Infection with SARS-CoV-2 during the first trimester did not adversely impact perinatal and obstetric outcomes subsequent to in vitro fertilization with frozen embryo transfer: a retrospective cohort study

Purpose To investigate the impact of first-trimester COVID-19 infection on the perinatal and obstetric outcomes following in vitro fertilization-frozen embryo transfer.

This retrospective study was conducted at a university-affiliated IVF center. The infection group included women who contracted SARS-CoV-2 during the first trimester following frozen embryo transfer in China’s initial pandemic wave that occurred from 7 December 2022 to 7 January 2023. The control group consisted of pregnant women from the pre-pandemic period, considering the widespread incidence of the disease among the Chinese population during such a large outbreak. The primary outcome was perinatal and obstetric parameters.

A total of 346 pregnant women who tested positive for COVID-19 during the first trimester were included in the analysis, while the control group comprised 705 uninfected women (pre-COVID-19 controls). Perinatal outcomes, such as preterm birth, low birthweight, birthweight Z scores, macrosomia, small for gestational age, large for gestational age, and congenital malformations, showed no significant differences between the infected and control groups in both the unadjusted and confounder-adjusted logistic regression models. Additionally, there were no significant differences between the groups concerning obstetric complications, including gestational diabetes mellitus, hypertensive disorders of pregnancy, placenta previa, preterm premature rupture of the membrane, and mode of delivery.

The current study demonstrated that contracting COVID-19 during the first trimester did not adversely impact future obstetric and perinatal outcomes following in vitro fertilization-frozen embryo transfer. This data holds practical significance and offers essential insights for reproductive specialists and obstetricians advising expectant mothers.

SARS-CoV-2, COVID-19, IVF, Frozen-thawed embryo transfer, Early miscarriage, Perinatal outcomes, Obstetric outcomes

Unlike most other countries, China did not experience the national pandemic of coronavirus disease 2019 (COVID-19) until the end of 2022. The shift in the government’s public health strategy on December 7, 2022, from a rigorous zero-COVID approach to a relaxation of all restrictions [1], led to a rapid outbreak of SARS-CoV-2, primarily driven by the Omicron variant, spreading throughout the entire country in the ensuing weeks [2]. Given the virus’s high transmissibility and China’s dense population, a significant portion, estimated at 70–80% of the population, contracted the disease [3, 4]. The surge in COVID-19 cases significantly disrupted the provision of fertility treatment services. Several ongoing in vitro fertilization (IVF) cycles had to be suspended for couples affected by acute SARS-CoV-2 infections. Many cycles were transitioned to frozen embryo transfer (FET) due to the uncertainties posed by the pandemic. While the temporary suspension of IVF treatments was discouraging for infertile patients, it was considered a reasonable measure until conditions stabilized or patients recovered from the infection. However, women who had finally achieved pregnancy through IVF but subsequently contracted COVID-19 during their pregnancy faced heightened levels of anxiety and distress [5]. They urgently sought advice from clinicians regarding the potential effects of SARS-CoV-2 infection on their pregnancies. Unfortunately, until today, reliable counseling remains a major challenge as the evidence on which to guide this population is scarce and conflicting. Most of the literature on this subject focused on women who contracted SARS-CoV-2 in the late second or third trimester of pregnancy [6–11], leaving a significant knowledge gap concerning the impact of COVID-19 on the early stages of pregnancy. The early pregnancy stage is critical, as the fetus is particularly vulnerable to external influences. Disruptions during this time can result in negative outcomes, including preterm birth (PTB) and low birth weight (LBW) [12]. Organ development occurs in the first trimester, making maternal infections during this period potentially more harmful than in later stages [13]. Most importantly, viral infections like Zika and cytomegalovirus are teratogenic, especially in the first trimester [14]. Nonetheless, whether the COVID-19 infection during the first trimester impairs the perinatal outcomes remains largely unknown. The objective of the present study was therefore to examine the impact of first-trimester SARS-CoV-2 infection on the perinatal and obstetric outcomes resulting from IVF. We typically focused on FET cycles considering the widespread adoption of this technology globally [15]. Furthermore, compared to fresh cycles, FET avoids the supraphysiologic estradiol levels that may predispose to adverse pregnancy outcomes [16, 17].

Study design and participants A retrospective cohort study was conducted at the Center for Reproductive Medicine of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. The infection group included women who had achieved a clinical pregnancy following FET and later contracted SARS-CoV-2 in the first trimester during the first pandemic wave in China that occurred from 7 December 2022 to 7 January 2023 [18]. Confirmation of infection was obtained through reverse transcription polymerase chain reaction (RT-PCR) or antigen testing for SARS-CoV-2. In the IVF context, a clinical pregnancy was characterized by the presence of at least one intrauterine gestational sac visualized on ultrasound 4 weeks post-embryo transfer [19]. The gestational age was calculated based on the date of embryo transfer and the number of culture days, defined as day 17 of the cycle for the cleavage-stage embryo and day 19 for the blastocyst transfer [20]. Exclusion criteria encompassed: (i) women infected with COVID-19 beyond the first trimester; (ii) individuals who experienced a miscarriage prior to the infection; and (iii) cases of suspected SARS-CoV-2 infection lacking PCR or antigen testing. The control group comprised pregnant women who had undergone FET prior to the onset of the global COVID-19 pandemic, predating the first reported case of COVID-19. This was imperative due to the widespread infection within the Chinese population during the