The Impact of IVF on the Risk of Placenta Abnormalities and Placenta- Related Complications in Twin Pregnancies: a Retrospective Study

The Impact of IVF on the Risk of Placenta Abnormalities and Placenta- Related Complications in Twin Pregnancies: a Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Impact of IVF on the Risk of Placenta Abnormalities and Placenta- Related Complications in Twin Pregnancies: a Retrospective Study Yi Yang, Ting Liu, Qian Gui, Xia Lan, Jing Xiong, Shujuan Luo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4711800/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Previous studies have confirmed that in-vitro fertilization (IVF) is associated with higher risks of placenta abnormalities and complications. Considering the increased risk of twin and higher-order multiple pregnancies, we tried to investigate the association between IVF and the risk of placenta outcomes in twin pregnancies. Methods This retrospective cohort study included 3845 cases of twin pregnancies delivered at Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022. Poisson regression modeling with restricted cubic splines of exact maternal age was used to estimate the absolute risk of placenta outcomes in IVF and non-IVF groups. Main outcomes include placenta abnormalities (placenta previa, placental abruption, placenta accrete, and abnormal morphology of placenta) and placenta-related complications (gestational hypertension, preeclampsia, eclampsia, preterm birth, fetal distress, and fetal growth restriction (FGR)). To dissect the influence of chorionicity on the results, we further did the same analysis on the mono- and di-chorionic sub-group. Results The absolute risk of placenta previa, placenta accreta, placental abruption, gestational hypertension, and preeclampsia are significantly higher in the IVF group than in the non-IVF group. While there are no significant differences in the absolute risk of abnormal placenta morphology, fetal distress, FGR, and preterm birth between the two groups. After we did further analysis on the dichorionic sub-group, we found the absolute risk of preterm birth was also higher in the IVF group than in the non-IVF group. Conclusions Twin pregnancies who received IVF treatment have a higher risk for most kinds of placenta abnormalities and placenta-related complications. Whether these risks have any further impact on maternal and fetal health needs further investigation. Twin pregnancy in-vitro fertilization placental abnormalities placenta-related complications Figures Figure 1 Background Placenta, as a temporary organ that forms in the uterus during pregnancy, plays an essential role in the exchange of nutrients and metabolic byproducts between mother and child. Hence, deviations from normal placenta functions can result in significant physiologic function changes in fetal development that increase the risk of many chronic diseases lifespan[1, 2]. Placental-related disorders of pregnancy are almost unique to the human species and affect around a third of human pregnancies[3]. Recent changes in human lifestyle, such as delayed childbirth and broad application of assisted reproductive technologies, may have increased the incidence of placental-related disorders[4]. The demand for assisted reproductive technologies is expected to grow even more since the increasing rates of infertility and delay in childbearing over the past four decades. An estimated 1.93 million IVF cycles resulted in >0.43 million babies were reported for the treatment year 2014 globally [5]. While in China, 0.9 million IVF cycles and 0.3 million IVF babies were reported in 2016[6]. With 5-year treads increased in success rates, the debate about the impact of assisted reproductive technologies (ART) on pregnancy outcomes increased too[5, 6]. Previous studies have reported differences between the placentas from IVF gestation and non-IVF, including placenta weight, apical microvilli, and vacuoles, morphologically[6, 7]. The proteome, genomic imprinting, and epigenetic differences were also reported at the molecular level[8]. During these documents, a population-based analysis focusing on placental abnormalities or complications after IVF treatment based on 17 million hospitalized deliveries between 2013 and 2018 in China confirmed that IVF is an independent risk factor for placental abnormalities and placental-related complications[9]. However, the relationship between IVF and placenta-related outcomes was not so clear in twin pregnancies, which were common because over one embryo were often transferred to patients during IVF treatment. The increasing success of in-vitro fertilization is complicated by an increased risk of twin and higher-order multiple pregnancies. A Previous study in 2003 based on data of twin gestations from the Department of Obstetrics and Gynecology claimed no differences in the incidences of pregnancy-induced hypertension or placenta previa except preterm labor between IVF and non-IVF group, which was different from the conclusion of the retrospective analysis in China[10]. Other studies also claimed that the risk of spontaneous preterm birth and congenital heart disease increased in IVF-conceived twin pregnancies. There are also prospective follow-up studies claimed similar neonatal outcomes between IVF twins and spontaneously conceived twins[11-13]. Here, we conducted a retrospective analysis based on the 3845 twin pregnancies delivered in Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022, aimed at concluding the absolute risk of placental abnormalities and complications during twin pregnancies and providing suggestions for clinical management optimization. Methods Study design and the characteristics of the population Figure 1 . The flowchart of this study. Twin pregnancies with complete medical records delivered in Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022 were analyzed. Five cases with maternal age below 20 or beyond 49 were excluded. All cases were grouped into the spontaneous-conception group or in-vitro-fertilization group, and the relative risk for placenta-related outcomes was analyzed. Then, all the cases were further divided into mono-chorionic and di-chorionic subgroups, and the relative risk of the spontaneous-conception group and in vitro fertilization group for placenta-related outcomes were analyzed. Data of 3845 twin pregnancies delivered in Chongqing Health Center for Women and Children between 2017 and 2022 were analyzed. Five cases with maternal age below 20 years (4 cases) or beyond 49 years (1 case) were excluded（Figure 1）. The retrospective cohort study was conducted on 2702 cases of IVF-conceived twin and 1138 non-IVF-conceived twin pregnancies. The baseline characteristics of this study include the year of discharge, maternal age at birth, chorionicity, and chronic disease before pregnancy (chronic hypertension, diabetes, thyroid diseases, anemia). The incidences of placenta disorders and placenta-related complications were analyzed. Placenta disorders include placenta previa, placental abruption, placenta accrete, and abnormal placenta morphology. Placenta-related complications include gestational hypertension, preeclampsia, eclampsia, preterm birth, fetal distress, and FGR. Statistical Analysis The general characteristics of the two twin pregnancy groups are listed in Table 1. Poisson regression models with restricted cubic splines for maternal age were applied in our study. The optimal number of knots for the restricted cubic splines, situated at default percentiles, was determined by the minimized Akaike Information Criterion (AIC) principle[14]. In detail, we first applied an unadjusted model only with maternal age spline to explore the crude relative risk (RR) and 95% confidence interval (CI) between IVF and non-IVF groups for each placenta-related outcome. Then, the multivariable model adjusted by maternal age (age at delivery), year (year of discharge), and chronic diseases (including chronic hypertension, diabetes, thyroid disease, and anemia) was applied to calculate the adjusted relative risk (aRR) and 95% confidence interval between IVF and non-IVF group. The absolute risk of each placenta-related complication was then graphically presented by maternal age. To address the additional influence of chorionicity on placental-related outcomes, we divided the IVF and non-IVF groups into monochorionic and dichorionic sub-groups. Both unadjusted and adjusted model was applied to the sub-group. All statistical analyses were conducted using glmnet, MASS, and splines package in R-4.1.0[15]. Two-tailed P value <0.05 was considered statistically significant. Results After accurate selection, the study included 3840 cases of twin pregnancies, including 2702 cases of IVF pregnancies and 1138 cases of non-IVF ones(Figure 1). The maternal age of the IVF group was significantly higher than the non-IVF group (31.56 ± 3.5 vs 29.29 ± 4.2, P < 0.0001), which was consistent with previous reports[ 9 ]. Since the difference in chorionicity of twin gestation, we further calculated the proportion of dichorionic and monochorionic placenta. Over 95% of placentas were dichorionic in the IVF group, while dichorionic and monochorionic account for almost 50% of placenta type, respectively, in the non-IVF group. As for the chronic disease before pregnancy, the proportion was slightly higher in the IVF group compared with the non-IVF group (Table 1 ). Table 1 Baseline characteristics of this study Sample characteristics Total (n = 3840) IVF (n = 2702) non-IVF (n = 1138) Year 2017 472 (12.3) 307 (11.4) 165 (14.5) 2018 594 (15.5) 445 (16.5) 149 (13.1) 2019 648 (16.9) 427 (15.8) 221 (19.4) 2020 659 (17.2) 486 (18.0) 173 (15.2) 2021 797 (20.8) 579 (21.4) 218 (19.2) 2022 670 (17.4) 458 (17.0) 212 (18.6) Maternal age at birth, mean (SD) 30.89 (3.9) 31.56 (3.5) 29.29 (4.2) 20–24 171 (4.5) 41 (1.5) 130 (11.4) 25–29 1208 (31.5) 710 (26.3) 498 (43.8) 30–34 1812 (47.2) 1430 (52.9) 382 (33.6) 35–39 582 (15.2) 467 (17.3) 115 (10.1) 40–44 60 (1.6) 48 (1.8) 12 (1.1) 45–49 7 (0.2) 6 (0.2) 1 (0.09) Chorionicity Monochorionic 712 (18.5) 128 (4.7) 584 (51.3) Dichorionic 3128 (81.5) 2574 (95.3) 554 (48.7) Chronic disease before pregnancy* 27 (0.7) 23 (0.9) 4 (0.4) *“Chronic disease before pregnancy” included chronic hypertension, diabetes, thyroid disease, anemia. Table 2 The placenta-related outcomes of twin pregnancy conceived by IVF or non-IVF Placenta-related outcomes Total (n = 3840) IVF (n = 2702) non-IVF (n = 1138) RR 1 (95% CI 3 ) aRR 2 (95% CI) Placental abnormalities Placenta previa 124 (3.2) 100 (3.7) 24 (2.1) 1.64 (1.03–2.61) 1.64 (1.03–2.62) Placenta accreta 630 (16.4) 507 (18.8) 123 (10.8) 1.54 (1.26–1.89) 1.53 (1.25–1.88) Placental abruption 63 (1.6) 46 (1.7) 17 (1.5) 1.22 (0.68–2.19) 1.23 (0.68–2.21) Abnormal placenta morphology 264 (6.9) 145 (5.4) 119 (10.5) 0.51 (0.39–0.65) 0.51 (0.39–0.65) Placenta-related complications Gestational hypertension 212 (5.5) 165 (6.1) 47 (4.1) 1.45 (1.03–2.04) 1.36 (0.96–1.93) Preeclampsia 501 (13.0) 379 (14.0) 122 (10.7) 1.29 (1.04–1.60) 1.27 (1.02–1.57) Fetal distress 200 (5.2) 123 (4.6) 77 (6.8) 0.66 (0.49–0.90) 0.68 (0.50–0.92) FGR 4 321 (8.4) 194 (7.2) 127 (11.2) 0.68 (0.53–0.86) 0.66 (0.52–0.84) Preterm birth 2252 (58.7) 1528 (56.6) 724 (63.6) 0.91 (0.83-1.00) 0.909 (0.83-1.00) 1. RR, relative risk; 2. aRR, adjusted relative risk; 3. CI, confidence interval; 4. FGR, fetal growth restriction; 5. The bold values mean has statistical significance. Excepted for abnormal placenta morphology, IVF was associated with a significantly increased risk of placenta abnormalities including placenta previa (adjusted relative risk [aRR]:1.64, 95% confidence interval [CI]:1.03–2.62), placental accreta (aRR: 1.53, 95% CI:1.25–1.88) and placenta abruption (aRR: 1.23, 95% CI: 0.68–2.21). We also evaluated the association of IVF with placental-related complications. The analysis revealed IVF was associated with a significantly increased rate of gestation hypertension (aRR:1.36, 95% CI: 0.96–1.93) and preeclampsia (aRR:1.27, 95% CI:1.02–1.57) (Table 2 ). Regarding the specificity of twin pregnancy, we further divided IVF and non-IVF groups into two sub-groups depending on chorionicity. As shown in Table 1 , over 95% of chorion conceived by IVF were dichorionic, while in spontaneous twin pregnancy, the ratio of dichorionic versus monochorionic was almost 1, ignoring the property of amniotic membrane. Despite the universality of preterm birth in twin pregnancy, the adjusted relative risk in the monochorionic and dichorionic subgroup of the IVF group still increased compared with the non-IVF group (aRR: 1.05, CI:0.83–1.33; aRR: 1.03, CI:0.90–1.17). Furthermore, IVF is still the independent risk factor for fetal distress in the monochorionic subgroup (aRR: 1.19, CI:0.61–2.29) despite the higher risk of second-born twins than their co-twins (Table 3 ). Table 3: The subgroup analysis of placenta-related outcomes of twin pregnancy from IVF or non-IVF group Chorionicity Placenta-related outcomes Total (n=3840 ） IVF (n=2702) non-IVF (n=1138) RR 1 (95% CI 3 ) aRR 2 (95% CI) Monochorionic Placental abnormalities Placenta previa 24 (0.6) 8 (0.3) 16 (1.4) 2.16 (0.88-5.35) 1.97 (0.79-4.94) Placenta accreta 97 (2.5) 27 (1) 70 (6.2) 1.54 (0.97-2.44) 1.48 (0.92-2.37) Placental abruption 10 (0.3) 1 (0.04) 9 (0.8) 0.60 (0.07-5.06) 0.66 (0.78-5.62) Abnormal placenta morphology 82 (2.1) 15 (0.6) 67 (5.9) 0.97 (0.54-1.74) 1.009 (0.56-1.82) Placenta-related complications Gestational hypertension 28 (0.7) 8 (0.3) 20 (1.8) 1.88 (0.76-4.64) 2.02 (0.81-5.03) Preeclampsia 84 (2.2) 19 (0.7) 65 (5.7) 1.26 (0.74-2.15) 1.16 (0.68-2.01) Fetal distress 62 (1.6) 12 (0.4) 50 (4.4) 1.13 (0.59-2.19) 1.19 (0.61-2.29) FGR 4 100 (2.6) 13 (0.5) 87 (7.6) 0.71 (0.39-1.30) 0.70 (0.38-1.30) Preterm birth 512 (13.3) 96 (3.6) 416 (36.6) 1.06 (0.84-1.34) 1.05 (0.83-1.33) Dichorionic Placental abnormalities Placenta previa 100 (2.6) 92 (3.4) 8 (0.7) 2.26 (1.09-4.72) 2.29 (1.10-4.77 ) Placenta accreta 533 (13.9) 480 (17.8) 53 (4.7) 1.76 (1.32-2.35) 1.73 (1.29-2.30) Placental abruption 53 (1.4) 45 (1.7) 8 (0.7) 1.27 (0.59-2.76) 1.28 (0.59-2.77) Abnormal placenta morphology 182 (4.7) 130 (4.8) 52 (4.6) 0.55 (0.39-0.77) 0.53 (0.38-0.74) Placenta-related complications Gestational hypertension 184 (4.8) 157 (5.8) 27 (2.4) 1.20 (0.79-1.84) 1.13 (0.74-1.73) Preeclampsia 417 (10.9) 360 (13.3) 57 (5.0) 1.38 (1.03-1.82) 1.34 (1.00-1.79 ) Fetal distress 138 (3.6) 111 (4.1) 27 (2.4) 0.87 (0.56-1.35) 0.91 (0.59-1.41) FGR 3 221 (5.8) 181 (6.7) 40 (3.5) 1.01 (0.71-1.44) 0.96 (0.67-1.38) Preterm birth 1740 (45.3) 1432 (53.0) 308 (27.1) 1.02 (0.90-1.16) 1.03 (0.90-1.17) RR, relative risk; aRR, adjusted relative risk; CI, confidence interval; FGR, fetal growth restriction; The bold values mean has statistical significance. Discussion Until 2019, over 8 million babies have been born through ART since the first IVF baby’s birth[ 1 ]. As the widespread habit of transferring in utero more than one in-vitro-produced embryo at a time, the incidence of twin pregnancies is high, especially in relatively young, good-prognosis patients. Even most guidelines recommend limiting the number of transferred embryos to obtain singleton pregnancies, and single embryo transfer is not widely practiced for many reasons[ 16 ]. Although twin pregnancies are frequently observed in IVF, several studies have focused on the additional risk of IVF on placenta-related outcomes[ 8 , 9 ]. Several studies demonstrated that IVF could be associated with changes in placental morphology, structure, growth dynamics, imprinted and non-imprinted genes, and other aspects regulating placentation[ 8 ]. A higher incidence of placenta previa was observed in several studies[ 17 , 18 ]. Moreover, significantly greater weight and higher placental weight-to-birth weight ratio were also observed in many studies[ 7 , 19 ]. A retrospective cohort study based on Chinese data also revealed that IVF was an independent risk factor for placenta abnormalities, including placenta previa, placental abruption, placental accrete, and abnormal morphology of placenta[ 9 ]. These findings support the hypothesis of IVF responsibility for placenta-related outcomes. However, it is still not known precisely if IVF twin pregnancies have an additional risk for placenta-related outcomes compared with spontaneously conceived twin pregnancies. IVF singleton pregnancies are associated with placenta previa, placenta abruption, placenta accreta, and abnormal placenta morphology, which have been well documented[ 20 – 29 ]. This study includes 3840 cases of twin pregnancies, which include 2702 cases conceived by IVF and 1138 cases of spontaneously conceived ones. The data presented here show that IVF is the independent risk factor for placenta previa, placental abruption, and placental accreta after adjusting for maternal age at birth, the year of IVF implementation, and chronic diseases before pregnancy. While there are no significant differences for abnormal placenta morphology in the incidence when twin pregnancies obtained by IVF or spontaneous conception are compared. We further analyzed the additional risk of IVF on placental-related complications, including gestational hypertension, preeclampsia, preterm birth, fetal distress, and FGR. A previous study has reported that twin pregnancy was an independent risk factor for pre-eclampsia but not for gestational hypertension[ 30 ]. While in our study, IVF-conceived twin pregnancy has a higher risk of gestational hypertension and pre-eclampsia. Based on a low-risk population derived from maternal characteristics (Caucasian, height of 164 cm, weight of 69 kg, no family or medical history), the risk of pre-eclampsia < 37 weeks was 0.6% in singletons, 9% in dichorionic twins and 14.2% in monochorionic twins[ 31 ]. For our data, the incidence of pre-eclampsia in the IVF group has no difference in both dichorionic and monochorionic twins (14% in dichorionic and 14.8% in monochorionic), while in the non-IVF group, the risk of pre-eclampsia was slightly higher in monochorionic twins (10.1% in dichorionic and 11.1% in monochorionic). Over 50% of twins are delivered before 37 weeks’ gestation, while monochorionic twins have an even higher incidence compared with dichorionic twins[ 32 ]. Ignoring the chorionicity, we find no significant difference in the incidence of preterm birth between the IVF and the non-IVF group. However, IVF is still the independent risk factor when we further divided the two groups into mono- and dichorionic sub-groups. Twins are known to have lower birth weight than singletons[ 33 ], and recent research has found that twins have a different growth trajectory than singletons, with growth being lower from 30 weeks in dichorionic twins compared to singletons, and monochorionic twins being generally smaller than both dichorionic twins and singletons throughout gestation[ 34 ]. It has been reported that second-born twins face higher risks of fetal distress than their co-twins, even in dichorionic pairs [ 35 ]. IVF is still the independent risk factor for fetal distress in the monochorionic sub-group. While the effect of maternal aging and chronic disease on pregnancy complications has been well documented [ 10 , 17 , 21 ]. We further showed the adjusted absolute risk and 95% confidence interval [CI] of each outcome that has significantly raised risk in both groups by maternal age. The absolute risk of placenta previa and placenta accreta in both groups increased with maternal age. The variance showed a growing trend, which meant more risk in IVF pregnancy with advanced maternal age. For placental abruption, the absolute risk increased