97.37) 548 (96.82) 172354 (97.37) 0.49 Yes 4672 (2.63) 18 (3.18) 4654 (2.63) Pre-existing diabetes No 175735 (98.96) 557 (98.41) 175178 (98.97) 0.27 Yes 1839 (1.04) 9 (1.59) 1830 (1.03) Thyroid dysfunction No 167668 (94.42) 533 (94.17) 167135 (94.42) 0.87 Yes 9906 (5.58) 33 (5.83) 9873 (5.58) Blood disease No 170093 (95.79) 543 (95.94) 169550 (95.79) 0.94 Yes 7481 (4.21) 23 (4.06) 7458 (4.21) Hepatitis B surface antigen positive No 160236 (90.24) 514 (90.81) 159722 (90.23) 0.86 Yes 15807 (8.90) 48 (8.48) 15759 (8.90) Missing 1531 (0.86) 4 (0.71) 1527 (0.86) Vaginitis No 166271 (93.63) 522 (92.23) 165749 (93.64) 0.20 Yes 11303 (6.37) 44 (7.77) 11259 (6.36) Folic acid consumption No 1616 (0.91) 6 (1.06) 1610 (0.91) 0.93 Yes 175956 (99.09) 560 (98.94) 175396 (99.09) Missing 2 (0.00) 0 (0.00) 2 (0.00) a Pregnancies exposed to HPV vaccine during the Peri-conception period. 3.2 Peri-conception HPV vaccination rates Among the 566 pregnancies exposed to the HPV vaccine, 300 pregnancies (53.00%) were administered during pre-30 days, and 151 pregnancies (26.68%) were administered during the first trimester. Since 2018, the rate of Peri-conception exposure to the HPV vaccine has shown a progressive increase over time (Fig. 3 ). Compared with that during 2018 (0.10%), the rate of HPV vaccine exposure during Peri-conception increased to 0.25% in 2019 (RR 2.50, 95% CI 1.83–3.42) and 0.58% in 2020 and 2021 (RR 5.80, 95% CI 4.35–7.73). The Peri-conception HPV vaccine exposure rate peaked at 0.84% (38/4,535) in January 2021 (Fig. 3 ). 3.3 Association between Peri-conception HPV vaccination exposure and birth defects After excluding individuals with missing data, 169,040 pregnancies were included in the analysis. The incidence of total birth defects, excluding chromosomal abnormalities, was 2.21% (12/542) and 2.73% (4,608/168,498) in the exposed and non-exposed groups, respectively. Following the implementation of the PSM strategy, the covariates were balanced between the exposed and unexposed groups, as indicated by an SMD of < 0.1. Our results showed that compared with the unexposed group, HPV vaccine exposure during Peri-conception did not increase the risk of total birth defects, with aRR of 0.77 (95% CI 0.42–1.42; Table 2 , Fig. 4 ). Similarly, no additional risk of HPV vaccination during Peri-conception was found for any organ system-specific birth defects (Table 2 ). Table S1 Categories and missing values of covariates included in the propensity score analysis Covariate Categories Timing of recording Missing, No. (%) Demographic and obstetrical characteristics Maternal age (years) 35 At the first antenatal visit 10 (0.01) Paternal age (years) 35 At the first antenatal visit 1349 (0.76) Pre-pregnancy body mass index (kg/m 2 ) =28.00 At the first antenatal visit 14 (0.01) Residence duration of at least one year Yes, No At the first antenatal visit 2261 (1.27) Transient population Yes, No At the first antenatal visit 134 (0.08) Region Town, Countryside At the first antenatal visit 12 (0.01) Marital status Married, Other At the first antenatal visit 240 (0.14) Irregular menstruation Yes, No At the first antenatal visit 419 (0.23) Consanguineous marriage Yes, No At the first antenatal visit 611 (0.34) Education level (years) 1–6, 7–9, 10–12, > 12, Other At the first antenatal visit 0 Alcohol consumption Yes, No At the first antenatal visit 1 (< 0.001) Parity Nullipara, Multipara At the first antenatal visit 149 (0.08) Multiple gestations Singletons, Twins, Triplets At the first antenatal visit 3 (< 0.001) Adverse pregnancy and childbirth history Yes, No At the first antenatal visit 0 Use of assisted fertility technology Yes, No At the first antenatal visit 0 Disease status and medications Hepatitis B surface antigen Yes, No At the first antenatal visit 1531 (0.86) Human immunodeficiency virus positive Yes, No At the first antenatal visit 1745 (0.98) Hyperemesis Yes, No During the first trimester 3 (< 0.001) Fever Yes, No During the first trimester 2 (< 0.001) Allergies Yes, No During the first trimester 5 (< 0.001) Thyroid dysfunction Yes, No At the first antenatal visit 0 Mental illness Yes, No At the first antenatal visit 487 (0.27) Blood disease Yes, No At the first antenatal visit 0 Chronic hypertension Yes, No At the first antenatal visit 0 Thalassemia Yes, No At the first antenatal visit 0 Pre-existing diabetes Yes, No At the first antenatal visit 0 Scarred uterus Yes, No At the first antenatal visit 0 Fatty liver Yes, No At the first antenatal visit 0 Viral hepatitis other than hepatitis B Yes, No At the first antenatal visit 0 Vaginitis Yes, No At the first antenatal visit 0 Abnormal lipid metabolism Yes, No At the first antenatal visit 0 Sexually transmitted diseases Yes, No At the first antenatal visit 0 Hysteromyoma Yes, No At the first antenatal visit 0 Ovarian cyst Yes, No At the first antenatal visit 0 Folic acid supplementation Yes, No At the first antenatal visit 2 (< 0.001) Contraceptive pill Yes, No At the first antenatal visit 1 (< 0.001) Laboratory test results Total bilirubin Continuous variable At the first antenatal visit 1534 (0.86) Serum creatinine Continuous variable At the first antenatal visit 1617 (0.91) Serum alanine aminotransferase Continuous variable At the first antenatal visit 1461 (0.82) Systolic blood pressure Continuous variable At the first antenatal visit 139 (0.08) Hemoglobin count Low, Normal, High At the first antenatal visit 729 (0.41) White blood count Low, Normal, High At the first antenatal visit 807 (0.45) Platelet count Low, Normal, High At the first antenatal visit 971 (0.55) Table 2 The association between Peri-conception HPV vaccine exposure and birth defects Outcome a aRR (95% CI) b P value Total birth defects 0.77 (0.42–1.42) 0.41 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 1.00 (0.11–8.90) 1.00 Congenital malformations of genital organs 1.99 (0.37–10.86) 0.43 Other congenital malformations of the digestive system 1.99 (0.18–21.95) 0.57 Congenital malformations of the circulatory system 0.80 (0.38–1.69) 0.56 a After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis. b aRR, adjusted relative risk. Table S2 Subgroup analysis results of the association between Peri-conception HPV vaccine exposure and birth defects Types of analysis Period of exposure Outcome a aRR (95% CI) b P value Total birth defects Pre-30 days Overall birth defects 0.59 (0.23–1.48) 0.26 Organ system specific birth defects Congenital malformations of genital organs 1.33 (0.14–12.72) 0.81 Other congenital malformations of the digestive system 1.00 (0.11–8.87) 1.00 Congenital malformations of the circulatory system 0.54 (0.16–1.80) 0.32 Congenital malformations of the nervous system 3.98 (0.25–63.49) 0.33 Other congenital malformations 3.98 (0.25–63.49) 0.33 First-trimester Overall birth defects 0.61 (0.14–2.69) 0.52 Organ system specific birth defects Other congenital malformations of the digestive system 3.99 (0.25–63.35) 0.33 Other congenital malformations 3.99 (0.25–63.35) 0.33 4vHPV vaccine Peri-conception Overall birth defects 1.25 (0.62–2.51) 0.54 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 1.33 (0.14–12.77) 0.80 Congenital malformations of genital organs 2.00 (0.18–21.97) 0.57 Other congenital malformations of the digestive system 4.00 (0.25–63.73) 0.33 Congenital malformations of the circulatory system 1.04 (0.43–2.54) 0.93 Pre-30 days Overall birth defects 0.93 (0.32–2.74) 0.90 Organ system specific birth defects Congenital malformations of the circulatory system 0.88 (0.19–4.04) 0.87 Other congenital malformations 3.96 (0.25–63.07) 0.33 First-trimester Overall birth defects 1.33 (0.27–6.49) 0.73 Organ system specific birth defects Other congenital malformations of the digestive system 4.00 (0.25–63.30) 0.33 9vHPV vaccine Peri-conception Overall birth defects 0.57 (0.13–2.49) 0.46 Organ system specific birth defects Congenital malformations of genital organs 2.00 (0.18–21.91) 0.57 Congenital malformations of the circulatory system 1.14 (0.24–5.44) 0.87 Rigorous Peri-conception Overall birth defects 0.50 (0.06–3.91) 0.51 Organ system specific birth defects Congenital malformations of genital organs 1.98 (0.18–21.59) 0.58 Congenital malformations of the circulatory system 0.79 (0.09–6.69) 0.83 a After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis. b aRR, adjusted relative risk. Table S3 Sensitivity analysis results of the association between Peri-conception HPV vaccine exposure and birth defects Period of exposure Outcome a aRR (95% CI) b P value >=2 doses c Peri-conception Total birth defects 1.09 (0.31–3.84) 0.89 Organ system specific birth defects Other congenital malformations of the digestive system 4.00 (0.25–63.39) 0.33 Congenital malformations of the circulatory system 1.00 (0.22–4.63) 1.00 Overlap weighting Peri-conception Total birth defects 0.82 (0.47–1.43) 0.60 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 0.54 (0.08–3.83) 0.62 Congenital malformations of genital organs 1.99 (0.5–8.01) 0.57 Other congenital malformations of the digestive system 1.69 (0.24–12.07) 0.75 Congenital malformations of the circulatory system 0.92 (0.46–1.84) 0.87 Congenital malformations of the nervous system 6.96 (0.95–51.01) 0.49 Other congenital malformations 1.64 (0.23–11.68) 0.76 Pre-30 days Total birth defects 0.65 (0.27–1.54) 0.45 Organ system specific birth defects Congenital malformations of genital organs 1.90 (0.27–13.55) 0.71 Other congenital malformations of the digestive system 3.16 (0.44–22.56) 0.58 Congenital malformations of the circulatory system 0.66 (0.21–2.03) 0.58 Congenital malformations of the nervous system 13.75 (1.87-101.06) 0.50 Other congenital malformations 3.20 (0.45–22.81) 0.57 First-trimester Total birth defects 0.53 (0.13–2.08) 0.46 Organ system specific birth defects Other congenital malformations of the digestive system 6.98 (0.98–49.79) 0.50 Congenital malformations of the nervous system 26.42 (3.58-195.25) 0.54 Other congenital malformations 5.92 (0.83–42.22) 0.50 1:10 PSM Peri-conception Total birth defects 0.88 (0.49–1.58) 0.68 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 0.90 (0.12–6.99) 0.92 Congenital malformations of genital organs 1.99 (0.44–9.05) 0.38 Other congenital malformations of the digestive system 4.97 (0.45–54.72) 0.19 Congenital malformations of the circulatory system 0.89 (0.44–1.83) 0.76 Congenital malformations of the nervous system 9.94 (0.62-158.68) 0.10 Other congenital malformations 3.31 (0.35–31.80) 0.30 Pre-30 days Total birth defects 0.53 (0.22–1.28) 0.16 Organ system specific birth defects Congenital malformations of genital organs 1.98 (0.23–16.90) 0.53 Other congenital malformations of the digestive system 1.10 (0.14–8.66) 0.93 Congenital malformations of the circulatory system 0.50 (0.16–1.57) 0.24 Congenital malformations of the nervous