Use of in vitro fertilization, twin pregnancies and advanced maternal age independently associated with adverse maternal outcomes

1. The relative risk of a twin pregnancy amongst women who had undergone in vitro fertilization (IVF) compared with those who had not was 20.8 amongst a cohort of more than 16 million patients in China.

2. The most common adverse outcomes following IVF pregnancy were cesarean delivery, low birth weight, preterm delivery, gestational diabetes, gestational hypertensive disorders, dystocia and postpartum hemorrhage.

Evidence Rating Level: 2 (Good)

Study Rundown: In vitro fertilization (IVF) techniques have advanced considerably in recent decades and allow millions of individuals to carry safe pregnancies, particularly after having difficulties conceiving naturally. It is known that IVF carries a higher risk of multiple pregnancy, although the obstetrical adverse effects of this technology remain poorly characterized. This retrospective cohort study conducted in China between 2013 and 2018 sought to evaluate the incidence of 16 adverse pregnancy outcomes following IVF pregnancy. 16,879,728 participants were included in this analysis, 269,738 (1.60%) of which were IVF pregnancies. Obstetrical outcomes, including 10 maternal outcomes and six neonatal outcomes, were evaluated in this retrospective cohort study. The proportion of all pregnancies which were IVF pregnancies increased over the study period from 1.1% in 2013 to 2.2% in 2018; the proportion of twin pregnancies also increased from 0.4% to 0.7% over that time. Patients receiving IVF were typically older and had higher rates of chronic comorbid disease compared to non-IVF patients. IVF patients had a higher risk of all maternal adverse events, and most neonatal adverse events compared to non-IVF patients. The risk of twin pregnancy was 20 times greater in IVF pregnancies compared to non-IV pregnancies. Only infant macrosomia and stillbirth were less common amongst the IVF group. The largest risk difference between the two groups was for placenta accreta (adjusted risk ratio 1.85 for IVF versus non-IVF). Notably, rates of low birth weight were objectively high amongst twin pregnancies, regardless of IVF use (43.8% in IVF twins, 43.3% in non-IVF twins). Finally, analysis of maternal age showed that advanced age was associated with increased risk of adverse outcomes independently of IVF use or multiple pregnancy. This study by Wang et al contributes helpful data to our understanding of the risks associated with IVF pregnancies, particularly for women of advanced age over 35 years. The primary benefit of this study was the strength and precision of the data owing to an extremely large sample size and longitudinal follow up time. This work is in agreement with the findings of previous studies evaluating risks of multiple pregnancies with IVF and was able to reinforce important trends in obstetrical care on a population level. One major drawback of this study was the retrospective nature of data collection and reliance on administrative databases. Some key information about paternal and family characteristics was unavailable, despite the strong influence of these factors on obstetrical outcomes and access to IVF. To substantiate the findings described here, further study of another population is warranted.

Click to read this study in JAMA Network Open

Click to read an accompanying editorial in JAMA Network Open

Relevant Reading: In vitro fertilization and adverse obstetric and perinatal outcomes

In-Depth [retrospective cohort study]: Patient data was collected through China’s national Health Quality Monitoring System (HQMS) databases. All pregnant women who had a live birth at 28+ weeks gestational age, or stillbirth at 20+ weeks gestational age, were included. IVF procedures were defined according to the International Classification of Disease codes. Findings were summarized using a relative risk (RR) statistic with 95% confidence intervals (95% CI). A sensitivity analysis based on the calendar year of delivery was performed, as the number of hospitals providing data to the HQMS increased drastically over the study period.  The adjusted RR for twin pregnancy in patients with IVF versus non-IVF was 20.8 (95% CI 20.6-20.9). 28.8% of IVF patients were over age 35, while 13.7% of the non-IVF patients were, and the rates of all chronic disease amongst IVF versus non-IVF patients was significantly different (p<0.001). The adjusted RR and 95% CI for the ten maternal adverse events for IVF versus non-IVF pregnancies are as follows: hypertension (1.37, 1.34-1.40), eclampsia and preeclampsia (1.26, 1.24-1.28), gestational diabetes (1.45, 1.44-1.47), placenta previa (1.82, 1.78-1.85), placental abruption (1.11, 1.07-1.15), placenta accreta (1.85, 1.81-1.89), preterm birth (1.18, 1.16-1.19), dystocia (1.33, 1.31-1.34), cesarean delivery (1.21, 1.20-1.22), and postpartum hemorrhage (1.63, 1.61-1.66). The adjusted RR and 95% CI for neonatal adverse events as reported in this study were: fetal growth restriction (1.09, 1.06-1.12), low birth weight (1.10, 1.09-1.11), very low birth weight (1.14, 1.11-1.17), and malformation (1.09, 1.06-1.13), macrosomia (0.98, 0.96-1.00) and stillbirth (0.68, 0.65-0.71). Stratification of adverse events by maternal age group regardless of IVF receipt demonstrated that advanced age independently increases obstetrical risk.

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