pandemic surge in December 2022, largely attributed to the heightened transmissibility of the Omicron variants [21]. Notably, our center, situated in Shanghai—the most populous city in China with a resident population exceeding 28.5 million—experienced a substantial rise in confirmed cases [22]. While a minority of women reported being asymptomatic or not officially diagnosed with COVID-19, their household contacts exhibited symptoms or tested positive for SARS-CoV-2. Consequently, a pre-pandemic historical cohort was utilized as a comparative control. To mitigate potential confounding factors stemming from the timing of FET procedures [23], the selection of the control group from the database was meticulously conducted to align with the same calendar month as the study period. Data capture and follow-up of pregnancy Demographic information and treatment-related characteristics were retrieved from the electronic patient records stored in the reproductive center’s database [24]. Following embryo transfer, pregnant women underwent regular ultrasound monitoring at our facility until the 8th week of pregnancy, after which they were referred to obstetric care. Subsequently, we conducted follow-up telephone interviews at each stage of pregnancy up to 1 week post-delivery. These interviews aimed to ascertain the status of the pregnancy and identify any instances of miscarriage, with recorded dates where applicable. Participants were also queried about potential SARS-CoV-2 infection, including the timing and method of diagnosis. Those without symptoms or a COVID-19 diagnosis were asked about household members with confirmed infections. Upon confirmation of deliveries, a questionnaire was administered to gather data on gestational age, obstetric complications, delivery method, newborn weight and length, gender, and neonatal health. Any adverse events were reviewed by a dedicated research nurse. In cases where contacting couples directly was unsuccessful, data collection was facilitated through interviews with the community family planning service. Endometrial preparation, embryo quality, and FET Three different approaches to endometrial preparation were employed at our clinic, as previously specified [25]. Briefly, a modified natural cycle-FET was used for women with spontaneous ovulation, with human chorionic gonadotropin used as an ovulation trigger. Women with irregular menstrual cycles were subjected to either an artificial cycle-FET or a mildly stimulated cycle-FET regimen [26]. The timing of embryo transfer was determined based on the developmental stage of the embryos at the time of vitrification. A day 3 high-quality embryo was defined as having at least 6 blastomeres with ≤ 20% fragmentation [27], while a day 5 or day 6 blastocyst graded as ≥ 3BB was considered to be of good quality [28]. According to Chinese legislation, one or two embryos were permitted to be transferred. Once pregnancy was confirmed, luteal phase support with progesterone was continued until 8–10 weeks of gestation. It is noteworthy that a freeze-all strategy using vitrification was consistently employed in our clinic as part of our standard procedure [29], as FET yields comparable live birth rates to fresh embryo cycles while reducing the risk of ovarian hyperstimulation syndrome [17, 30, 31]. Furthermore, none of the embryos underwent preimplantation genetic diagnosis due to the unavailability of this technology in our facility. Importantly, the cryopreservation techniques, laboratory conditions, and IVF protocols remained consistent throughout the entire duration of the study [32]. Outcome measurements and statistical analyses The primary outcome of interest was perinatal outcomes and obstetric complications. The secondary endpoint of the present study was the rates of early pregnancy loss, which was termed as the loss of a spontaneous clinical pregnancy < 13 weeks of gestation. Perinatal outcomes examined included the infant’s gender, gestational age, mean birthweight, and birthweight Z scores, PTB (< 37 gestational weeks), LBW (< 2500 g), small for gestational age (SGA, birthweight the 90th percentiles), and congenital malformations. Congenital malformations were defined according to the ICD-10 [33]. Obstetrical complications encompassed hypertensive disorder of pregnancy (HDP) (International Statistical Classification of Diseases and Related Health Problems-10th Revision [ICD-10 code] O13-O15), gestational diabetes mellitus (GDM) (ICD-10 code O24.4), preterm premature rupture of membranes (PPROM) (ICD-10 code O42), placenta previa (ICD-10 code O44) as well as the mode of delivery. The analysis only included singleton live births for the primary outcome assessment. All statistical analyses were processed with SPSS 26.0 (IBM, NY, USA). Continuous variables were expressed as mean ± standard deviation, while categorical variables were described as the number of cases (n) with corresponding percentages (%). Maternal and treatment characteristics were compared by Student’s t test for continuous data and Pearson’s Chi-squared test for categorical data, where appropriate. To investigate the independent effect of SARS-CoV-2 infection on the main outcome measurements, multivariable logistic regression analyses were undertaken. The following confounding variables were included in the multivariable models: maternal age, body mass index (BMI), parity, gravidity, embryo transfer rank, infertility duration, the main cause of infertility, prior early miscarriage, insemination method, the type of endometrial preparation, endometrial thickness, the number of embryos transferred, embryo development stage, and embryo quality. A P value was considered statistically significant if < 0.05. Power analysis showed that at least 236 patients would be needed (118 in each group) to have 80% power to detect a 15% difference in the primary outcomes.