system 9.91 (0.62-157.97) 0.11 Other congenital malformations 4.95 (0.45–54.46) 0.19 First-trimester Total birth defects 0.57 (0.14–2.33) 0.43 Organ system specific birth defects Other congenital malformations of the digestive system 4.95 (0.45–54.31) 0.19 Other congenital malformations 4.95 (0.45–54.31) 0.19 Exclude previous HPV vaccination d Peri-conception Total birth defects 0.71 (0.39–1.31) 0.28 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 0.50 (0.06–3.98) 0.51 Congenital malformations of genital organs 2.66 (0.45–15.87) 0.28 Other congenital malformations of the digestive system 0.66 (0.08–5.51) 0.71 Congenital malformations of the circulatory system 0.91 (0.43–1.95) 0.81 Congenital malformations of the nervous system 1.99 (0.18–21.95) 0.57 Other congenital malformations 1.00 (0.11–8.90) 1.00 Pre-30 days Total birth defects 0.64 (0.25–1.64) 0.36 Organ system specific birth defects Congenital malformations of genital organs 1.99 (0.18–21.89) 0.57 Congenital malformations of the circulatory system 0.52 (0.16–1.72) 0.29 First-trimester Total birth defects 0.36 (0.09–1.53) 0.17 Organ system specific birth defects Other congenital malformations 2.00 (0.18–21.87) 0.57 1:4 PSM using imputed data Peri-conception Total birth defects 0.87 (0.44–1.73) 0.68 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 0.61 (0.07–5.73) 0.67 Congenital malformations of genital organs 3.68 (0.36–37.27) 0.27 Other congenital malformations of the digestive system 1.44 (0.14–14.76) 0.76 Congenital malformations of the circulatory system 0.93 (0.38–2.23) 0.86 Other congenital malformations 2.24 (0.14–36.90) 0.57 Pre-30 days Total birth defects 0.61 (0.23–1.62) 0.32 Organ system specific birth defects Congenital malformations of genital organs 2.19 (0.12–41.51) 0.60 Congenital malformations of the circulatory system 0.61 (0.17–2.16) 0.44 Other congenital malformations 2.79 (0.16–48.22) 0.48 First-trimester Total birth defects 0.58 (0.15–2.22) 0.42 Overlap weighting using imputed data Peri-conception Total birth defects 0.84 (0.40–1.77) 0.65 Organ system specific birth defects Congenital malformations and deformations of the musculoskeletal system 0.51 (0.05–5.69) 0.58 Congenital malformations of genital organs 1.94 (0.18–21.09) 0.59 Other congenital malformations of the digestive system 1.58 (0.07–37.23) 0.78 Congenital malformations of the circulatory system 0.99 (0.39–2.51) 0.99 Other congenital malformations 1.59 (0.07–37.63) 0.77 Pre-30 days Total birth defects 0.62 (0.20–1.89) 0.40 Organ system specific birth defects Congenital malformations of genital organs 1.82 (0.07–49.38) 0.72 Other congenital malformations of the digestive system 3.04 (0.06-158.43) 0.58 Congenital malformations of the circulatory system 0.64 (0.15–2.71) 0.54 Other congenital malformations 2.93 (0.06-144.43) 0.59 First-trimester Total birth defects 0.56 (0.13–2.40) 0.43 Negative control exposure e Total birth defects 0.93 (0.52–1.66) 0.81 Organ system specific birth defects Cleft lip and cleft palate 0.80 (0.09–6.83) 0.84 Congenital malformations and deformations of the musculoskeletal system 0.44 (0.06–3.50) 0.44 Congenital malformations of eye, ear, face and neck 1.33 (0.27–6.58) 0.73 Congenital malformations of genital organs 2.00 (0.18-22.00) 0.57 Other congenital malformations of the digestive system 0.99 (0.11–8.92) 1.00 Congenital malformations of the circulatory system 0.80 (0.36–1.79) 0.59 a After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis. b aRR, adjusted relative risk. c > = 2 doses: defining exposure as those pregnancies with two or more doses of the HPV vaccine administered during the Peri-conception period. d Pregnancies with previous exposure to HPV vaccine (preceding 90 days before last menstrual period) were excluded. e Negative control exposure: pregnancies among women who received HPV vaccination between 365 days and 90 days before the last menstrual period. Subgroup analysis results for different exposure periods also indicated that HPV vaccination during pre-30 days (aRR 0.59, 95% CI 0.23–1.48) and during the first trimester (aRR 0.61, 95% CI 0.14–2.69) were not associated with a higher risk of total birth defects (Table S2, Fig. 4 ). Similarly, analyses by the vaccine type indicated that exposure to the 4vHPV (aRR 1.25, 95% CI 0.62–2.51) or 9vHPV (aRR 0.57, 95% CI 0.13–2.49) vaccine during Peri-conception were not associated with a higher risk of total birth defects (Table S2, Fig. 4 ). Due to the limited number of subjects who received the 2vHPV vaccine in this study, this HPV type was not included in the subgroup analysis. Furthermore, the results of the six sensitivity analyses were consistent with the primary results, and the negative control exposure analysis revealed no significant association between exposure and outcomes (Table S3, Fig. 5 ), suggesting the robustness of the findings in this study. 4 Discussion 4.1 Principal findings This study utilized data from a population-based pregnancy registry in Xiamen, China, to specifically investigate the impact of Peri-conception HPV vaccination on the risk of birth defects, which represents the largest sample size of original studies in this field to date. This study revealed a consistent annual increase in the vaccination rates among pregnant women in China. Furthermore, our study found that, compared with the unexposed group, exposure to the HPV vaccine during the Peri-conception period, pre-30 days, and first trimester did not increase the risk of birth defects. This provides reliable evidence for the safety of HPV vaccination during the Peri-conception period, helping to alleviate pregnant women's concerns about the potential risks of HPV vaccination. 4.2 Results in the context of what is known The safety of HPV vaccine exposure during the Peri-conception period is a subject of concern. Several studies have evaluated the risk of HPV vaccination for miscarriage, stillbirth, low birth weight, and preterm birth, suggesting that the HPV vaccine does not increase the risk of these adverse pregnancy outcomes 11 , 15 , 18 , 21 , 38 . For example, by including three cohort studies, a meta-analysis showed that receiving the HPV vaccine during or around pregnancy does not increase the risk of miscarriage (RR 2.01, 95% CI 0.66–6.13) or stillbirth (RR 2.02, 95% CI 0.65–6.27) 18 . Additionally, several cohort studies have indicated that exposure to the HPV vaccine during the Peri-conception period does not increase the risk of spontaneous abortion (hazard ratio 0.71, 95% CI 0.45–1.14), low birth weight (odds ratio 1.10, 95% CI 0.85–1.43), and preterm birth (odds ratio 1.15, 95% CI 0.93–1.42) 11 , 15 , 21 , 38 . For birth defects, although limited participants were included, previous studies have shown no additional risk of Peri-conceptional HPV vaccination 10 , 21 , 38 . A recent meta-analysis that included four RCTs and five cohort studies suggested that Peri-conceptional exposure to the HPV vaccine was not associated with a higher risk of birth defects 17 . However, our study had several discrepancies with the findings of these studies. First, most previous studies were based on pregnant women in Europe and the US, and no studies have been conducted on pregnant Asian women. Additionally, some studies relied on patients’ self-reported outcomes, which may lead to inaccurate outcome measurements 39 – 41 . Second, some of the included studies did not clarify whether the HPV vaccine was administered before or after conception, and some studies included exposure during the second or third trimester 10 , 16 , 39 , 40 , 42 , when such exposure is not traditionally regarded as a teratogenic-sensitive period. Third, published studies rarely evaluated the 9vHPV vaccine and did not clearly distinguish the dosage of the HPV vaccine. By including a large sample of 177,574 pregnancies from a population-based pregnancy registry, our results indicated that Peri-conceptional HPV vaccination did not exhibit a higher risk of birth defects than those who were not vaccinated, which is consistent with the existing literature 11 , 21 , 38 . It is worth stressing that, in comparison to previous studies, this is the first study to explore the association between HPV vaccination and birth defects in pregnant Asian women. Simultaneously, the measurements of exposure and outcomes in this study were more accurate, with HPV vaccine exposure reported by clinicians at the vaccination sites and birth defect outcomes documented by clinicians following diagnosis. Furthermore, we conducted an in-depth nuanced investigation. First, apart from Peri-conception, we focused on the teratogenically sensitive periods of pregnancy, specifically the pre-30 days and first trimester, as previous studies have overlooked the precise measurement of HPV vaccine exposure during these critical developmental windows. Second, our study covered birth defects in more detail and examined the association between Peri-conceptional HPV vaccination and both total birth defect and 10 organ system-specific birth defects, in contrast to previous studies that focused solely on overall birth defects. Third, we included three types of HPV vaccines (2vHPV, 4vHPV, and 9vHPV) and conducted analyses based on stratification by the vaccine type (4vHPV and 9vHPV) and by 2-dose vaccination for any HPV vaccine, whereas previous studies only focused on a single HPV vaccine and did not clearly distinguish between vaccine doses. These results provide comprehensive evidence regarding the safety of the HPV vaccine during the Peri-conception period. 4.3 Clinical and research implications The findings of this study have important public health implications, supporting the safety of HPV vaccination during the Peri-conception period and alleviating concerns regarding the potential risks of birth defects. This evidence is crucial for healthcare providers and policymakers, especially in cases of unintended pregnancy, and may contribute to enhanced willingness among women of childbearing age to receive HPV vaccination. 4.4 Strengths and limitations This study has several strengths. First, it is likely to be the largest cohort study to date to examine the association between Peri-conception HPV vaccination and birth defects. Second, we used a well-established population-based pregnancy registry, which included comprehensive vaccination records and national surveillance data on birth defects, to reduce the risk of misclassification due to information bias. Third, the study offers a comprehensive analysis of the relationship between HPV vaccination and birth defects, considering various exposure periods (Peri-conception, pre-30 days, and the first trimester) and stratifying the results by the HPV vaccine type. Finally, multiple sensitivity analyses, such as two doses of the HPV vaccine and a negative control exposure analysis, were conducted to enhance the credibility of our findings. This study has two limitations. First, although this study included 177,574 pregnancies, the number of pregnancies in the HPV vaccine-treated group was limited, particularly when focusing on the different HPV vaccines. Nevertheless, this study had the largest sample size among the original studies to date in this field. Second, although this study addressed the risk of birth defects in live births, birth defects in spontaneous abortions and stillbirths were not considered. However, controlling live birth bias, which accurately records birth defects in pregnancy loss (especially early pregnancy loss), represents a significant challenge in pharmacoepidemiological studies involving pregnant women. 