first, followed by a decrease, which was inconsistent with the previous study[ 9 ]. This might be because of limited cases, especially cases with maternal age > 35 years. The absolute risk curve was shown to be ‘ J-shaped ’ in gestation hypertension and preeclampsia, which means the absolute risk decreased with age until the turning points and then increased with age (Additional Fig. 1). Few studies focus on the effect of male infertility on pregnancy complications and outcomes[ 36 , 37 ]. Increased paternal age has been reported to affect testicular function, reproductive hormones, sperm parameters, sperm DNA integrity, telomere length, de novo mutation rate, chromosomal structure, and epigenetic factors[ 3 , 38 – 45 ]. So, the effect of parental condition on IVF-conceived pregnancy needs further investigation. It is well known that maternal complications are more common in twin pregnancy than in singleton pregnancy. At the same time, IVF as an independent risk factor for placenta-related outcomes has also been reported[ 9 ]. However, it is unclear whether twin pregnancies after IVF have a higher risk for placenta-related diseases than spontaneously conceived ones. The data we presented herein show that, after adjusting for maternal age at birth, the year of IVF implementation, and chronic diseases before pregnancy, IVF is still the independent risk factor for placental abnormalities, including placenta previa, placental abruption, and placental accreta and for placental related complications, including gestational hypertension and preeclampsia. When we further divided the twin pregnancies by their chorionicity, we confirmed IVF as the independent factor for preterm birth in dichorionic and monochorionic twin pregnancies and fetal distress in monochorionic twin pregnancies. In conclusion, this study confirmed that IVF-conceived twin pregnancies have a higher risk of most placenta-related pregnancy complications, which may require more stringent surveillance during gestation. Abbreviations IVF in-vitro fertilization CQHCWC Chongqing Health Center for Women and Children FGR fetal growth restriction ART assisted reproductive technologies,AIC,Akaike Information Criterion RR relative risk CI confidence interval aRR adjusted relative risk. Declarations Ethic approval and consent to participate The studies involving human participants were reviewed and approved by Ethics Committee of Chongqing Health Center for Women and Children (ID: 2022-011). To protect patient privacy, all personal identifying information was removed from the cases, and all data obtained were kept anonymous. Competing interests The authors declare no conflict of interests. Funding This work was supported by the Natural Science Foundation of Chongqing (grant number CSTB2023NSCQ-MSX0384). Author Contribution L. W. and Y.C. conceived and designed the study. Y.Y. did the statistical analyses and drafted the manuscript. T. L., Q. G., X. L., J. X., S. L., C. Z. contributed to the data collection and collation. All authors reviewed and revised the manuscripts. All authors read the final manuscript and approved submission. Acknowledgement The authors would like to thank all the fellows in Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children. Data Availability The datasets used in the current study are available from the corresponding author on reasonable request, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of corresponding author (Ya Chen, [email protected] or Lan Wang [email protected] ). References Thornburg KL, Kolahi K, Pierce M, Valent A, Drake R, Louey S. Biological features of placental programming. Placenta. 2016;48(Suppl 1):S47–53. Thornburg KL, Marshall N. 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Incidence and risk factors for placenta accreta/increta/percreta in the UK: a national case-control study. PLoS ONE. 2012;7(12):e52893. Laine K, Murzakanova G, Sole KB, Pay AD, Heradstveit S, Raisanen S. Prevalence and risk of pre-eclampsia and gestational hypertension in twin pregnancies: a population-based register study. BMJ Open. 2019;9(7):e029908. Francisco C, Wright D, Benko Z, Syngelaki A, Nicolaides KH. Competing-risks model in screening for pre-eclampsia in twin pregnancy by maternal characteristics and medical history. Ultrasound Obstet Gynecol. 2017;50(4):501–6. Roman A, Ramirez A, Fox NS. Prevention of preterm birth in twin pregnancies. Am J Obstet Gynecol MFM. 2022;4(2S):100551. Gielen M, Lindsey PJ, Derom C, Loos RJ, Souren NY, Paulussen AD, Zeegers MP, Derom R, Vlietinck R, Nijhuis JG. Twin-specific intrauterine 'growth' charts based on cross-sectional birthweight data. Twin Res Hum Genet. 2008;11(2):224–35. Stirrup OT, Khalil A, D'Antonio F, Thilaganathan B, Southwest Thames Obstetric Research C. Fetal growth reference ranges in twin pregnancy: analysis of the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy cohort. Ultrasound Obstet Gynecol. 2015;45(3):301–7. Hartley R, Hitti J. Second-born twins have more fetal distress and low apgars than their co-twins. Am J Obstet Gynecol. 2003;189(6):S121–121. Halvaei I, Litzky J, Esfandiari N. Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health. Reprod Biol Endocrinol. 2020;18(1):110. Gourinat A, Mazeaud C, Hubert J, Eschwege P, Koscinski I. Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review. Andrology. 2023;11(6):973–86. Handelsman DJ, Staraj S. Testicular size: the effects of aging, malnutrition, and illness. J Androl. 1985;6(3):144–51. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589–98. Agarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008;59(1):2–11. Moskovtsev SI, Willis J, Mullen JB. Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility. Fertil Steril. 2006;85(2):496–9. Broer L, Codd V, Nyholt DR, Deelen J, Mangino M, Willemsen G, Albrecht E, Amin N, Beekman M, de Geus EJ, et al. Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Eur J Hum Genet. 2013;21(10):1163–8. Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1(1):40–7. Reichman NE, Teitler JO. Paternal age as a risk factor for low birthweight. Am J Public Health. 2006;96(5):862–6. Curley JP, Mashoodh R, Champagne FA. Epigenetics and the origins of paternal effects. Horm Behav. 2011;59(3):306–14. Additional Declarations No competing interests reported. Supplementary Files AdditionalFigure1.EstimatedabsoluterisksateachmaternalageintheIVFandnonIVFgroup.pdf.pdf Additional Figure 1.Estimated absolute risks at each maternal age in the IVF and non-IVF group. Estimated absolute risks of placenta-related outcomes with significantly higher risk in the IVF group are shown at each maternal age. Estimated absolute risks were calculated by Poisson regression model with restricted cubic splines of maternal age, adjusting for maternal age, year, and chronic disease before pregnancy. IVF, in vitro fertilization; non-IVF, non-in vitro fertilization; GHP, gestational hypertension; PE, preeclampsia. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Jul, 2024 Editor assigned by journal 12 Jul, 2024 Submission checks completed at journal 12 Jul, 2024 First submitted to journal 09 Jul, 2024 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4711800","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":327640924,"identity":"183db93f-b5e1-4300-ad20-975867eb6f72","order_by":0,"name":"Yi Yang","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Yang","suffix":""},{"id":327640926,"identity":"3a241358-a6d1-4fcd-b233-3979d527d4c0","order_by":1,"name":"Ting Liu","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Liu","suffix":""},{"id":327640928,"identity":"e0778162-25ae-436d-b2ea-f055192c2b05","order_by":2,"name":"Qian Gui","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Gui","suffix":""},{"id":327640929,"identity":"21187356-bc5c-4a7b-87ac-a2f813bab790","order_by":3,"name":"Xia Lan","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Lan","suffix":""},{"id":327640930,"identity":"b216d00c-2cc1-46b7-bf56-12719856b997","order_by":4,"name":"Jing Xiong","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Xiong","suffix":""},{"id":327640932,"identity":"f7efe78d-38f4-4cd5-957f-bafcb032c8ce","order_by":5,"name":"Shujuan Luo","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shujuan","middleName":"","lastName":"Luo","suffix":""},{"id":327640935,"identity":"9e0e8fbe-91de-4e52-97e0-ea9fc2aeafd0","order_by":6,"name":"Chen Zhang","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Zhang","suffix":""},{"id":327640937,"identity":"4df0da28-6e54-4a33-9adc-39022d4a7f30","order_by":7,"name":"Ya Chen","email":"","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ya","middleName":"","lastName":"Chen","suffix":""},{"id":327640938,"identity":"948fedb9-3ebb-43da-bb8f-010df795b55c","order_by":8,"name":"Lan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApklEQVRIiWNgGAWjYBACNvbGxgdAWgbIJFILH8/hwwYMDAY8xGuRk0hLkyBNCxtDjlnFx7Y/PPzsbQkMPyq2EaPljNnNmW0GPJI9xw4w9py5TYQWxh6z27xALQY30huYGduI0cLMY1ZMohY2tjRmiJa0A0Rq4WE+LDnjnDHILwkHifKL/PyHjR8+lMnJAUPM8MGPCiK0oIADJKofBaNgFIyCUYALAAD2rDQgHPzdZAAAAABJRU5ErkJggg==","orcid":"","institution":"Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-07-09 11:44:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4711800/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4711800/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62218696,"identity":"9cf069b4-6a8a-49b9-87d8-cc99eb7a51bd","added_by":"auto","created_at":"2024-08-11 12:06:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":214908,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe flowchart of this study.