Demographics A total of 574 women achieved a clinical pregnancy during the first pandemic wave from 7 December 2022 to 7 January 2023. Among them, 132 (23%) claimed to have never been infected with COVID-19, while 434 women tested positive for SARS-CoV-2, and 8 women were lost to follow-up. All cases of infection occurred in December 2022. Out of the 132 uninfected women, 61 had household contacts with a COVID-19 diagnosis. Among those who contracted SARS-CoV-2, 72 were infected with the virus beyond the first trimester. Furthermore, ten pregnant women experienced a miscarriage prior to contracting COVID-19, while six women exhibited COVID-19 symptoms but were not formally tested. Consequently, a total of 346 pregnant women with first-trimester COVID-19 infection were included in the final analysis. Figure 1 illustrates a flow chart of the study population. The data presented in Table 1 depicts the baseline and treatment characteristics. In the group affected by COVID-19, the average maternal age was slightly higher compared to the control cohort (33.03 ± 4.54 years vs. 32.36 ± 4.43 years; P = 0.022). While the majority of women in both groups were nulliparous, there was a significant difference in parity status (88.3% vs. 83.5%; P = 0.006). Other demographic factors such as BMI, gravidity, infertility cause and duration, and prior early miscarriage rates were similar between the two groups. In terms of parameters related to FET, no significant differences were observed in terms of embryo transfer rank, fertilization method, endometrial thickness, endometrial preparation method, number of embryos transferred, and embryo quality. However, there was a significant difference in the developmental stage of embryos at transfer, with a higher percentage of patients in the control group receiving day-3 embryo transfers compared to the COVID-19-infected group (74.9% vs. 66.8%, P = 0.006). Table 1. | Group | Control group | Infected group | P value | |---|---|---|---| | Patient | n = 705 | n = 346 | | | Age at embryo transfer (years) | 32.36 ± 4.43 | 33.03 ± 4.54 | 0.022a | | BMI (kg/m2) | 22.31 ± 3.32 | 22.73 ± 3.67 | 0.066a | | Infertility duration (years) | 3.10 ± 2.86 | 3.23 ± 2.87 | 0.498a | | Gravidity | 0.965b | || | 0 | 378(53.6) | 187(54.0) | | | 1 | 160(22.7) | 76(22.0) | | | ≥ 2 | 167(23.7) | 83(24.0) | | | Parity | 0.006b | || | 0 | 631(88.3) | 289(83.5) | | | ≥ 1 | 74(10.5) | 57(16.5) | | | Prior early miscarriage | 0.662b | || | 0 | 618(87.7) | 300(86.7) | | | ≥ 1 | 87(12.3) | 46(13.3) | | | Main infertility cause | 0.492b | || | Tubal | 218(30.9) | 99(28.6) | | | PCOS | 105(14.9) | 51(14.7) | | | Endometriosis | 56(7.9) | 38(11.0) | | | DOR | 84(11.9) | 37(10.7) | | | Male | 162(23.0) | 88(25.4) | | | Unexplained | 80(11.3) | 33(9.5) | | | Embryo transfer rank | 0.332b | || | 1 | 316(44.8) | 157(45.4) | | | 2 | 229(32.5) | 99(28.6) | | | ≥ 3 | 160(22.7) | 90(26.0) | | | Fertilization method | 0.150b | || | IVF | 352(49.9) | 153(44.2) | | | ICSI | 236(33.5) | 122(35.3) | | | IVF + ICSI | 117(16.6) | 71(20.5) | | | Endometrial thickness (mm) | 11.04 ± 2.40 | 10.94 ± 2.56 | 0.536a | | Endometrial preparation | 0.151b | || | Modified natural cycle | 214(30.4) | 115(33.2) | | | Stimulated cycles | 218(30.9) | 87(25.1) | | | Hormonal replacement | 273(38.7) | 144(41.6) | | | Number of embryos transferred | 0.300b | || | 1 | 278(39.4) | 125(36.1) | | | 2 | 427(60.6) | 221(63.9) | | | Embryo developmental stage | 0.006b | || | Day 3 | 528(74.9) | 231(66.8) | | | Day 5/6 | 177(25.1) | 115(33.2) | | | Embryo quality at transfer of best embryo transferred (%) | 0.810b | || | Grade 1 (good-quality) | 637(90.4) | 311(89.9) | | | Grade 2 (poor-quality) | 68(9.6) | 35(10.1) | Data are presented as mean ± SD or n (%) aStudent’s t test bχ2 test Reproductive outcomes are detailed in Table 2. The incidence of early miscarriage in the COVID-19 infected group was comparable to that of the control cohort in the crude analysis (11.6% vs. 13%; P = 0.494) (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.59–1.29). Furthermore, even after adjusting for all covariates in the multivariate regression analyses, no significant differences in early miscarriage rates were observed (adjusted OR (aOR), 0.80; 95% CI: 0.52–1.21; P = 0.283). A total of 587 and 295 live births (including twins and singletons) were born in the control and infected groups, respectively. Table 2. | Group | Control group | Infected group | P value | |---|---|---|---| | n = 705 | n = 346 | || | Early miscarriage | 92 (13.0) | 40 (11.6) | | | OR (95% CI) | Ref | 0.87 (0.59–1.29) | 0.494 | | aOR (95% CI)a | Ref | 0.80 (0.52–1.21) | 0.283 | | Ongoing pregnancy | 613 (87.0) | 306 (88.4) | | | OR (95% CI) | Ref | 1.15 (0.77–1.71) | 0.494 | | aOR (95% CI)a | Ref | 1.26 (0.83–1.91) | 0.283 | | Live birth | 587 (83.3) | 295 (85.3) | | | OR (95% CI) | Ref | 1.16 (0.81–1.66) | 0.408 | | aOR (95% CI)a | Ref | 1.30 (0.89–1.89) | 0.173 | aAnalyses were adjusted for age, BMI, infertility duration, gravidity, parity, prior early miscarriage, main infertility cause, embryo transfer rank, fertilization method, endometrial thickness, endometrial preparation, number of embryos transferred, embryo developmental stage, and embryo quality at transfer of best embryo transferred Maternal outcomes of each study cohort are shown in Tables 3 and 4. Compared to the control group, pregnancies derived from the infected group did not increase the risks of GDM (aOR, 1.27; 95% CI: 0.74–2.17; P = 0.391), HDP (aOR, 1.07; 95% CI: 0.44–2.57; P = 0.887), placenta previa (aOR, 2.86; 95% CI: 0.89–9.25; P = 0.079), PPROM (aOR, 0.57; 95% CI: 0.24–1.38; P = 0.214) as well as cesarean section (aOR, 0.78; 95% CI: 0.53–1.09; P = 0.138) after correction for several key confounders. Table 3. | Control group | Infected group | P value | | |---|---|---|---| | n = 499 | n = 245 | || | Gestational diabetes mellitus | 41 (8.2) | 29 (11.8) | 0.112a | | Hypertensive disorders of pregnancyb | 17 (3.4) | 11 (4.5) | 0.466a | | Placenta previa | 6 (1.2) | 7 (2.9) | 0.105a | | Preterm premature rupture of the membrane | 22 (4.4) | 8 (3.3) | 0.456a | | Caesarean section | 351 (70.3) | 165 (67.3) | 0.405a | aχ2 test bIncluding pregnancy-induced hypertension and pre-eclampsia Table 4. | OR (95% CI) | P value | AOR (95% CI) | P value | | |---|---|---|---|---| | Gestational diabetes mellitusa | 1.50 (0.91–2.48) | 0.114 | 1.27 (0.74–2.17) | 0.391 | | Hypertensive disorders of pregnancya | 1.33 (0.61–2.89) | 0.467 | 1.07 (0.44–2.57) | 0.887 | | Placenta praeviaa | 2.41 (0.80–7.27) | 0.116 | 2.86 (0.89–9.25) | 0.079 | | Preterm premature rupture of the membranea | 0.73 (0.32–1.67) | 0.458 | 0.57 (0.24–1.38) | 0.214 | | Caesarean sectionb | 0.87 (0.63–1.21) | 0.405 | 0.78 (0.53–1.09) | 0.138 | aAnalyses were adjusted for age, BMI, infertility duration, gravidity, parity, prior early miscarriage, main infertility cause, embryo transfer rank, fertilization method, endometrial thickness, endometrial preparation, number of embryos transferred, embryo developmental