5 Conclusion This population-based cohort study suggests that Peri-conception HPV vaccination is not associated with a higher risk of total birth defects and organ system-specific birth defects. However, further studies are required to identify the risks associated with specific birth defect types. Declarations Ethics approval and consent to participate This population-based retrospective cohort study was approved by the Ethics Committee of West China Hospital (2019 − 825) of Sichuan University in China. As patient information in this database is completely anonymous, no informed consent of the patient is required. Consent for publication Not applicable. Competing interests All authors declare that they have no competing interests. Funding This study was funded by National Natural Science Foundation of China (72004148, 82474335, 72174132), Natural Science Foundation of Sichuan Province (2024NSFSC1668), National Key Research and Development Program of China (2023YFC2414404), The National Science Fund for Distinguished Young Scholars (82225049), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD23004), Xiamen Science and Technology Plan Project (3502Z20224004). Author Contribution J.G: manuscript writing and data analysis; Y.X: manuscript revise and project development; P.Z and C.L: data cleaning and standardization; Y.R and K.Z: technical or material support; G.Y, Y.Q, B.R, H.Q, M.C, H.L: data collection; X.S, J.T: manuscript revise and project development. Acknowledgements None. Data Availability The data are not available to be shared publicly. References Burger EA, Portnoy A, Campos NG, Sy S, Regan C, Kim JJ. 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Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials. Obstet Gynecol Dec. 2009;114(6):1179–88. 10.1097/AOG.0b013e3181c2ca21 . Chen W, Zhao Y, Xie X, et al. Safety of a quadrivalent human papillomavirus vaccine in a Phase 3, randomized, double-blind, placebo-controlled clinical trial among Chinese women during 90 months of follow-up. Vaccine Feb. 2019;4(6):889–97. 10.1016/j.vaccine.2018.12.030 . Additional Declarations No competing interests reported. Supplementary Files HPVvaccinesandBDstables3.5gj2024.08.13.docx HPVvaccineandbirthdefectsfigures2024.10.106.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArklEQVRIiWNgGAWjYLCCBAYbBgYJErWkkaqFgeEwCVrkZ+Qek3i443xi/+z2h595GOzyCGoxuJGXbJB45nbijDtnjKV5GJKLCWuRyDF8kNh2O3eDRA4bMw/DgcQGwg7LMTiQ2HYOqCX9GXFaGG6AbTkA1JJgRpwWgzNvjA0S25LrZ9zIMZacY5BMhMPac8wkf7bZGfPPSH/44U2FHREOQ7OURPWjYBSMglEwCrADADDqOtYtaN+QAAAAAElFTkSuQmCC","orcid":"","institution":"Chinese Evidence-based Medicine Center, Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Sun","suffix":""},{"id":370117045,"identity":"a1886c02-bd39-42a2-8453-5ea65110c725","order_by":14,"name":"Jing Tan","email":"","orcid":"","institution":"Chinese Evidence-based Medicine Center, Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Tan","suffix":""}],"badges":[],"createdAt":"2024-10-19 13:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5294774/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5294774/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":68293764,"identity":"dc0a7f4f-3159-4344-a409-9cab41fefcae","added_by":"auto","created_at":"2024-11-05 17:57:08","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":303584,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.101.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/7396a80297aac8689af91f40.jpg"},{"id":68293768,"identity":"d2f888b2-e4cd-4fbd-b64b-ec710456b89c","added_by":"auto","created_at":"2024-11-05 17:57:08","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":789681,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.102.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/debd010cccd3712f8119ee2e.jpg"},{"id":68293767,"identity":"3a92af6d-22d2-429d-84d2-2d7c545c3781","added_by":"auto","created_at":"2024-11-05 17:57:08","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":467706,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.103.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/0873d4aa92e5eeeb5712f5ea.jpg"},{"id":68293762,"identity":"416d4d56-06cf-4982-976f-3c49ba252bda","added_by":"auto","created_at":"2024-11-05 17:57:08","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":390137,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.104.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/a00a6f7df061c71b0ab6902c.jpg"},{"id":68293766,"identity":"20d4b62d-2aad-4910-b475-e296dd029429","added_by":"auto","created_at":"2024-11-05 17:57:08","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":650181,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.105.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/b017a947f6f0deefb7adad22.jpg"},{"id":69802073,"identity":"6c526c33-f49c-459c-92d1-981ed5c7d16e","added_by":"auto","created_at":"2024-11-25 11:17:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4515046,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/fdb8bac5-82fd-4cbb-8bf4-364e613efbe5.pdf"},{"id":68293871,"identity":"30c988e3-9174-40da-970d-7b540c15573d","added_by":"auto","created_at":"2024-11-05 18:05:08","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":58856,"visible":true,"origin":"","legend":"","description":"","filename":"HPVvaccinesandBDstables3.5gj2024.08.13.docx","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/10341638c06192d879e9896d.docx"},{"id":68293872,"identity":"cc4f2ceb-4ab1-4368-982b-2684f4ff8170","added_by":"auto","created_at":"2024-11-05 18:05:08","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":630978,"visible":true,"origin":"","legend":"","description":"","filename":"HPVvaccineandbirthdefectsfigures2024.10.106.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5294774/v1/aa11abbcce284a3de69d4d17.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Peri-conception human papillomavirus vaccination exposure and risk of birth defects: a population-based retrospective cohort study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003ePersistent infection with high-risk human papillomavirus (HPV) is the main cause of cervical cancer\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, with an estimated 604,127 cases worldwide in 2020\u003csup\u003e2\u003c/sup\u003e. HPV vaccines, including bivalent (2vHPV), quadrivalent (4vHPV), and 9-valent (9vHPV)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, are currently the most effective ways to prevent cervical cancer\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The Advisory Committee on Immunization Practices (ACIP) recommends HPV vaccination for women aged 11\u0026ndash;26 years, with vaccination extended to the age of 45 years based on clinical conditions\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In 2017, the HPV vaccination rate reached 51% among American women aged 22\u0026ndash;26\u003csup\u003e7\u003c/sup\u003e, and the coverage rate of the HPV vaccine has been on the rise in recent years, with a global rate of approximately 21% in 2022\u003csup\u003e8,9\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough HPV vaccination is not recommended during pregnancy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, previous studies have shown that the rate of HPV vaccination during the Peri-conception period (from 90 days before the last menstrual period [LMP] to the end of the first trimester) ranges from 1.0\u0026ndash;1.5%\u003csup\u003e10\u0026ndash;12\u003c/sup\u003e. As the target population of the HPV vaccine includes women of childbearing age, there is a critical risk of Peri-conception HPV vaccination exposure, especially among women with unplanned pregnancies\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Several studies have investigated the association between Peri-conceptional HPV vaccination and adverse pregnancy outcomes\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. For example, a meta-analysis of randomized controlled trials (RCTs) published in 2023 indicated that HPV vaccine exposures during the Peri-conception period or during pregnancy did not increase the risks of spontaneous abortion (pooled relative risk [RR] 1.15, 95% confidence interval [CI] 0.91\u0026ndash;1.46) and preterm birth (pooled RR 0.94, 95% CI 0.67\u0026ndash;1.32)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, as one of the most concerning adverse pregnancy outcomes, whether Peri-conception exposure to the HPV vaccine increases the risk of birth defects remains determined\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.Owing to the low rate of HPV vaccination during pregnancy and the very-low incidence of birth defects, only large-sample studies can evaluate this association; however, such studies are still relatively rare. Additionally, previous studies have mostly focused on total birth defects, neglected specific types, and mainly considered only a single type of HPV vaccine.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Some studies have also relied on patients\u0026rsquo; self-reported vaccination data instead of rigorous registry-collected data\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Furthermore, due to variations in HPV infection and vaccination rates across ethnic groups\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, the relationship between Peri-conception HPV vaccination and birth defects in Asian populations remains unclear.\u003c/p\u003e \u003cp\u003eTo provide further safety evidence for HPV vaccination, we conducted this population-based cohort study involving 177,574 pregnancies, including subgroup analyses for the pre-30 days (from 30 days preceding the LMP to 97 days after the LMP), the first trimester, 4vHPV vaccine, and 9vHPV vaccine, along with seven sensitivity analyses, to comprehensively evaluate the risk of Peri-conception HPV vaccination for birth defects.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cp\u003eThis population-based retrospective cohort study was registered at ClinicalTrials.gov (NCT06180447, December 21, 2023).