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.Theflowchartofthisstudy.png","url":"https://assets-eu.researchsquare.com/files/rs-4711800/v1/690ec172eaa6b2c13d9dd94e.png"},{"id":62219392,"identity":"b883beb5-0e7d-4d6d-8c68-e6b8978764c7","added_by":"auto","created_at":"2024-08-11 12:14:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1024246,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4711800/v1/e8adbfb9-82f8-41f3-bbb8-7aabf68b1c23.pdf"},{"id":62218695,"identity":"d94b2e65-af7e-459d-9e3e-471be046765d","added_by":"auto","created_at":"2024-08-11 12:06:03","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":337446,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional Figure 1\u003c/strong\u003e.\u003cstrong\u003eEstimated absolute risks at each maternal age in the IVF and non-IVF group\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eEstimated absolute risks of placenta-related outcomes with significantly higher risk in the IVF group are shown at each maternal age. Estimated absolute risks were calculated by Poisson regression model with restricted cubic splines of maternal age, adjusting for maternal age, year, and chronic disease before pregnancy. IVF, in vitro fertilization; non-IVF, non-in vitro fertilization; GHP, gestational hypertension; PE, preeclampsia.\u003c/p\u003e","description":"","filename":"AdditionalFigure1.EstimatedabsoluterisksateachmaternalageintheIVFandnonIVFgroup.pdf.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4711800/v1/9c286ebdafd7b94025e826ff.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Impact of IVF on the Risk of Placenta Abnormalities and Placenta- Related Complications in Twin Pregnancies: a Retrospective Study","fulltext":[{"header":"Background","content":"\u003cp\u003ePlacenta, as a temporary organ that forms in the uterus during pregnancy, plays an essential role in the exchange of nutrients and metabolic byproducts between mother and child. Hence, deviations from normal placenta functions can result in significant physiologic function changes in fetal development that increase the risk of many chronic diseases lifespan[1, 2]. Placental-related disorders of\u0026nbsp;pregnancy are almost unique to the human species and affect around a third of human pregnancies[3].\u0026nbsp;Recent changes in human lifestyle, such as delayed childbirth and broad application of assisted reproductive technologies, may have increased the incidence of placental-related disorders[4].\u003c/p\u003e\n\u003cp\u003eThe demand for assisted reproductive technologies is expected to grow even more since the increasing rates of infertility and delay in childbearing over the past four decades. An estimated 1.93 million IVF cycles resulted in \u0026gt;0.43 million babies were reported for the treatment year 2014 globally\u0026nbsp;[5]. While in China, 0.9 million IVF cycles and 0.3 million IVF babies were reported in 2016[6]. With 5-year treads increased in success rates, the debate about the impact of assisted reproductive technologies (ART) on pregnancy outcomes increased too[5, 6]. Previous studies have reported differences between the placentas from IVF\u0026nbsp;gestation and non-IVF, including placenta weight, apical microvilli, and vacuoles, morphologically[6, 7]. The proteome, genomic imprinting, and epigenetic differences were also reported at the molecular level[8].\u0026nbsp;During these documents, a\u0026nbsp;population-based analysis focusing on placental abnormalities or complications after IVF treatment based on 17 million hospitalized deliveries between 2013 and 2018 in China confirmed that IVF is an independent risk factor for placental abnormalities and placental-related complications[9]. However, the relationship between IVF and placenta-related outcomes was not so clear in twin pregnancies, which were common because over one embryo were often transferred to patients during IVF treatment.\u003c/p\u003e\n\u003cp\u003eThe increasing success of in-vitro fertilization is complicated by an increased risk of twin and higher-order multiple pregnancies. A Previous study in 2003 based on data of twin gestations from the Department of Obstetrics and Gynecology claimed no differences in the incidences of pregnancy-induced hypertension or placenta previa except preterm labor between IVF and non-IVF group, which was different from the conclusion of the retrospective analysis in China[10]. Other studies also claimed that the risk of spontaneous preterm birth and congenital heart disease increased in IVF-conceived twin pregnancies. There are also prospective follow-up studies claimed similar neonatal outcomes between IVF twins and spontaneously conceived twins[11-13]. Here, we conducted a retrospective analysis based on the 3845 twin pregnancies delivered in Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022, aimed at concluding the absolute risk of placental abnormalities and complications during twin pregnancies and providing suggestions for clinical management optimization.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ethe characteristics of the\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003epopulation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e.\u0026nbsp;\u003cstrong\u003eThe flowchart of this study.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwin pregnancies with complete medical records delivered in Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022 were analyzed. Five cases with maternal age below 20 or beyond 49 were excluded. All cases were grouped into the spontaneous-conception group or in-vitro-fertilization group, and the relative risk for placenta-related outcomes was analyzed. Then, all the cases were further divided into mono-chorionic and di-chorionic subgroups, and the relative risk of the spontaneous-conception group and in vitro fertilization group for placenta-related outcomes were analyzed.\u003c/p\u003e\n\u003cp\u003eData of 3845 twin pregnancies delivered in Chongqing Health Center for Women and Children between 2017 and 2022 were analyzed. Five cases with maternal age below 20 years (4 cases) or beyond 49 years (1 case) were excluded（Figure 1）. The retrospective cohort study was conducted on 2702 cases of IVF-conceived twin and 1138 non-IVF-conceived twin pregnancies. The baseline characteristics of this study include the year of discharge, maternal age at birth, chorionicity, and chronic disease before pregnancy (chronic hypertension, diabetes, thyroid diseases, anemia). The incidences of placenta disorders and placenta-related complications were analyzed. Placenta disorders include placenta previa, placental abruption, placenta accrete, and abnormal placenta morphology. Placenta-related complications include gestational hypertension, preeclampsia, eclampsia, preterm birth, fetal distress, and FGR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe general characteristics of the two twin pregnancy groups are listed in Table 1. Poisson regression models with restricted cubic splines for maternal age were applied in our study. The optimal number of knots for the restricted cubic splines, situated at default percentiles, was determined by the minimized Akaike Information Criterion (AIC) principle[14]. In detail, we first applied an unadjusted model only with maternal age spline to explore the crude relative risk (RR) and 95% confidence interval (CI) between IVF and non-IVF groups for each placenta-related outcome. Then, the multivariable model adjusted by maternal age (age at delivery), year (year of discharge), and chronic diseases (including chronic hypertension, diabetes, thyroid disease, and anemia) was applied to calculate the adjusted relative risk (aRR) and 95% confidence interval between IVF and non-IVF group. The absolute risk of each placenta-related complication was then graphically presented by maternal age. To address the additional influence of chorionicity on placental-related outcomes, we divided the IVF and non-IVF groups into monochorionic and dichorionic sub-groups. Both unadjusted and adjusted model was applied to the sub-group. All statistical analyses were conducted using glmnet, MASS, and splines package in R-4.1.0[15]. Two-tailed P value \u0026lt;0.05 was considered statistically significant.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAfter accurate selection, the study included 3840 cases of twin pregnancies, including 2702 cases of IVF pregnancies and 1138 cases of non-IVF ones(Figure 1). The maternal age of the IVF group was significantly higher than the non-IVF group (31.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 vs 29.29\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), which was consistent with previous reports[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Since the difference in chorionicity of twin gestation, we further calculated the proportion of dichorionic and monochorionic placenta. Over 95% of placentas were dichorionic in the IVF group, while dichorionic and monochorionic account for almost 50% of placenta type, respectively, in the non-IVF group. As for the chronic disease before pregnancy, the proportion was slightly higher in the IVF group compared with the non-IVF group (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\u003eBaseline characteristics of this study\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=\"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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;3840)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVF (n\u0026thinsp;=\u0026thinsp;2702)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003enon-IVF (n\u0026thinsp;=\u0026thinsp;1138)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear\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\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e472 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e307 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e165 (14.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e594 (15.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e445 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e149 (13.