stage and embryo quality at transfer of best embryo transferred bAnalyses were adjusted for age, BMI, infertility duration, gravidity, parity, prior early miscarriage, main infertility cause, embryo transfer rank, fertilization method, endometrial thickness, endometrial preparation, number of embryos transferred, embryo developmental stage and embryo quality at transfer of best embryo transferred, gestational diabetes, hypertensive disorder of pregnancy, placenta previa, preterm premature rupture of membranes There were 499 and 245 singletons, resulting from the control and infected groups, respectively. As shown in Tables 5 and 6, comparisons between the two groups did not reveal any significant difference in terms of gestational age (38.28 ± 1.67 weeks vs. 38.10 ± 1.52 weeks, P = 0.149), mean birthweight (3306.65 ± 503.00 g vs. 3248.80 ± 458.09 g, P = 0.13), birthweight Z scores (0.30 ± 1.04 vs. 0.20 ± 0.98, P = 0.21) and the distribution of newborn gender (P = 0.983). Moreover, the prevalences of PTB (aOR, 1.07; 95% CI: 0.45–2.56; P = 0.878), LBW (aOR, 0.54; 95% CI: 0.18–1.60; P = 0.269), macrosomia (aOR, 0.78; 95% CI: 0.40–1.50; P = 0.45), SGA (aOR, 0.70; 95% CI: 0.30–1.61; P = 0.396), LGA (aOR, 0.79; 95% CI: 0.52–1.20; P = 0.27), and congenital malformations (aOR, 1.38; 95% CI: 0.40–4.71; P = 0.61) were all similar between the two cohorts in both the unadjusted and confounder-adjusted analyses. Table 5. | Control group | Infected group | P value | | |---|---|---|---| | n = 499 | n = 245 | || | Gestational age | 38.28 ± 1.67 | 38.10 ± 1.52 | 0.149a | | PTB | 46 (9.2) | 23 (9.4) | 0.940b | | Babies born | 499 | 245 | | | Gender | 0.983b | || | Female | 244 (48.9) | 120 (49.0) | | | Male | 255 (51.1) | 125 (51.0) | | | Birthweight | 3306.65 ± 503.00 | 3248.80 ± 458.09 | 0.130a | | Z score | 0.30 ± 1.04 | 0.20 ± 0.98 | 0.210a | | LBW (< 2500 g) | 26 (5.2) | 11 (4.5) | 0.671b | | Macrosomia (≥ 4000 g) | 38 (7.6) | 15 (6.1) | 0.457b | | SGA ( 90th percentile) | 108 (21.6) | 46 (18.8) | 0.364b | | Congenital malformations | 9 (1.8) | 7 (2.9) | 0.352b | Data are mean ± SD or n (%) aStudent’s t test bχ2 test PTB Preterm birth; LBW low birth weight; SGA small for gestational age; LGA large for gestational age Table 6. | OR (95% CI) | P value | AOR (95% CI) | P value | | |---|---|---|---|---| | PTB (< 37 week) | 1.02 (0.60–1.73) | 0.940 | 1.07 (0.45–2.56) | 0.878 | | LBW (< 2500 g) | 0.86 (0.42–1.76) | 0.671 | 0.54 (0.18–1.60) | 0.269 | | Macrosomia (≥ 4000 g) | 0.79 (0.43–1.47) | 0.458 | 0.78 (0.40–1.50) | 0.450 | | SGA ( 90th percentile) | 0.84 (0.57–1.23) | 0.365 | 0.79 (0.52–1.20) | 0.270 | | Congenital malformations | 1.60 (0.59–4.35) | 0.356 | 1.38 (0.40–4.71) | 0.610 | Analyses were adjusted for age, BMI, infertility duration, gravidity, parity, prior early miscarriage, main infertility cause, embryo transfer rank, fertilization method, endometrial thickness, endometrial preparation, number of embryos transferred, embryo developmental stage and embryo quality at transfer of best embryo transferred, gestational diabetes, hypertensive disorder of pregnancy, placenta previa, preterm premature rupture of membranes

It has been over 4 years since the first documentation of COVID-19 in late December 2019 [34]. Despite notable progress in our understanding of COVID-19 and our ability to manage this virus, our knowledge of its impact on pregnancy, particularly in the early stages, remains limited. The present study, focused exclusively on women who conceived via IVF-FET, demonstrated that contracting SARS-CoV-2 during the first trimester did not adversely affect subsequent birth and maternal outcomes. Additionally, an early pregnancy infection with SARS-CoV-2 does not appear to elevate the risk of miscarriage. Existing data on the association between COVID-19 infection during the first trimester and subsequent perinatal outcomes are scarce and conflicting. A retrospective multicenter study examined how the timing of maternal SARS-CoV-2 infection impacts neonatal outcomes [12]. The study revealed elevated risks of PTB and stillbirth in pregnancies with SARS-CoV-2 infection across all trimesters (p < 0.05 for all pregnancies), with the most significant increase observed after the first trimester. It is important to note that the study included a total of 882 women affected by COVID-19, with only 85 cases occurring in the first trimester. The small sample size limited the ability to draw definitive conclusions. Furthermore, differences in ethnic backgrounds, study populations, and potential confounders between their study and ours contribute to the disparity in results. A population-based cohort study reported follow-up data on pregnancies affected by SARS-CoV-2 infection during the first or early second trimester. Out of the 141 positive cases of early pregnancy observed in the study, there were no elevated risks of PTB, perinatal death, SGA, or preeclampsia compared to the uninfected cases [35]. Additionally, another study based on registries investigated the potential risk of congenital malformations in pregnancies exposed to SARS-CoV-2 during the first trimester [36]. The researchers noted that the incidence of congenital malformations in infected pregnant individuals was comparable to that of their counterparts who tested negative for SARS-CoV-2. The aforementioned studies did not specify whether pregnancies resulted from natural conception or fertility treatment, unlike our study, which focused solely on cohorts who underwent IVF. Research has shown significant differences in birth and obstetric outcomes depending on the method of conception [37, 38]. Prior studies on viral infections during pregnancy were conducted prior to the Omicron variant emergence. A UK national prospective study revealed notable variations in pregnancy and perinatal outcomes based on the predominant SARS-CoV-2 variants [39]. Therefore, direct comparisons between our findings and existing data may not be feasible. The current study also demonstrated that contracting COVID-19 in the early stages of pregnancy does not raise the risk of miscarriage. Previous research findings on this topic have been conflicting, with some studies indicating a notably higher rate of first-trimester miscarriage post-infection [40, 41] while other researchers found no connection between SARS-CoV-2 infection and pregnancy loss [42, 43]. Although there is an ongoing clinical debate, a recent meta-analysis concluded that pregnant