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data source\u003c/h2\u003e \u003cp\u003eTo assess HPV vaccine exposure in pregnant women, we developed a population-based pregnancy vaccine database using a unique ID (i.e., citizen health identification number) to link two population-based databases in Xiamen, China: an established pregnancy registry database (REPRESENT)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and a vaccine prescription database. First, REPRESENT, described in detail elsewhere\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, is a population-based, large-scale, longitudinal pregnancy registry database that collects healthcare data (e.g., sociodemographics, laboratory test results, and maternal and neonatal outcomes) from pregnant women and their offspring across all medical institutions in Xiamen City, China. As of December 2021, REPRESENT included 920,236 delivery pregnancies. Second, the vaccine prescription database was established by collecting vaccination information registered and collected by all hospitals and primary healthcare facilities in Xiamen City (i.e., 15 tertiary hospitals, 39 primary healthcare facilities, and 272 health stations) from January 2013 to December 2021, including the generic and trade name of vaccine, vaccination dates, and so on. The vaccination and information recording processes in all medical institutions in Xiamen were conducted in strict accordance with the requirements and standards set forth by the Chinese Center for Disease Control and Prevention\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. In this pregnancy vaccine database, HPV vaccination can be accurately located at a specific period of the pregnancy life course by calculating the time difference between the date of vaccine administration and the LMP.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Inclusion exclusion criteria\u003c/h2\u003e \u003cp\u003eBecause there has been a persistent discrepancy between HPV vaccine supply and demand since the HPV vaccine was approved in mainland China (the 2vHPV, 4vHPV, and 9vHPV vaccines were approved in July 2016, May 2017, and April 2018, respectively)\u003csup\u003e\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, we included HPV vaccinations administered between January 2018 and December 2021. To obtain information on HPV vaccine exposure during the Peri-conception period (from 90 days preceding to 97 days after the LMP), we included only pregnancies with LMP between March 2018 and December 2021.\u003c/p\u003e \u003cp\u003eThese pregnancies were excluded from this study: (1) pregnancies had not delivered by December 31, 2021; (2) pregnancies that resulted in miscarriage or stillbirth; (3) pregnancies that exposed to known risk factors for birth defects, including smoking, syphilis infection, exposure to radiation, epilepsy, insulin-dependent diabetes mellitus, adverse pregnancy history of Edward\u0026rsquo;s disease and Down syndrome, and family history of neural tube defect; and (4) pregnancies using medications known to increase the risk of birth defects during Peri-conception, including diazepam, flunitrazepam, midazolam, alprazolam, lorazepam, fluoxetine, olanzapine, oxycodone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Exposure and control\u003c/h2\u003e \u003cp\u003eIn this study, HPV vaccine exposure was defined as at least one dose of vaccine (2vHPV, 4vHPV, or 9vHPV) administered during the Peri-conception period, spanning from 90 days preceding the LMP to 97 days after the LMP (i.e., 13\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e gestational weeks)\u003csup\u003e\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. We further delineated the HPV vaccine exposure window into two specific periods (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): (1) pre-30 days, from 30 days preceding the LMP to 97 days after the LMP, and (2) the first trimester, from the LMP to 97 days after the LMP. The control group included pregnancies that were not exposed to the HPV vaccine during the Peri-conception period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Outcomes\u003c/h2\u003e \u003cp\u003eFollowing the National Health Standard Criteria\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e, a standardized questionnaire was employed to uniformly collect data on birth defects in REPRESENT. Birth defects are identified through prenatal ultrasound examinations or genetic testing, which detects malformations encompassing structural, functional, and metabolic disorders. Furthermore, diagnoses made by clinicians within the first 42 days post-birth, based on physical examinations or further tests, were included. The primary outcome of this study was total birth defects, excluding chromosomal abnormalities (ICD-10 code: Q00-Q89).\u003c/p\u003e \u003cp\u003eThe secondary outcomes were 10 organ system-specific birth defects, namely, congenital malformations of the nervous system (Q00-Q07), congenital malformations of eye, ear, face and neck (Q10-Q18), congenital malformations of the circulatory system (Q20-Q28), congenital malformations of the respiratory system (Q30-Q34), cleft lip and cleft palate (Q35-Q37), other congenital malformations of the digestive system (Q38-Q45), congenital malformations of genital organ (Q50-Q56), congenital malformations of the urinary system (Q60-Q64), congenital malformations and deformations of the musculoskeletal system (Q65-Q79), and other congenital malformations (Q80-Q89). For multiple pregnancies, we defined a pregnancy as having a birth defect if one of the births had a birth defect.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Covariates\u003c/h2\u003e \u003cp\u003eTo minimize confounding, we incorporated an extensive range of covariates, including demographic characteristics (such as maternal age, pre-pregnancy body mass index [BMI], marital status, and education level), obstetrical characteristics (such as parity, multiple gestations, adverse pregnancy, and childbirth history), disease status (such as hepatitis B virus positivity, pre-existing diabetes, and chronic hypertension), and laboratory test results (such as total bilirubin, serum creatinine, and systolic blood pressure) (detailed in Table S1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical analyses\u003c/h2\u003e \u003cp\u003eThe HPV vaccination rate was calculated by dividing the number of pregnancies in which the HPV vaccine was administered during the Peri-conception period by the total number of pregnancies within a specific period.\u003c/p\u003e \u003cp\u003ePropensity score matching (PSM)-based Poisson regression was used to estimate the adjusted relative risk (aRR) and 95% CIs for the risk of HPV vaccination for birth defects. Propensity scores were calculated based on logistic regression models that estimated the probability of HPV vaccine administration based on all the covariates listed above. After propensity scores were calculated, nearest neighbor 1:4 PSM with a caliper width of 0.02 was used to match exposure and control\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. After PSM, the balance in covariates was assessed using standardized mean difference (SMD) of \u0026lt;\u0026thinsp;0.1\u003csup\u003e35\u003c/sup\u003e. Given the low rate of missing data in this study, the full dataset was used in the primary analysis, after excluding missing data.\u003c/p\u003e \u003cp\u003eSubgroup analyses were conducted, stratified by (1) HPV vaccine type: 4vHPV and 9vHPV, and (2) different exposure windows: pre-30 and first trimester.\u003c/p\u003e \u003cp\u003eWe performed six sensitivity analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), namely, (1) exposure group restricted to pregnancies administered two or more doses of the HPV vaccine during the Peri-conception period; (2) using propensity score overlap weighting approach (OW) to estimate aRR\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e; (3) using 1:10 PSM with a caliper width of 0.02; (4) excluding pregnancies with previous HPV vaccination (i.e., exposure to the HPV vaccine preceding 90 days before the LMP); (5) using 1:4 PSM with a caliper width of 0.02 based on imputed dataset by using multiple imputation by chained equations (MICE)\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e; and (6) using propensity score OW based on imputed dataset. Furthermore, a negative control exposure analysis was implemented to identify potential biases comprising pregnancies exposed to the HPV vaccine between 365 and 90 days preceding the LMP. It was hypothesized that vaccination during this period will not result in an increased incidence of birth defects.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eContinuous variables are presented as mean and standard deviation (SD) if normally distributed, otherwise as median and interquartile range (IQR). Categorical variables are expressed as frequencies and proportions. Differences between groups for continuous variables were assessed using the t-test or Mann-Whitney U test, as appropriate, and differences between categorical variables were evaluated using the chi-square test. All analyses were conducted using R software (version 4.2.3; R Project for Statistical Computing, Vienna, Austria). The significance level for the tests was established at a two-tailed \u003cem\u003eP\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05. The overall level of significance was not adjusted for multiple testing because all analyses were exploratory.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Characteristics of the population\u003c/h2\u003e \u003cp\u003eThis study included 177,574 pregnancies with live births between March 2018 and December 2021 (Figure S1). Among these pregnancies, the mean maternal age was 29.21\u0026thinsp;\u0026plusmn;\u0026thinsp;4.54 years, 2.77% were obese (BMI\u0026thinsp;\u0026ge;\u0026thinsp;28.00), 57.47% had more than 12 years of education, and 43.38% were nulliparous.\u003c/p\u003e \u003cp\u003eA total of 566 pregnancies (0.32%) were exposed to the HPV vaccine during the Peri-conception period, whereas 177,008 pregnancies (99.68%) were not. Among the exposed pregnancies, 338 (59.72%) were exposed to the 4vHPV vaccine, 157 (27.74%) to the 9vHPV vaccine, 71 (12.54%) to the 2vHPV vaccine, and 105 (18.55%) to two doses of the HPV vaccine. Compared with the unexposed group, pregnancies exposed to the HPV vaccine during the Peri-conception period were characterized by lower age, a lower prevalence of obesity, and a higher proportion of individuals with higher education levels. The baseline characteristics of the patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of pregnant women included in this study (n, %)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOverall \u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;177574)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExposed \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e (N\u0026thinsp;=\u0026thinsp;566)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-exposed (N\u0026thinsp;=\u0026thinsp;177008)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal age (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24879 (14.