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e648 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e427 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e221 (19.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e659 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e486 (18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e173 (15.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e797 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e579 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e218 (19.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e670 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e458 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e212 (18.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal age at birth, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30.89 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.56 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.29 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e171 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e130 (11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026ndash;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1208 (31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e710 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e498 (43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1812 (47.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1430 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e382 (33.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e35\u0026ndash;39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e582 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e467 (17.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e115 (10.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (1.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e45\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (0.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChorionicity\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\u003eMonochorionic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e712 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e584 (51.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDichorionic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3128 (81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2574 (95.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e554 (48.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChronic disease before pregnancy*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4 (0.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \n\u003cp\u003e \u003cem\u003e*\u0026ldquo;Chronic disease before pregnancy\u0026rdquo; included chronic hypertension, diabetes, thyroid disease, anemia.\u003c/em\u003e \u003c/p\u003e \n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe placenta-related outcomes of twin pregnancy conceived by IVF or non-IVF\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=\"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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacenta-related outcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3840)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2702)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003enon-IVF\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1138)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(95% CI\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaRR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacental abnormalities\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 \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacenta previa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003cp\u003e(3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003cp\u003e(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003cp\u003e(2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.64\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.03\u0026ndash;2.61)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.64\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.03\u0026ndash;2.62)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacenta accreta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e630\u003c/p\u003e \u003cp\u003e(16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e507\u003c/p\u003e \u003cp\u003e(18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e123\u003c/p\u003e \u003cp\u003e(10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.54\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.26\u0026ndash;1.89)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.53\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.25\u0026ndash;1.88)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacental abruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003cp\u003e(1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003cp\u003e(1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.22\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(0.68\u0026ndash;2.19)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.23\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(0.68\u0026ndash;2.21)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal\u003c/p\u003e \u003cp\u003eplacenta morphology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e264\u003c/p\u003e \u003cp\u003e(6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003cp\u003e(5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e119\u003c/p\u003e \u003cp\u003e(10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003cp\u003e(0.39\u0026ndash;0.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003cp\u003e(0.39\u0026ndash;0.65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlacenta-related complications\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\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\u003eGestational hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e212\u003c/p\u003e \u003cp\u003e(5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e165\u003c/p\u003e \u003cp\u003e(6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003cp\u003e(4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.45\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.03\u0026ndash;2.04)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.36\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(0.96\u0026ndash;1.93)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreeclampsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e501\u003c/p\u003e \u003cp\u003e(13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e379\u003c/p\u003e \u003cp\u003e(14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e122\u003c/p\u003e \u003cp\u003e(10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.29\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.04\u0026ndash;1.60)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.27\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(1.02\u0026ndash;1.57)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal distress\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e200\u003c/p\u003e \u003cp\u003e(5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e123\u003c/p\u003e \u003cp\u003e(4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77\u003c/p\u003e \u003cp\u003e(6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003cp\u003e(0.49\u0026ndash;0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003cp\u003e(0.50\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGR\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e321\u003c/p\u003e \u003cp\u003e(8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e194\u003c/p\u003e \u003cp\u003e(7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e127\u003c/p\u003e \u003cp\u003e(11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003cp\u003e(0.53\u0026ndash;0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003cp\u003e(0.52\u0026ndash;0.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreterm birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2252\u003c/p\u003e \u003cp\u003e(58.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1528\u003c/p\u003e \u003cp\u003e(56.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e724\u003c/p\u003e \u003cp\u003e(63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003cp\u003e(0.83-1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003cp\u003e(0.83-1.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e1. \u003cem\u003eRR, relative risk;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e2. \u003cem\u003eaRR, adjusted relative risk;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e3. \u003cem\u003eCI, confidence interval;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e4. \u003cem\u003eFGR, fetal growth restriction;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\u003ctd colspan=\"6\"\u003e5. \u003cem\u003eThe bold values mean has statistical significance.\u003c/em\u003e \u003c/td\u003e\u003c/tr\u003e \n \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003eExcepted for abnormal placenta morphology, IVF was associated with a significantly increased risk of placenta abnormalities including placenta previa (adjusted relative risk [aRR]:1.64, 95% confidence interval [CI]:1.03\u0026ndash;2.62), placental accreta (aRR: 1.53, 95% CI:1.25\u0026ndash;1.88) and placenta abruption (aRR: 1.23, 95% CI: 0.68\u0026ndash;2.21). We also evaluated the association of IVF with placental-related complications. The analysis revealed IVF was associated with a significantly increased rate of gestation hypertension (aRR:1.36, 95% CI: 0.96\u0026ndash;1.93) and preeclampsia (aRR:1.27, 95% CI:1.02\u0026ndash;1.57) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding the specificity of twin pregnancy, we further divided IVF and non-IVF groups into two sub-groups depending on chorionicity. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, over 95% of chorion conceived by IVF were dichorionic, while in spontaneous twin pregnancy, the ratio of dichorionic versus monochorionic was almost 1, ignoring the property of amniotic membrane. Despite the universality of preterm birth in twin pregnancy, the adjusted relative risk in the monochorionic and dichorionic subgroup of the IVF group still increased compared with the non-IVF group (aRR: 1.05, CI:0.83\u0026ndash;1.33; aRR: 1.03, CI:0.90\u0026ndash;1.17). Furthermore, IVF is still the independent risk factor for fetal distress in the monochorionic subgroup (aRR: 1.19, CI:0.61\u0026ndash;2.29) despite the higher risk of second-born twins than their co-twins (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \n\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e The subgroup analysis of placenta-related outcomes of twin pregnancy from IVF or non-IVF group\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\"\u003e\n \u003cp\u003e\u003cstrong\u003eChorionicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.3971119133574%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacenta-related outcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.71841155234657%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=3840\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.913357400722022%\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVF\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=2702)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.913357400722022%\"\u003e\n \u003cp\u003e\u003cstrong\u003enon-IVF\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1138)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.635379061371841%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRR\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI\u003csup\u003e3\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.274368231046932%\"\u003e\n \u003cp\u003e\u003cstrong\u003eaRR\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\" rowspan=\"11\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonochorionic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.3971119133574%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacental abnormalities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.815884476534295%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.815884476534295%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.913357400722022%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.635379061371841%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.274368231046932%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacenta previa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e(0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e(1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.16\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.88-5.35)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.97\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.79-4.94)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacenta accreta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003cp\u003e(2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003cp\u003e(6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.54\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.97-2.44)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.48\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.92-2.37)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacental abruption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003cp\u003e(0.07-5.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003cp\u003e(0.78-5.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eAbnormal\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eplacenta morphology\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003cp\u003e(2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003cp\u003e(5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.97\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.54-1.74)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.009\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.56-1.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacenta-related complications\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eGestational hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.88\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.76-4.64)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.02\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.81-5.03)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePreeclampsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003cp\u003e(2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003cp\u003e(5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.26\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.74-2.15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.16\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.68-2.01)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eFetal distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003cp\u003e(1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e(4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.13\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.59-2.19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.19\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.61-2.29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eFGR\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e(0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003cp\u003e(7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003cp\u003e(0.39-1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003cp\u003e(0.38-1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePreterm birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e512\u003c/p\u003e\n \u003cp\u003e(13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e416\u003c/p\u003e\n \u003cp\u003e(36.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.06\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.84-1.34)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.05\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.83-1.33)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\" rowspan=\"11\"\u003e\n \u003cp\u003e\u003cstrong\u003eDichorionic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.3971119133574%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacental abnormalities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.815884476534295%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.815884476534295%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.913357400722022%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.635379061371841%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.274368231046932%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacenta previa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003cp\u003e(2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003cp\u003e(3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.26\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.09-4.72)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.29\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.10-4.77\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacenta accreta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e533\u003c/p\u003e\n \u003cp\u003e(13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e480\u003c/p\u003e\n \u003cp\u003e(17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003cp\u003e(4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.76\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.32-2.35)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.73\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.29-2.30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePlacental abruption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003cp\u003e(1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003cp\u003e(1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.27\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.59-2.76)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.28\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.59-2.77)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eAbnormal\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eplacenta morphology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e182\u003c/p\u003e\n \u003cp\u003e(4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003cp\u003e(4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003cp\u003e(4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003cp\u003e(0.39-0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003cp\u003e(0.38-0.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacenta-related complications\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eGestational hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e184\u003c/p\u003e\n \u003cp\u003e(4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e157\u003c/p\u003e\n \u003cp\u003e(5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.20\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.79-1.84)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.13\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.74-1.73)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePreeclampsia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e417\u003c/p\u003e\n \u003cp\u003e(10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e360\u003c/p\u003e\n \u003cp\u003e(13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003cp\u003e(5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.38\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.03-1.