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

doi:10.21203/rs.3.rs-4711800/v1

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Research Article

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

https://doi.org/10.21203/rs.3.rs-4711800/v1

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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

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.

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.

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)	RR¹ (95% CI³)	aRR² (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)
FGR⁴	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)

RR¹

(95% CI³)

aRR²

(95% CI)

Monochorionic

Placental abnormalities

Placenta previa

(0.6)

(0.3)

(1.4)

2.16

(0.88-5.35)

1.97

(0.79-4.94)

Placenta accreta

(2.5)

(1)

(6.2)

1.54

(0.97-2.44)

1.48

(0.92-2.37)

Placental abruption

(0.3)

(0.04)

(0.8)

0.60

(0.07-5.06)

0.66

(0.78-5.62)

Abnormal

placenta morphology

(2.1)

(0.6)

(5.9)

0.97

(0.54-1.74)

1.009

(0.56-1.82)

Placenta-related complications

Gestational hypertension

(0.7)

(0.3)

(1.8)

1.88

(0.76-4.64)

2.02

(0.81-5.03)

Preeclampsia

(2.2)

(0.7)

(5.7)

1.26

(0.74-2.15)

1.16

(0.68-2.01)

Fetal distress

(1.6)

(0.4)

(4.4)

1.13

(0.59-2.19)

1.19

(0.61-2.29)

FGR⁴

100

(2.6)

(0.5)

(7.6)

0.71

(0.39-1.30)

0.70

(0.38-1.30)

Preterm birth

512

(13.3)

(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)

(3.4)

(0.7)

2.26

(1.09-4.72)

2.29

(1.10-4.77)

Placenta accreta

533

(13.9)

480

(17.8)

(4.7)

1.76

(1.32-2.35)

1.73

(1.29-2.30)

Placental abruption

(1.4)

(1.7)

(0.7)

1.27

(0.59-2.76)

1.28

(0.59-2.77)

Abnormal

placenta morphology

182

(4.7)

130

(4.8)

(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)

(2.4)

1.20

(0.79-1.84)

1.13

(0.74-1.73)

Preeclampsia

417

(10.9)

360

(13.3)

(5.0)

1.38

(1.03-1.82)

1.34

(1.00-1.79)

Fetal distress

138

(3.6)

111

(4.1)

(2.4)

0.87

(0.56-1.35)

0.91

(0.59-1.41)

FGR³

221

(5.8)

181

(6.7)

(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.

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.

IVF

in-vitro fertilization

CQHCWC

Chongqing Health Center for Women and Children

FGR

fetal growth restriction

ART

assisted reproductive technologies,AIC,Akaike Information Criterion

relative risk

confidence interval

aRR

adjusted relative risk.

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]).

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No competing interests reported.

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.

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

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