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77 (13.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e24802 (14.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72575 (40.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e262 (46.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72313 (40.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u0026ndash;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57740 (32.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e172 (30.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57568 (32.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22370 (12.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e55 (9.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22315 (12.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePre-pregnancy body mass index (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31604 (17.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e107 (18.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e31497 (17.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.50-23.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98445 (55.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e338 (59.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e98107 (55.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.00-27.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42588 (23.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e110 (19.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e42478 (24.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;28.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4923 (2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11 (1.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4912 (2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTransient population\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e135485 (76.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e499 (88.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e134986 (76.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41955 (23.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67 (11.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e41888 (23.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e134 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e134 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e158594 (89.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e503 (88.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e158091 (89.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountryside\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18968 (10.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63 (11.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18905 (10.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMarital status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e160482 (90.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e522 (92.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e159960 (90.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16852 (9.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43 (7.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16809 (9.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e240 (0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e239 (0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducation level (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3049 (1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3048 (1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u0026ndash;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39424 (22.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43 (7.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e39381 (22.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32476 (18.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56 (9.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32420 (18.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e102047 (57.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e464 (81.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e101583 (57.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e578 (0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (0.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e576 (0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultipara\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100385 (56.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e295 (52.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e100090 (56.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNullipara\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77040 (43.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e271 (47.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e76769 (43.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e149 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e149 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultiple gestations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingletons\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e175881 (99.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e564 (99.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e175317 (99.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTriplets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1680 (0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (0.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1678 (0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThalassemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e172902 (97.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e548 (96.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e172354 (97.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4672 (2.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (3.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4654 (2.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePre-existing diabetes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e175735 (98.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e557 (98.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e175178 (98.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1839 (1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (1.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1830 (1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThyroid dysfunction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e167668 (94.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e533 (94.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e167135 (94.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9906 (5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33 (5.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9873 (5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e170093 (95.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e543 (95.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e169550 (95.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7481 (4.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (4.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7458 (4.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHepatitis B surface antigen positive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e160236 (90.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e514 (90.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e159722 (90.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15807 (8.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48 (8.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15759 (8.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1531 (0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4 (0.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1527 (0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVaginitis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e166271 (93.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e522 (92.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e165749 (93.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11303 (6.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e44 (7.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11259 (6.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFolic acid consumption\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1616 (0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6 (1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1610 (0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e175956 (99.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e560 (98.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e175396 (99.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003e Pregnancies exposed to HPV vaccine during the Peri-conception period.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Peri-conception HPV vaccination rates\u003c/h2\u003e \u003cp\u003eAmong the 566 pregnancies exposed to the HPV vaccine, 300 pregnancies (53.00%) were administered during pre-30 days, and 151 pregnancies (26.68%) were administered during the first trimester. Since 2018, the rate of Peri-conception exposure to the HPV vaccine has shown a progressive increase over time (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Compared with that during 2018 (0.10%), the rate of HPV vaccine exposure during Peri-conception increased to 0.25% in 2019 (RR 2.50, 95% CI 1.83\u0026ndash;3.42) and 0.58% in 2020 and 2021 (RR 5.80, 95% CI 4.35\u0026ndash;7.73). The Peri-conception HPV vaccine exposure rate peaked at 0.84% (38/4,535) in January 2021 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Association between Peri-conception HPV vaccination exposure and birth defects\u003c/h2\u003e \u003cp\u003eAfter excluding individuals with missing data, 169,040 pregnancies were included in the analysis. The incidence of total birth defects, excluding chromosomal abnormalities, was 2.21% (12/542) and 2.73% (4,608/168,498) in the exposed and non-exposed groups, respectively. Following the implementation of the PSM strategy, the covariates were balanced between the exposed and unexposed groups, as indicated by an SMD of \u0026lt;\u0026thinsp;0.1. Our results showed that compared with the unexposed group, HPV vaccine exposure during Peri-conception did not increase the risk of total birth defects, with aRR of 0.77 (95% CI 0.42\u0026ndash;1.42; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Similarly, no additional risk of HPV vaccination during Peri-conception was found for any organ system-specific birth defects (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCategories and missing values of covariates included in the propensity score analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCategories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTiming of recording\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMissing, No. (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic and obstetrical characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25, 25\u0026ndash;30, 30\u0026ndash;35, \u0026gt;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (0.