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.34\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(1.00-1.79\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eFetal distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e138\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003cp\u003e(4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003cp\u003e(0.56-1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003cp\u003e(0.59-1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003eFGR\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e221\u003c/p\u003e\n \u003cp\u003e(5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e181\u003c/p\u003e\n \u003cp\u003e(6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003cp\u003e(3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003cp\u003e(0.71-1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003cp\u003e(0.67-1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.618736383442265%\"\u003e\n \u003cp\u003ePreterm birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\"\u003e\n \u003cp\u003e1740\u003c/p\u003e\n \u003cp\u003e(45.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.468409586056644%\" colspan=\"2\"\u003e\n \u003cp\u003e1432\u003c/p\u003e\n \u003cp\u003e(53.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.379084967320262%\"\u003e\n \u003cp\u003e308\u003c/p\u003e\n \u003cp\u003e(27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.250544662309368%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.02\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.90-1.16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.814814814814815%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.03\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(0.90-1.17)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003col\u003e\n \u003cli\u003e\u003cem\u003eRR, relative risk;\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eaRR, adjusted relative risk;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eCI, confidence interval;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eFGR, fetal growth restriction;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eThe bold values mean has statistical significance.\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Discussion","content":"\u003cp\u003eUntil 2019, over 8\u0026nbsp;million babies have been born through ART since the first IVF baby\u0026rsquo;s birth[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. As the widespread habit of transferring in utero more than one in-vitro-produced embryo at a time, the incidence of twin pregnancies is high, especially in relatively young, good-prognosis patients. Even most guidelines recommend limiting the number of transferred embryos to obtain singleton pregnancies, and single embryo transfer is not widely practiced for many reasons[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough twin pregnancies are frequently observed in IVF, several studies have focused on the additional risk of IVF on placenta-related outcomes[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Several studies demonstrated that IVF could be associated with changes in placental morphology, structure, growth dynamics, imprinted and non-imprinted genes, and other aspects regulating placentation[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A higher incidence of placenta previa was observed in several studies[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Moreover, significantly greater weight and higher placental weight-to-birth weight ratio were also observed in many studies[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A retrospective cohort study based on Chinese data also revealed that IVF was an independent risk factor for placenta abnormalities, including placenta previa, placental abruption, placental accrete, and abnormal morphology of placenta[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These findings support the hypothesis of IVF responsibility for placenta-related outcomes. However, it is still not known precisely if IVF twin pregnancies have an additional risk for placenta-related outcomes compared with spontaneously conceived twin pregnancies.\u003c/p\u003e \u003cp\u003eIVF singleton pregnancies are associated with placenta previa, placenta abruption, placenta accreta, and abnormal placenta morphology, which have been well documented[\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This study includes 3840 cases of twin pregnancies, which include 2702 cases conceived by IVF and 1138 cases of spontaneously conceived ones. The data presented here show that IVF is the independent risk factor for placenta previa, placental abruption, and placental accreta after adjusting for maternal age at birth, the year of IVF implementation, and chronic diseases before pregnancy. While there are no significant differences for abnormal placenta morphology in the incidence when twin pregnancies obtained by IVF or spontaneous conception are compared.\u003c/p\u003e \u003cp\u003eWe further analyzed the additional risk of IVF on placental-related complications, including gestational hypertension, preeclampsia, preterm birth, fetal distress, and FGR. A previous study has reported that twin pregnancy was an independent risk factor for pre-eclampsia but not for gestational hypertension[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. While in our study, IVF-conceived twin pregnancy has a higher risk of gestational hypertension and pre-eclampsia. Based on a low-risk population derived from maternal characteristics (Caucasian, height of 164 cm, weight of 69 kg, no family or medical history), the risk of pre-eclampsia\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks was 0.6% in singletons, 9% in dichorionic twins and 14.2% in monochorionic twins[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. For our data, the incidence of pre-eclampsia in the IVF group has no difference in both dichorionic and monochorionic twins (14% in dichorionic and 14.8% in monochorionic), while in the non-IVF group, the risk of pre-eclampsia was slightly higher in monochorionic twins (10.1% in dichorionic and 11.1% in monochorionic). Over 50% of twins are delivered before 37 weeks\u0026rsquo; gestation, while monochorionic twins have an even higher incidence compared with dichorionic twins[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Ignoring the chorionicity, we find no significant difference in the incidence of preterm birth between the IVF and the non-IVF group. However, IVF is still the independent risk factor when we further divided the two groups into mono- and dichorionic sub-groups. Twins are known to have lower birth weight than singletons[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], and recent research has found that twins have a different growth trajectory than singletons, with growth being lower from 30 weeks in dichorionic twins compared to singletons, and monochorionic twins being generally smaller than both dichorionic twins and singletons throughout gestation[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. It has been reported that second-born twins face higher risks of fetal distress than their co-twins, even in dichorionic pairs [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. IVF is still the independent risk factor for fetal distress in the monochorionic sub-group.\u003c/p\u003e \u003cp\u003eWhile the effect of maternal aging and chronic disease on pregnancy complications has been well documented [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We further showed the adjusted absolute risk and 95% confidence interval [CI] of each outcome that has significantly raised risk in both groups by maternal age. The absolute risk of placenta previa and placenta accreta in both groups increased with maternal age. The variance showed a growing trend, which meant more risk in IVF pregnancy with advanced maternal age. For placental abruption, the absolute risk increased first, followed by a decrease, which was inconsistent with the previous study[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This might be because of limited cases, especially cases with maternal age\u0026thinsp;\u0026gt;\u0026thinsp;35 years. The absolute risk curve was shown to be \u0026lsquo;\u003cem\u003eJ-shaped\u003c/em\u003e\u0026rsquo; in gestation hypertension and preeclampsia, which means the absolute risk decreased with age until the turning points and then increased with age (Additional Fig.\u0026nbsp;1). Few studies focus on the effect of male infertility on pregnancy complications and outcomes[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Increased paternal age has been reported to affect testicular function, reproductive hormones, sperm parameters, sperm DNA integrity, telomere length, de novo mutation rate, chromosomal structure, and epigenetic factors[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39 CR40 CR41 CR42 CR43 CR44\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. So, the effect of parental condition on IVF-conceived pregnancy needs further investigation.