women with SARS-CoV-2 infection in the first or second trimester do not face an elevated risk of miscarriage compared to pregnant women without the infection [44]. Viral infections during pregnancy are associated with increased risks of adverse pregnancy outcomes and birth defects [45, 46]. Although vertical transmission of SARS-CoV-2 is possible, it remains a rare occurrence, with almost all instances occurring in the third trimester [47]. A systematic review indicated that determining the prevalence of vertical transmission during early pregnancy is challenging due to the limited data available from the first trimester [47]. Notably, a recent observational study conducted in China revealed that SARS-CoV-2 RNA was absent in all placental and fetal samples during infection in the first trimester [48]. Furthermore, two previous studies indicated that COVID-19 infection during the first trimester did not elevate the risk of adverse prenatal biochemical or ultrasound markers associated with fetal anomalies when compared to healthy controls, and laboratory tests for SARS-CoV-2 in the amniotic fluid samples from affected women were negative [13, 43]. However, these studies were limited by being case series or having small sample sizes. Therefore, the question of whether SARS-CoV-2 can cross the placental barrier and lead to significant fetal complications remains to be thoroughly investigated. In addition to the risk of direct fetal infection and subsequent teratogenic effects, the indirect impacts of COVID-19 infection on the fetus are a significant concern. The pro-inflammatory state induced by SARS-CoV-2 can disrupt both the structure and function of the placenta, potentially leading to adverse delivery outcomes [49]. SARS-COV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor and utilizes the transmembrane protease serine (TMPRSS2) to facilitate the fusion of viral and cellular membranes [50]. While ACE2 receptors are present in the placenta, the coexpression of ACE2 and TMPRSS2 is minimal during any trimester [51]. Furthermore, COVID-19-related symptoms, such as fever, may also pose teratogenic risks to the fetus. However, maternal and neonatal outcomes may vary based on the severity of maternal infection [39]. In our cohort, all women experienced mild symptoms of COVID-19, and none required hospitalization due to the infection. Compared to earlier strains, the Omicron variant exhibits significantly lower pathogenicity and virulence [52]. Importantly, SARS-CoV-2 vaccines may also elicit an acute pro-inflammatory response. A large observational study encompassing 42,156 pregnant women found no association between first-trimester COVID-19 vaccination and an increased risk of major structural birth defects [53]. Our work has limitations. Firstly, it was conducted retrospectively, introducing inherent bias and unknown confounders. Secondly, the control group comprised women who conceived by FET during the pre-pandemic period, rather than uninfected women treated during the pandemic. This selection was motivated by the fact that a significant portion of individuals contracted SARS-CoV-2 during the initial epidemic wave in China [3]. Thirdly, the present study was restricted to women who conceived by IVF-FET; thus, caution should be made when extrapolating these results to women who conceived naturally or those conceived by IVF fresh cycles. Fourthly, although the power analysis suggested that our study population is adequate for detecting significant differences in the primary outcome measures, the sample size that was included remained relatively small. Hence, caution should be made when interpreting our findings, particularly when assessing rare outcomes such as congenital malformations. Finally, it is essential to acknowledge that our findings may not be generalizable to other COVID-19 variants or diverse ethnic populations, given that the omicron variant predominantly shaped the pandemic landscape in China [2]. Despite the limitations, our work also had strengths. The major strength was the large sample size of COVID-19-infected pregnant women. This study is the largest sample study reporting the influence of the first trimester COVID-19 infection on the perinatal and obstetric outcomes in the field of IVF. In addition, we accounted for several potential confounders that might otherwise have biased the findings. Unlike national register-based cohort studies, our data originated from a single IVF center, ensuring consistent practices. Noteworthy is that IVF protocols, laboratory conditions, and cryopreservation methods remained consistent throughout the study period [32].

Despite that the World Health Organization declared the end of the emergency phase of COVID-19 in May 2023 [54], the sporadic outbreaks persist, leading to infections among pregnant women. Currently, our nation is amidst another surge in COVID-19 cases. Pregnant women, particularly those who have undergone stressful and costly infertility treatments to achieve pregnancy, remain at risk of contracting SARS-CoV-2 during gestation [42]. Our clinical data holds clinical value, indicating that maternal SARS-CoV-2 infection during the first trimester does not negatively impact perinatal and obstetric outcomes or elevate the likelihood of early pregnancy loss following IVF-FET. Author contribution J.Z., X.Y.M., and L.W. conceived and designed this study. J.Z., J.Y., and H.Y.G. contributed to data acquisition and analysis and data interpretation and drafted the manuscript. X.Y.M. and J.Z. were responsible for the collection of data. All authors interpreted the data. Funding This study was supported by The Fund for Excellent Young Scholars of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (grant no. JYYQ004), and the National Natural Science Foundation of China (grant no. 82171685). Data availability The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Declarations Ethical approval and consent to participate The study received approval from the hospital’s Institutional Review Board, and due to its retrospective nature and anonymized data analysis, written consent was not required. Competing interests The authors declare no competing interests. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Jie Zhang, Jing Ye, and Hongyuan Gao contributed equally to this work. Contributor Information Jie Zhang, Email: [email protected]. Xiaoyan Mao, Email: [email protected]. Ling Wu, Email: [email protected].