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaternal age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25, 25\u0026ndash;30, 30\u0026ndash;35, \u0026gt;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1349 (0.76)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-pregnancy body mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.50, 18.50-23.99, 24.00-27.99, \u0026gt;=28.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (0.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResidence duration of at least one year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2261 (1.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransient population\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e134 (0.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTown, Countryside\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (0.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarital status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried, Other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e240 (0.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrregular menstruation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e419 (0.23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsanguineous marriage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e611 (0.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation level (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;6, 7\u0026ndash;9, 10\u0026ndash;12, \u0026gt;\u0026thinsp;12, Other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol consumption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNullipara, Multipara\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e149 (0.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple gestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingletons, Twins, Triplets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse pregnancy and childbirth history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of assisted fertility technology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease status and medications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis B surface antigen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1531 (0.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHuman immunodeficiency virus positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1745 (0.98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperemesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDuring the first trimester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDuring the first trimester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllergies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDuring the first trimester\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental illness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e487 (0.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThalassemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-existing diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScarred uterus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatty liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViral hepatitis other than hepatitis B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaginitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal lipid metabolism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSexually transmitted diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHysteromyoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian cyst\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolic acid supplementation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContraceptive pill\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory test results\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1534 (0.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1617 (0.91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum alanine aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1461 (0.82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic blood pressure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous variable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e139 (0.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow, Normal, High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e729 (0.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow, Normal, High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e807 (0.45)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow, Normal, High\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt the first antenatal visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e971 (0.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe association between Peri-conception HPV vaccine exposure and birth defects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaRR (95% CI) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.77 (0.42\u0026ndash;1.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.11\u0026ndash;8.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.99 (0.37\u0026ndash;10.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.99 (0.18\u0026ndash;21.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.80 (0.38\u0026ndash;1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003ea\u003c/sup\u003e After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eb\u003c/sup\u003e aRR, adjusted relative risk.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis results of the association between Peri-conception HPV vaccine exposure and birth defects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeriod of exposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOutcome \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eaRR (95% CI) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"10\" rowspan=\"11\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59 (0.23\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.33 (0.14\u0026ndash;12.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00 (0.11\u0026ndash;8.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.54 (0.16\u0026ndash;1.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.98 (0.25\u0026ndash;63.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.98 (0.25\u0026ndash;63.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.61 (0.14\u0026ndash;2.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.99 (0.25\u0026ndash;63.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.99 (0.25\u0026ndash;63.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"12\" rowspan=\"13\"\u003e \u003cp\u003e\u003cb\u003e4vHPV vaccine\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.25 (0.62\u0026ndash;2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.33 (0.14\u0026ndash;12.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.00 (0.18\u0026ndash;21.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.00 (0.25\u0026ndash;63.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.04 (0.43\u0026ndash;2.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93 (0.32\u0026ndash;2.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.19\u0026ndash;4.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.96 (0.25\u0026ndash;63.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.33 (0.27\u0026ndash;6.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.00 (0.25\u0026ndash;63.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cb\u003e9vHPV vaccine\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.57 (0.13\u0026ndash;2.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.00 (0.18\u0026ndash;21.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.14 (0.24\u0026ndash;5.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eRigorous\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e Peri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOverall birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.50 (0.06\u0026ndash;3.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.98 (0.18\u0026ndash;21.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.79 (0.09\u0026ndash;6.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e aRR, adjusted relative risk.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable S3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analysis results of the association between Peri-conception HPV vaccine exposure and birth defects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeriod of exposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOutcome \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eaRR (95% CI) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;=2 doses\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.09 (0.31\u0026ndash;3.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.00 (0.25\u0026ndash;63.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00 (0.22\u0026ndash;4.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"19\" rowspan=\"20\"\u003e \u003cp\u003e\u003cb\u003eOverlap weighting\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.82 (0.47\u0026ndash;1.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.54 (0.08\u0026ndash;3.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.99 (0.5\u0026ndash;8.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.69 (0.24\u0026ndash;12.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.92 (0.46\u0026ndash;1.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.96 (0.95\u0026ndash;51.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.64 (0.23\u0026ndash;11.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.65 (0.27\u0026ndash;1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.90 (0.27\u0026ndash;13.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.16 (0.44\u0026ndash;22.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.66 (0.21\u0026ndash;2.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.75 (1.87-101.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.20 (0.45\u0026ndash;22.