\u003c/p\u003e \u003cp\u003eIt is well known that maternal complications are more common in twin pregnancy than in singleton pregnancy. At the same time, IVF as an independent risk factor for placenta-related outcomes has also been reported[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, it is unclear whether twin pregnancies after IVF have a higher risk for placenta-related diseases than spontaneously conceived ones. The data we presented herein show that, after adjusting for maternal age at birth, the year of IVF implementation, and chronic diseases before pregnancy, IVF is still the independent risk factor for placental abnormalities, including placenta previa, placental abruption, and placental accreta and for placental related complications, including gestational hypertension and preeclampsia. When we further divided the twin pregnancies by their chorionicity, we confirmed IVF as the independent factor for preterm birth in dichorionic and monochorionic twin pregnancies and fetal distress in monochorionic twin pregnancies. In conclusion, this study confirmed that IVF-conceived twin pregnancies have a higher risk of most placenta-related pregnancy complications, which may require more stringent surveillance during gestation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ein-vitro fertilization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCQHCWC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChongqing Health Center for Women and Children\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFGR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efetal growth restriction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eART\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eassisted reproductive technologies,AIC,Akaike Information Criterion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erelative risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadjusted relative risk.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthic approval and consent to participate\u003c/h2\u003e \u003cp\u003eThe studies involving human participants were reviewed and approved by Ethics Committee of Chongqing Health Center for Women and Children (ID: 2022-011). To protect patient privacy, all personal identifying information was removed from the cases, and all data obtained were kept anonymous.\u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interests.\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the Natural Science Foundation of Chongqing (grant number CSTB2023NSCQ-MSX0384).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL. W. and Y.C. conceived and designed the study. Y.Y. did the statistical analyses and drafted the manuscript. T. L., Q. G., X. L., J. X., S. L., C. Z. contributed to the data collection and collation. All authors reviewed and revised the manuscripts. All authors read the final manuscript and approved submission.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank all the fellows in Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used in the current study are available from the corresponding author on reasonable request, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of corresponding author (Ya Chen, [email protected] or Lan Wang [email protected]).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThornburg KL, Kolahi K, Pierce M, Valent A, Drake R, Louey S. Biological features of placental programming. Placenta. 2016;48(Suppl 1):S47\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThornburg KL, Marshall N. The placenta is the center of the chronic disease universe. Am J Obstet Gynecol. 2015;213(4 Suppl):S14\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrahem S, Mehdi M, Elghezal H, Saad A. The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population. J Assist Reprod Genet. 2011;28(5):425\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee ED, Mistry HD. Placental Related Disorders of Pregnancy. Int J Mol Sci 2022, 23(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChambers GM, Dyer S, Zegers-Hochschild F, de Mouzon J, Ishihara O, Banker M, Mansour R, Kupka MS, Adamson GD. International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology, 2014dagger. 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J Assist Reprod Genet. 2019;36(9):1917\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVermey BG, Buchanan A, Chambers GM, Kolibianakis EM, Bosdou J, Chapman MG, Venetis CA. Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis. BJOG. 2019;126(2):209\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoque M, Valle M, Sampaio M, Geber S. Obstetric outcomes after fresh versus frozen-thawed embryo transfers: A systematic review and meta-analysis. JBRA Assist Reprod. 2018;22(3):253\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThurn L, Lindqvist PG, Jakobsson M, Colmorn LB, Klungsoyr K, Bjarnadottir RI, Tapper AM, Bordahl PE, Gottvall K, Petersen KB, et al. Abnormally invasive placenta-prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries. BJOG. 2016;123(8):1348\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitzpatrick KE, Sellers S, Spark P, Kurinczuk JJ, Brocklehurst P, Knight M. Incidence and risk factors for placenta accreta/increta/percreta in the UK: a national case-control study. PLoS ONE. 2012;7(12):e52893.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaine K, Murzakanova G, Sole KB, Pay AD, Heradstveit S, Raisanen S. Prevalence and risk of pre-eclampsia and gestational hypertension in twin pregnancies: a population-based register study. BMJ Open. 2019;9(7):e029908.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancisco C, Wright D, Benko Z, Syngelaki A, Nicolaides KH. Competing-risks model in screening for pre-eclampsia in twin pregnancy by maternal characteristics and medical history. 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Second-born twins have more fetal distress and low apgars than their co-twins. Am J Obstet Gynecol. 2003;189(6):S121\u0026ndash;121.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalvaei I, Litzky J, Esfandiari N. Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health. Reprod Biol Endocrinol. 2020;18(1):110.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGourinat A, Mazeaud C, Hubert J, Eschwege P, Koscinski I. Impact of paternal age on assisted reproductive technology outcomes and offspring health: a systematic review. Andrology. 2023;11(6):973\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHandelsman DJ, Staraj S. Testicular size: the effects of aging, malnutrition, and illness. J Androl. 1985;6(3):144\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgarwal A, Makker K, Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008;59(1):2\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoskovtsev SI, Willis J, Mullen JB. Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility. Fertil Steril. 2006;85(2):496\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBroer L, Codd V, Nyholt DR, Deelen J, Mangino M, Willemsen G, Albrecht E, Amin N, Beekman M, de Geus EJ, et al. Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Eur J Hum Genet. 2013;21(10):1163\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1(1):40\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReichman NE, Teitler JO. Paternal age as a risk factor for low birthweight. Am J Public Health. 2006;96(5):862\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurley JP, Mashoodh R, Champagne FA. Epigenetics and the origins of paternal effects. Horm Behav. 2011;59(3):306\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Twin pregnancy, in-vitro fertilization, placental abnormalities, placenta-related complications","lastPublishedDoi":"10.21203/rs.3.rs-4711800/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4711800/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePrevious studies have confirmed that in-vitro fertilization (IVF) is associated with higher risks of placenta abnormalities and complications. Considering the increased risk of twin and higher-order multiple pregnancies, we tried to investigate the association between IVF and the risk of placenta outcomes in twin pregnancies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included 3845 cases of twin pregnancies delivered at Chongqing Health Center for Women and Children (CQHCWC) between 2017 and 2022. Poisson regression modeling with restricted cubic splines of exact maternal age was used to estimate the absolute risk of placenta outcomes in IVF and non-IVF groups. Main outcomes include placenta abnormalities (placenta previa, placental abruption, placenta accrete, and abnormal morphology of placenta) and placenta-related complications (gestational hypertension, preeclampsia, eclampsia, preterm birth, fetal distress, and fetal growth restriction (FGR)). To dissect the influence of chorionicity on the results, we further did the same analysis on the mono- and di-chorionic sub-group.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe absolute risk of placenta previa, placenta accreta, placental abruption, gestational hypertension, and preeclampsia are significantly higher in the IVF group than in the non-IVF group. While there are no significant differences in the absolute risk of abnormal placenta morphology, fetal distress, FGR, and preterm birth between the two groups. After we did further analysis on the dichorionic sub-group, we found the absolute risk of preterm birth was also higher in the IVF group than in the non-IVF group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eTwin pregnancies who received IVF treatment have a higher risk for most kinds of placenta abnormalities and placenta-related complications. Whether these risks have any further impact on maternal and fetal health needs further investigation.\u003c/p\u003e","manuscriptTitle":"The Impact of IVF on the Risk of Placenta Abnormalities and Placenta- Related Complications in Twin Pregnancies: a Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-11 12:05:58","doi":"10.21203/rs.3.rs-4711800/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-16T10:57:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-12T10:38:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-12T10:37:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-07-09T11:43:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4651464d-8fa8-4a01-aabc-784ce70df085","owner":[],"postedDate":"August 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-21T16:08:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-11 12:05:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4711800","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4711800","identity":"rs-4711800","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}