- 1.Qin L, Duan X, Dong JZ, Chang Y, Han Y, Li Y, Jiang W, Fan H, Hou X, Cao W, Zhu H, Li T. The unreversible reduced but persistent activated NK and CD8(+) T cells in severe/critical COVID-19 during omicron pandemic in China. Emerg Microbes Infect. 2023;12:2208679. 10.1080/22221751.2023.2208679. [DOI] [PMC free article] [PubMed] [Google Scholar] - 2.Zheng L, Liu S, Lu F. Impact of National Omicron Outbreak at the end of 2022 on the future outlook of COVID-19 in China. Emerg Microbes Infect. 2023;12:2191738. 10.1080/22221751.2023.2191738. [DOI] [PMC free article] [PubMed] [Google Scholar] - 3.Bureau CsB. China says 80% of population have had Covid-19, as millions travel for Lunar New Year. Cable News Network. https://www.cnn.com/2023/01/22/china/china-covid-80-lunar-new-year-intl-hnk/index.html. Accessed July 1, 2023. - 4.Liang J, Liu R, He W, Zeng Z, Wang Y, Wang B, Liang L, Zhang T, Chen CLP, Chang C, Hon C, Lau EHY, Yang Z, Tong K. Infection rates of 70% of the population observed within 3 weeks after release of COVID-19 restrictions in Macao. China J Infect. 2023;86:402–4. 10.1016/j.jinf.2023.01.029. [DOI] [PMC free article] [PubMed] [Google Scholar] - 5.Domar AD, Shah JS, Gompers A, Meyers AJ, Khodakhah DR, Hacker MR, Penzias AS, Sakkas D, Toth TL, Vaughan DA. The psychological impact of the coronavirus disease 2019 pandemic on women who become pregnant after receiving treatment for infertility: a longitudinal study. F S Rep. 2022;3:71–8. 10.1016/j.xfre.2022.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar] - 6.Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, Debenham L, Llavall AC, Dixit A, Zhou D, Balaji R, Lee SI, Qiu X, Yuan M, Coomar D, Sheikh J, Lawson H, Ansari K, van Wely M, van Leeuwen E, Kostova E, Kunst H, Khalil A, Tiberi S, Brizuela V, Broutet N, Kara E, Kim CR, Thorson A, Oladapo OT, Mofenson L, Zamora J, Thangaratinam S. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020;370:m3320. 10.1136/bmj.m3320. [DOI] [PMC free article] [PubMed] [Google Scholar] - 7.Chen L, Li Q, Zheng D, Jiang H, Wei Y, Zou L, Feng L, Xiong G, Sun G, Wang H, Zhao Y, Qiao J. Clinical characteristics of pregnant women with Covid-19 in Wuhan, China. N Engl J Med. 2020;382:e100. 10.1056/NEJMc2009226. [DOI] [PMC free article] [PubMed] [Google Scholar] - 8.Hantoushzadeh S, Shamshirsaz AA, Aleyasin A, Seferovic MD, Aski SK, Arian SE, Pooransari P, Ghotbizadeh F, Aalipour S, Soleimani Z, Naemi M, Molaei B, Ahangari R, Salehi M, Oskoei AD, Pirozan P, Darkhaneh RF, Laki MG, Farani AK, Atrak S, Miri MM, Kouchek M, Shojaei S, Hadavand F, Keikha F, Hosseini MS, Borna S, Ariana S, Shariat M, Fatemi A, Nouri B, Nekooghadam SM, Aagaard K. Maternal death due to COVID-19. Am J Obstet Gynecol. 2020;223:109.e1-e16. 10.1016/j.ajog.2020.04.030. [DOI] [PMC free article] [PubMed] [Google Scholar] - 9.Knight M, Bunch K, Vousden N, Morris E, Simpson N, Gale C, O’Brien P, Quigley M, Brocklehurst P, Kurinczuk JJ. Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107. 10.1136/bmj.m2107. [DOI] [PMC free article] [PubMed] [Google Scholar] - 10.Yan J, Guo J, Fan C, Juan J, Yu X, Li J, Feng L, Li C, Chen H, Qiao Y, Lei D, Wang C, Xiong G, Xiao F, He W, Pang Q, Hu X, Wang S, Chen D, Zhang Y, Poon LC, Yang H. Coronavirus disease 2019 in pregnant women: a report based on 116 cases. Am J Obstet Gynecol. 2020;223:111.e1-e14. 10.1016/j.ajog.2020.04.014. [DOI] [PMC free article] [PubMed] [Google Scholar] - 11.Sentilhes L, De Marcillac F, Jouffrieau C, Kuhn P, Thuet V, Hansmann Y, Ruch Y, Fafi-Kremer S, Deruelle P. Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth. Am J Obstet Gynecol. 2020;223:914.e1-e15. 10.1016/j.ajog.2020.06.022. [DOI] [PMC free article] [PubMed] [Google Scholar] - 12.Piekos SN, Roper RT, Hwang YM, Sorensen T, Price ND, Hood L, Hadlock JJ. The effect of maternal SARS-CoV-2 infection timing on birth outcomes: a retrospective multicentre cohort study. Lancet Digit Health. 2022;4:e95–104. 10.1016/s2589-7500(21)00250-8. [DOI] [PMC free article] [PubMed] [Google Scholar] - 13.Cosma S, Carosso AR, Borella F, Cusato J, Bovetti M, Bevilacqua F, Carosso M, Gervasoni F, Sciarrone A, Marozio L, Revelli A, Rolfo A, Filippini C, Ghisetti V, Di Perri G, Benedetto C. Prenatal biochemical and ultrasound markers in COVID-19 pregnant patients: a prospective case-control study. Diagnostics (Basel). 2021;11. 10.3390/diagnostics11030398. [DOI] [PMC free article] [PubMed] - 14.Auger N, Arbour L, Lewin A, Brousseau É, Healy-Profitós J, Luu TM. Congenital anomalies during Covid-19: artifact of surveillance or a real TORCH? Eur J Epidemiol. 2024;39:613–21. 10.1007/s10654-024-01122-8. [DOI] [PubMed] [Google Scholar] - 15.Wyns C, De Geyter C, Calhaz-Jorge C, Kupka MS, Motrenko T, Smeenk J, Bergh C, Tandler-Schneider A, Rugescu IA, Goossens V. ART in Europe, 2018: results generated from European registries by ESHRE. Hum Reprod Open. 2022;2022:hoac022. 10.1093/hropen/hoac022. [DOI] [PMC free article] [PubMed] [Google Scholar] - 16.Jwa SC, Seto S, Takamura M, Kuwahara A, Kajihara T, Ishihara O. Ovarian stimulation increases the risk of ectopic pregnancy for fresh embryo transfers: an analysis of 68,851 clinical pregnancies from the Japanese Assisted Reproductive Technology registry. Fertil Steril. 2020;114:1198–206. 