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.53 (0.13\u0026ndash;2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.98 (0.98\u0026ndash;49.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.42 (3.58-195.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.92 (0.83\u0026ndash;42.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"18\" rowspan=\"19\"\u003e \u003cp\u003e\u003cb\u003e1:10 PSM\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.49\u0026ndash;1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.90 (0.12\u0026ndash;6.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.99 (0.44\u0026ndash;9.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.97 (0.45\u0026ndash;54.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.89 (0.44\u0026ndash;1.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.94 (0.62-158.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.31 (0.35\u0026ndash;31.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.53 (0.22\u0026ndash;1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.98 (0.23\u0026ndash;16.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.10 (0.14\u0026ndash;8.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.50 (0.16\u0026ndash;1.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.91 (0.62-157.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.95 (0.45\u0026ndash;54.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.57 (0.14\u0026ndash;2.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.95 (0.45\u0026ndash;54.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.95 (0.45\u0026ndash;54.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"14\" rowspan=\"15\"\u003e \u003cp\u003e\u003cb\u003eExclude previous HPV vaccination\u003c/b\u003e \u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.71 (0.39\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.50 (0.06\u0026ndash;3.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.66 (0.45\u0026ndash;15.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.66 (0.08\u0026ndash;5.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91 (0.43\u0026ndash;1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the nervous system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.99 (0.18\u0026ndash;21.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00 (0.11\u0026ndash;8.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.64 (0.25\u0026ndash;1.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.99 (0.18\u0026ndash;21.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.52 (0.16\u0026ndash;1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.36 (0.09\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.00 (0.18\u0026ndash;21.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"12\" rowspan=\"13\"\u003e \u003cp\u003e\u003cb\u003e1:4 PSM using imputed data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87 (0.44\u0026ndash;1.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.61 (0.07\u0026ndash;5.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.68 (0.36\u0026ndash;37.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.44 (0.14\u0026ndash;14.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93 (0.38\u0026ndash;2.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.24 (0.14\u0026ndash;36.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.61 (0.23\u0026ndash;1.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.19 (0.12\u0026ndash;41.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.61 (0.17\u0026ndash;2.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.79 (0.16\u0026ndash;48.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58 (0.15\u0026ndash;2.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"13\" rowspan=\"14\"\u003e \u003cp\u003e\u003cb\u003eOverlap weighting using imputed data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u003cb\u003ePeri-conception\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.84 (0.40\u0026ndash;1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.51 (0.05\u0026ndash;5.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.94 (0.18\u0026ndash;21.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.58 (0.07\u0026ndash;37.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.99 (0.39\u0026ndash;2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.59 (0.07\u0026ndash;37.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u003cb\u003ePre-30 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.62 (0.20\u0026ndash;1.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.82 (0.07\u0026ndash;49.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.04 (0.06-158.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.64 (0.15\u0026ndash;2.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.93 (0.06-144.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFirst-trimester\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.56 (0.13\u0026ndash;2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003e\u003cb\u003eNegative control exposure\u003c/b\u003e \u003csup\u003e\u003cb\u003ee\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eTotal birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93 (0.52\u0026ndash;1.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOrgan system specific birth defects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCleft lip and cleft palate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80 (0.09\u0026ndash;6.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations and deformations of the musculoskeletal system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44 (0.06\u0026ndash;3.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of eye, ear, face and neck\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.33 (0.27\u0026ndash;6.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of genital organs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.00 (0.18-22.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOther congenital malformations of the digestive system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.99 (0.11\u0026ndash;8.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongenital malformations of the circulatory system\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80 (0.36\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e After propensity score matching, these specific birth defects that with a frequency of zero were excluded from further analysis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e aRR, adjusted relative risk.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ec\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;2 doses: defining exposure as those pregnancies with two or more doses of the HPV vaccine administered during the Peri-conception period.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ed\u003c/sup\u003e Pregnancies with previous exposure to HPV vaccine (preceding 90 days before last menstrual period) were excluded.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ee\u003c/sup\u003e Negative control exposure: pregnancies among women who received HPV vaccination between 365 days and 90 days before the last menstrual period.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSubgroup analysis results for different exposure periods also indicated that HPV vaccination during pre-30 days (aRR 0.59, 95% CI 0.23\u0026ndash;1.48) and during the first trimester (aRR 0.61, 95% CI 0.14\u0026ndash;2.69) were not associated with a higher risk of total birth defects (Table S2, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Similarly, analyses by the vaccine type indicated that exposure to the 4vHPV (aRR 1.25, 95% CI 0.62\u0026ndash;2.51) or 9vHPV (aRR 0.57, 95% CI 0.13\u0026ndash;2.49) vaccine during Peri-conception were not associated with a higher risk of total birth defects (Table S2, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Due to the limited number of subjects who received the 2vHPV vaccine in this study, this HPV type was not included in the subgroup analysis.\u003c/p\u003e \u003cp\u003eFurthermore, the results of the six sensitivity analyses were consistent with the primary results, and the negative control exposure analysis revealed no significant association between exposure and outcomes (Table S3, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), suggesting the robustness of the findings in this study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Principal findings\u003c/h2\u003e \u003cp\u003eThis study utilized data from a population-based pregnancy registry in Xiamen, China, to specifically investigate the impact of Peri-conception HPV vaccination on the risk of birth defects, which represents the largest sample size of original studies in this field to date. This study revealed a consistent annual increase in the vaccination rates among pregnant women in China. Furthermore, our study found that, compared with the unexposed group, exposure to the HPV vaccine during the Peri-conception period, pre-30 days, and first trimester did not increase the risk of birth defects. This provides reliable evidence for the safety of HPV vaccination during the Peri-conception period, helping to alleviate pregnant women's concerns about the potential risks of HPV vaccination.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Results in the context of what is known\u003c/h2\u003e \u003cp\u003eThe safety of HPV vaccine exposure during the Peri-conception period is a subject of concern. Several studies have evaluated the risk of HPV vaccination for miscarriage, stillbirth, low birth weight, and preterm birth, suggesting that the HPV vaccine does not increase the risk of these adverse pregnancy outcomes\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. For example, by including three cohort studies, a meta-analysis showed that receiving the HPV vaccine during or around pregnancy does not increase the risk of miscarriage (RR 2.01, 95% CI 0.66\u0026ndash;6.13) or stillbirth (RR 2.02, 95% CI 0.65\u0026ndash;6.27)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Additionally, several cohort studies have indicated that exposure to the HPV vaccine during the Peri-conception period does not increase the risk of spontaneous abortion (hazard ratio 0.71, 95% CI 0.45\u0026ndash;1.14), low birth weight (odds ratio 1.10, 95% CI 0.85\u0026ndash;1.43), and preterm birth (odds ratio 1.15, 95% CI 0.93\u0026ndash;1.42)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor birth defects, although limited participants were included, previous studies have shown no additional risk of Peri-conceptional HPV vaccination\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. A recent meta-analysis that included four RCTs and five cohort studies suggested that Peri-conceptional exposure to the HPV vaccine was not associated with a higher risk of birth defects\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, our study had several discrepancies with the findings of these studies. First, most previous studies were based on pregnant women in Europe and the US, and no studies have been conducted on pregnant Asian women. Additionally, some studies relied on patients\u0026rsquo; self-reported outcomes, which may lead to inaccurate outcome measurements\u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Second, some of the included studies did not clarify whether the HPV vaccine was administered before or after conception, and some studies included exposure during the second or third trimester\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, when such exposure is not traditionally regarded as a teratogenic-sensitive period. Third, published studies rarely evaluated the 9vHPV vaccine and did not clearly distinguish the dosage of the HPV vaccine.