10.1016/j.fertnstert.2020.06.032. [DOI] [PubMed] [Google Scholar] - 17.Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375:523–33. 10.1056/NEJMoa1513873. [DOI] [PubMed] [Google Scholar] - 18.Lu Y, He Y, Wang Y, Zhu Q, Qi J, Li X, Ding Y, Huang J, Ding Z, Xu Y, Yang Y, Lindheim SR, Wei Z, Sun Y. Effects of SARS-COV-2 infection during the frozen-thawed embryo transfer cycle on embryo implantation and pregnancy outcomes. Hum Reprod. 2024;39:1239–46. 10.1093/humrep/deae068. [DOI] [PubMed] [Google Scholar] - 19.Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The international glossary on infertility and fertility care, 2017. Hum Reprod. 2017;32:1786–801. 10.1093/humrep/dex234. [DOI] [PMC free article] [PubMed] [Google Scholar] - 20.Nelissen EC, Van Montfoort AP, Coonen E, Derhaag JG, Geraedts JP, Smits LJ, Land JA, Evers JL, Dumoulin JC. Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum Reprod. 2012;27:1966–76. 10.1093/humrep/des145. [DOI] [PubMed] [Google Scholar] - 21.Chen Z, Deng X, Fang L, Sun K, Wu Y, Che T, Zou J, Cai J, Liu H, Wang Y, Wang T, Tian Y, Zheng N, Yan X, Sun R, Xu X, Zhou X, Ge S, Liang Y, Yi L, Yang J, Zhang J, Ajelli M, Yu H. Epidemiological characteristics and transmission dynamics of the outbreak caused by the SARS-CoV-2 Omicron variant in Shanghai, China: a descriptive study. Lancet Reg Health West Pac. 2022;29:100592. 10.1016/j.lanwpc.2022.100592. [DOI] [PMC free article] [PubMed] [Google Scholar] - 22.Shi W, Sun C, Chen Q, Ye M, Niu J, Meng Z, Bukulmez O, Chen M, Teng X. Association between ambient air pollution and pregnancy outcomes in patients undergoing in vitro fertilization in Shanghai, China: a retrospective cohort study. Environ Int. 2021;148:106377. 10.1016/j.envint.2021.106377. [DOI] [PubMed] [Google Scholar] - 23.Cao M, Wu Y, Lin Y, Xu Z, Liang Z, Huang Q, Li S, Liu H, An C, Luo Y, Liu H, Liu J. Inactivated Covid-19 vaccine did not undermine live birth and neonatal outcomes of women with frozen-thawed embryo transfer. Hum Reprod. 2022;37:2942–51. 10.1093/humrep/deac220. [DOI] [PMC free article] [PubMed] [Google Scholar] - 24.Wei M, Chen D, Feng G, Mao X, Wu L, Chai W, Zhang J. Association of infertility cause with perinatal outcomes in a freeze-all policy: an analysis including 10,151 singleton newborns. AJOG Glob Rep. 2023;3:100098. 10.1016/j.xagr.2022.100098. [DOI] [PMC free article] [PubMed] [Google Scholar] - 25.Wang B, Zhang J, Zhu Q, Yang X, Wang Y. Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons. Hum Reprod. 2020;35:1612–22. 10.1093/humrep/deaa093. [DOI] [PubMed] [Google Scholar] - 26.Zhang J, Liu H, Wang Y, Mao X, Chen Q, Fan Y, Xiao Y, Kuang Y. Letrozole use during frozen embryo transfer cycles in women with polycystic ovary syndrome. Fertil Steril. 2019;112:371–7. 10.1016/j.fertnstert.2019.04.014. [DOI] [PubMed] [Google Scholar] - 27.Medicine ASiR, Embryology ESIGo. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting†. Hum Reprod. 2011;26:1270–83. 10.1093/humrep/der037. [DOI] [PubMed] - 28.Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004;81:551–5. 10.1016/j.fertnstert.2003.07.023. [DOI] [PubMed] [Google Scholar] - 29.Zhang J, Liu H, Mao X, Chen Q, Fan Y, Xiao Y, Wang Y, Kuang Y. Effect of body mass index on pregnancy outcomes in a freeze-all policy: an analysis of 22,043 first autologous frozen-thawed embryo transfer cycles in China. BMC Med. 2019;17:114. 10.1186/s12916-019-1354-1. [DOI] [PMC free article] [PubMed] [Google Scholar] - 30.Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med. 2018;378:126–36. 10.1056/NEJMoa1705334. [DOI] [PubMed] [Google Scholar] - 31.Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2021;2:Cd01118. 10.1002/14651858.CD011184.pub3. [DOI] [PMC free article] [PubMed] [Google Scholar] - 32.Chen D, Xu Q, Mao X, Zhang J, Wu L. Obstetric and perinatal outcomes after embryos cultured in one-step versus sequential culture media systems in vitrified-warmed single blastocyst transfer cycles. Reprod Biomed Online. 2023;47:103227. 10.1016/j.rbmo.2023.04.018. [DOI] [PubMed] [Google Scholar] - 33.World Health Organization. Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities. In: International Statistical Classification of Diseases and Related Health Problems. 10th revision. 2019:Q00-Q99. https://icd.who.int/browse10/2019/en#/XVII. Accessed 23 May 2024 - 34.Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–33. 10.1056/NEJMoa2001017. [DOI] [PMC free article] [PubMed] [Google Scholar] - 35.Crovetto F, Crispi F, Llurba E, Pascal R, Larroya M, Trilla C, Camacho M, Medina C, Dobaño C, Gomez-Roig MD, Figueras F, Gratacos E. Impact of severe acute respiratory syndrome coronavirus 2 infection on pregnancy outcomes: a population-based study. Clin Infect Dis. 2021;73:1768–75. 10.1093/cid/ciab104. [DOI] [PMC free article] [PubMed] [Google Scholar] - 36.Hernández-Díaz S, Smith LH, Wyszynski DF, Rasmussen SA. First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy. Birth Defects Res. 2022;114:906–14. 10.1002/bdr2.2070. [DOI] [PMC free article] [PubMed] [Google Scholar] - 37.Luke B, Gopal D, Cabral H, Stern JE, Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am J Obstet Gynecol. 2017;217:327.e1-e14. 10.1016/j.ajog.2017.