\u003c/p\u003e \u003cp\u003eBy including a large sample of 177,574 pregnancies from a population-based pregnancy registry, our results indicated that Peri-conceptional HPV vaccination did not exhibit a higher risk of birth defects than those who were not vaccinated, which is consistent with the existing literature\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. It is worth stressing that, in comparison to previous studies, this is the first study to explore the association between HPV vaccination and birth defects in pregnant Asian women. Simultaneously, the measurements of exposure and outcomes in this study were more accurate, with HPV vaccine exposure reported by clinicians at the vaccination sites and birth defect outcomes documented by clinicians following diagnosis. Furthermore, we conducted an in-depth nuanced investigation. First, apart from Peri-conception, we focused on the teratogenically sensitive periods of pregnancy, specifically the pre-30 days and first trimester, as previous studies have overlooked the precise measurement of HPV vaccine exposure during these critical developmental windows. Second, our study covered birth defects in more detail and examined the association between Peri-conceptional HPV vaccination and both total birth defect and 10 organ system-specific birth defects, in contrast to previous studies that focused solely on overall birth defects. Third, we included three types of HPV vaccines (2vHPV, 4vHPV, and 9vHPV) and conducted analyses based on stratification by the vaccine type (4vHPV and 9vHPV) and by 2-dose vaccination for any HPV vaccine, whereas previous studies only focused on a single HPV vaccine and did not clearly distinguish between vaccine doses. These results provide comprehensive evidence regarding the safety of the HPV vaccine during the Peri-conception period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Clinical and research implications\u003c/h2\u003e \u003cp\u003eThe findings of this study have important public health implications, supporting the safety of HPV vaccination during the Peri-conception period and alleviating concerns regarding the potential risks of birth defects. This evidence is crucial for healthcare providers and policymakers, especially in cases of unintended pregnancy, and may contribute to enhanced willingness among women of childbearing age to receive HPV vaccination.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Strengths and limitations\u003c/h2\u003e \u003cp\u003eThis study has several strengths. First, it is likely to be the largest cohort study to date to examine the association between Peri-conception HPV vaccination and birth defects. Second, we used a well-established population-based pregnancy registry, which included comprehensive vaccination records and national surveillance data on birth defects, to reduce the risk of misclassification due to information bias. Third, the study offers a comprehensive analysis of the relationship between HPV vaccination and birth defects, considering various exposure periods (Peri-conception, pre-30 days, and the first trimester) and stratifying the results by the HPV vaccine type. Finally, multiple sensitivity analyses, such as two doses of the HPV vaccine and a negative control exposure analysis, were conducted to enhance the credibility of our findings.\u003c/p\u003e \u003cp\u003eThis study has two limitations. First, although this study included 177,574 pregnancies, the number of pregnancies in the HPV vaccine-treated group was limited, particularly when focusing on the different HPV vaccines. Nevertheless, this study had the largest sample size among the original studies to date in this field. Second, although this study addressed the risk of birth defects in live births, birth defects in spontaneous abortions and stillbirths were not considered. However, controlling live birth bias, which accurately records birth defects in pregnancy loss (especially early pregnancy loss), represents a significant challenge in pharmacoepidemiological studies involving pregnant women.\u003c/p\u003e \u003c/div\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis population-based cohort study suggests that Peri-conception HPV vaccination is not associated with a higher risk of total birth defects and organ system-specific birth defects. However, further studies are required to identify the risks associated with specific birth defect types.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThis population-based retrospective cohort study was approved by the Ethics Committee of West China Hospital (2019\u0026thinsp;\u0026minus;\u0026thinsp;825) of Sichuan University in China. As patient information in this database is completely anonymous, no informed consent of the patient is required.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was funded by National Natural Science Foundation of China (72004148, 82474335, 72174132), Natural Science Foundation of Sichuan Province (2024NSFSC1668), National Key Research and Development Program of China (2023YFC2414404), The National Science Fund for Distinguished Young Scholars (82225049), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD23004), Xiamen Science and Technology Plan Project (3502Z20224004).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.G: manuscript writing and data analysis; Y.X: manuscript revise and project development; P.Z and C.L: data cleaning and standardization; Y.R and K.Z: technical or material support; G.Y, Y.Q, B.R, H.Q, M.C, H.L: data collection; X.S, J.T: manuscript revise and project development.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data are not available to be shared publicly.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBurger EA, Portnoy A, Campos NG, Sy S, Regan C, Kim JJ. 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Vaccine Feb. 2019;4(6):889\u0026ndash;97. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.vaccine.2018.12.030\u003c/span\u003e\u003cspan address=\"10.1016/j.vaccine.2018.12.030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HPV vaccine, Birth defects, Peri-conception, Pregnancy, Population-based cohort","lastPublishedDoi":"10.21203/rs.3.rs-5294774/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5294774/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eWith the global push for human papillomavirus (HPV) vaccination, many women of childbearing age may receive this vaccine around the time of conception. Previous studies have clarified the association between Peri-conception HPV vaccination and several adverse pregnancy outcomes (e.g., spontaneous abortion). However, the risk for birth defects remains controversial due to limited large-scale studies. This study aims to investigate whether peri-conception HPV vaccination is associated with an increased risk of birth defects.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis population-based retrospective cohort study included 177,574 pregnancies conceived between March 2018 and December 2021 in Xiamen, China. Peri-conception HPV exposure was defined as vaccination occurring from 90 days before the LMP to the end of the first trimester (i.e.,13\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e gestational weeks, approximately 97 days after the LMP). Propensity score matching (PSM) based Poisson regression was used to estimate the adjusted relative risk (aRR) of HPV vaccine exposure for total birth defects, excluding chromosomal abnormalities and 10 organ system-specific birth defects. Two subgroup analyses, including different exposure windows (pre-30 days [30 days preceding the LMP to 97 days after the LMP] vs. first trimester) and vaccine valences (quadrivalent vs. 9-valent), six sensitivity analyses, and a negative control analysis were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 177,574 pregnancies were included, of which 566 were exposed to the HPV vaccine during the Peri-conception period. The rate of Peri-conception vaccine exposure increased from 0.10% in 2018 to 0.58% in 2021. After 1:4 PSM, Peri-conception HPV vaccination was not associated with an increased risk of total birth defects (2.22% vs. 2.88%; aRR 0.77, 95% confidence interval [CI] 0.42\u0026ndash;1.42). Similarly, no significant association was found between HPV vaccination and the risk of 10 organ system-specific birth defects. In subgroup analyses, exposure during pre-30 days (aRR 0.59, 95% CI 0.23\u0026ndash;1.48) and the first trimester (aRR 0.61, 95% CI 0.14\u0026ndash;2.69) and exposure to the 4vHPV (aRR 1.25, 95% CI 0.62\u0026ndash;2.51) and 9vHPV (aRR 0.57, 95% CI 0.13\u0026ndash;2.49) vaccines were not associated with a higher risk of total birth defects. All sensitivity and negative control analyses demonstrated the robustness of the results.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur evidence suggests that exposure to the HPV vaccine before and during early pregnancy does not increase the risk of birth defects. This conclusion helps increase the willingness of women of childbearing age to receive HPV vaccination.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eThis population-based retrospective cohort study was registered at ClinicalTrials.gov (NCT06180447, December 21, 2023).\u003c/p\u003e","manuscriptTitle":"Peri-conception human papillomavirus vaccination exposure and risk of birth defects: a population-based retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-05 17:57:03","doi":"10.21203/rs.3.rs-5294774/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"71e45f13-45ca-490d-988b-601e6d359a02","owner":[],"postedDate":"November 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-25T11:09:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-05 17:57:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5294774","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5294774","identity":"rs-5294774","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}