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar] - 38.Berntsen S, Söderström-Anttila V, Wennerholm UB, Laivuori H, Loft A, Oldereid NB, Romundstad LB, Bergh C, Pinborg A. The health of children conceived by ART: ‘the chicken or the egg?’ Hum Reprod Update. 2019;25:137–58. 10.1093/humupd/dmz001. [DOI] [PubMed] [Google Scholar] - 39.Vousden N, Ramakrishnan R, Bunch K, Morris E, Simpson NAB, Gale C, O’Brien P, Quigley M, Brocklehurst P, Kurinczuk JJ, Knight M. Severity of maternal infection and perinatal outcomes during periods of SARS-CoV-2 wildtype, alpha, and delta variant dominance in the UK: prospective cohort study. BMJ Med. 2022;1:e000053. 10.1136/bmjmed-2021-000053. [DOI] [PMC free article] [PubMed] [Google Scholar] - 40.Sacinti KG, Kalafat E, Sukur YE, Koc A. Increased incidence of first-trimester miscarriage during the COVID-19 pandemic. Ultrasound Obstet Gynecol. 2021;57:1013–4. 10.1002/uog.23655. [DOI] [PMC free article] [PubMed] [Google Scholar] - 41.Balachandren N, Davies MC, Hall JA, Stephenson JM, David AL, Barrett G, O’Neill HC, Ploubidis GB, Yasmin E, Mavrelos D. SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic. Hum Reprod. 2022;37:1126–33. 10.1093/humrep/deac062. [DOI] [PMC free article] [PubMed] [Google Scholar] - 42.Cosma S, Carosso AR, Cusato J, Borella F, Carosso M, Bovetti M, Filippini C, D’Avolio A, Ghisetti V, Di Perri G, Benedetto C. Coronavirus disease 2019 and first-trimester spontaneous abortion: a case-control study of 225 pregnant patients. Am J Obstet Gynecol. 2021;224:391.e1-e7. 10.1016/j.ajog.2020.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar] - 43.la Cour FN, Egerup P, Hviid KVR, Severinsen ER, Kolte AM, Westergaard D, Fich Olsen L, Prætorius L, Zedeler A, Christiansen AH, Nielsen JR, Bang D, Berntsen S, Ollé-López J, Ingham A, Bello-Rodríguez J, Storm DM, Ethelberg-Findsen J, Hoffmann ER, Wilken-Jensen C, Jørgensen FS, Westh H, Jørgensen HL, Nielsen HS. SARS-CoV-2 in first trimester pregnancy: a cohort study. Hum Reprod. 2021;36:40–7. 10.1093/humrep/deaa311. [DOI] [PMC free article] [PubMed] [Google Scholar] - 44.van Baar JAC, Kostova EB, Allotey J, Thangaratinam S, Zamora JR, Bonet M, Kim CR, Mofenson LM, Kunst H, Khalil A, van Leeuwen E, Keijzer J, Strikwerda M, Clark B, Verschuuren M, Coomarasamy A, Goddijn M, van Wely M. COVID-19 in pregnant women: a systematic review and meta-analysis on the risk and prevalence of pregnancy loss. Hum Reprod Update. 2024;30:133–52. 10.1093/humupd/dmad030. [DOI] [PMC free article] [PubMed] [Google Scholar] - 45.Mullins E, Evans D, Viner RM, O’Brien P, Morris E. Coronavirus in pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol. 2020;55:586–92. 10.1002/uog.22014. [DOI] [PubMed] [Google Scholar] - 46.Schwartz DA, Graham AL. Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections. Viruses. 2020;12. 10.3390/v12020194. [DOI] [PMC free article] [PubMed] - 47.Kotlyar AM, Grechukhina O, Chen A, Popkhadze S, Grimshaw A, Tal O, Taylor HS, Tal R. Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis. Am J Obstet Gynecol. 2021;224:35-53.e3. 10.1016/j.ajog.2020.07.049. [DOI] [PMC free article] [PubMed] [Google Scholar] - 48.Xu J, Mao D, Liang P, Du P, Zhang X, Dang X, Wu H, Zhu B, Sun L. Undetectable intrauterine transmission during the first trimester of pregnancy in woman after COVID-19 infection. J Infect. 2023;87:80–1. 10.1016/j.jinf.2023.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar] - 49.León-Juárez M, Martínez-Castillo M, González-García LD, Helguera-Repetto AC, Zaga-Clavellina V, García-Cordero J, Flores-Pliego A, Herrera-Salazar A, Vázquez-Martínez ER, Reyes-Muñoz E. Cellular and molecular mechanisms of viral infection in the human placenta. Pathog Dis. 2017;75. 10.1093/femspd/ftx093. [DOI] [PMC free article] [PubMed] - 50.Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271-80.e8. 10.1016/j.cell.2020.02.052. [DOI] [PMC free article] [PubMed] [Google Scholar] - 51.Pique-Regi R, Romero R, Tarca AL, Luca F, Xu Y, Alazizi A, Leng Y, Hsu CD, Gomez-Lopez N. Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? Elife. 2020;9. 10.7554/eLife.58716. [DOI] [PMC free article] [PubMed] - 52.Suzuki R, Yamasoba D, Kimura I, Wang L, Kishimoto M, Ito J, Morioka Y, Nao N, Nasser H, Uriu K, Kosugi Y, Tsuda M, Orba Y, Sasaki M, Shimizu R, Kawabata R, Yoshimatsu K, Asakura H, Nagashima M, Sadamasu K, Yoshimura K, Sawa H, Ikeda T, Irie T, Matsuno K, Tanaka S, Fukuhara T, Sato K. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. Nature. 2022;603:700–5. 10.1038/s41586-022-04462-1. [DOI] [PMC free article] [PubMed] [Google Scholar] - 53.Kharbanda EO, DeSilva MB, Lipkind HS, Romitti PA, Zhu J, Vesco KK, Boyce TG, Daley MF, Fuller CC, Getahun D, Jackson LA, Williams JTB, Zerbo O, Weintraub ES, Vazquez-Benitez G. COVID-19 vaccination in the first trimester and major structural birth defects among live births. JAMA Pediatr. 2024;178:823–9. 10.1001/jamapediatrics.2024.1917. [DOI] [PMC free article] [PubMed] [Google Scholar] - 54.World health organization. https://www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic. Accessed July 1, 2023. Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Data Availability Statement The datasets used and analysed during the current study are available from the corresponding author on reasonable request.