Perinatal Complications and Live – Birth Outcomes following Assisted Reproductive Technology: A Retrospective Cohort Study
In the world of reproductive medicine, assisted reproductive technology (ART) has brought hope to many couples struggling with infertility. Since the birth of Louise Brown in 1978, in vitro fertilization (IVF) has become an effective way to treat infertility and has produced millions of babies worldwide. The number of ART births per year has increased worldwide, with the total number of IVFs approximately 5 million. In developing countries, IVF accounts for 1.7% to 4% of the total population, and 1% of the Chinese population.
However, with the development of ART and its increasing success rate, more attention has been paid to its safety. ART allows multiple eggs to mature simultaneously via controlled ovarian hyperstimulation, and fertilization and early embryo development are accomplished by in vitro culture and micromanipulation. These techniques interfere with the process of germ cell proliferation, fertilization, development, and differentiation and may have adverse effects on the embryo. Several studies have shown that ART increases the incidence of adverse pregnancy outcomes, including preeclampsia, gestational hypertension, placenta previa, gestational diabetes mellitus (GDM), preterm delivery, low birth weight, and birth defects. But is it the ART technology itself or multiple births that cause these adverse outcomes?
Methods
This was a retrospective cohort study conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, between January 2013 and December 2015. All ART pregnancies were paired 1:3 with spontaneous pregnancies as the control group during the same time period. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Informed written consent was obtained from all patients. Quantitative data are presented as the mean ± standard deviation (SD). Fisher exact and x2 tests were performed to test for differences in the proportions of categorical variables. Logistic regression analysis was done to identify possible predictors of pregnancy complications and the association of ART and spontaneous pregnancy.
Results
Maternal Characteristics
From January 2013 to December 2015, 2256 ART-derived pregnancies and 6768 matched spontaneous pregnancies were enrolled. The ART group had older women, more nulliparous patients, and a higher cesarean section rate.
Pregnancy Complications
After adjustment for various factors, pregnancies conceived by ART were associated with a significantly increased incidence of GDM (OR 1.88, 95% CI 1.56–2.27), gestational hypertension (OR 2.18, 95% CI 1.83–2.60), and intrahepatic cholestasis of pregnancy (ICP) (OR 2.79, 95% CI 2.15–3.64), compared with spontaneous conception. These associations were similar for the singleton group. In the twin group, only the incidence of ICP was significantly higher than in controls.
Perinatal Complications
Pregnancies conceived by ART were associated with perinatal complications, including placental abruption (OR 2.14, 95% CI 1.33–3.45), premature rupture of membranes (PROM; OR 1.24, 95% CI 1.06–1.45), postpartum hemorrhage (OR 2.89, 95% CI 2.33–3.59) and polyhydramnios (OR 2.01, 95% CI 1.29–3.16). The singleton group had a similar result with placental abruption, but not with fetal membranes ruptures before labor and polyhydramnios. There were no significant differences in the incidence of these perinatal complications in the twin group.
Neonatal Outcomes
Some neonatal outcomes, including preterm labor (OR 4.29, 95% CI 3.84–4.80) and low birth weight (OR 1.72, 95% CI 1.42–2.08), were more likely to occur with singleton births after ART. However, there were no significant differences for these outcomes from twin pregnancies.
Subgroup Analyses
Perinatal complications and neonatal outcomes were consistent between the IVF and ICSI subgroups. The FET and ET subgroups showed a similar increase in complications, except for the incidence of placental abruption. After taking into account the effects of parity, birth plurality and maternal age, the ART group still exhibited increased maternal and neonatal complications, although some differences narrowed or disappeared.
Discussion
Multiple Pregnancies
Our study found that the twin pregnancy rate in the ART group was over 20 times that in the spontaneous pregnancy group (35.6% vs. 1.5%). Twin pregnancy increased the incidence of adverse pregnancy and birth outcomes. For example, the incidence of GDM was higher in the twin ART group than in singleton ART group (9.10% vs. 7.69%). The incidence of hypertension during pregnancy in the twin ART group was higher than in singleton ART group (11.2% vs. 9.5%). Single embryo transfer (SET) is considered the only effective method to avoid multiple pregnancies in ART. Actively promoting SET should be a standard trend for ART in China.
Infertility Factors
In our study, the increased risks were found in ART conceived singletons compared with spontaneously conceived singletons. We conclude that infertility factors in women requiring ART procedures to conceive contribute to adverse obstetric and perinatal outcomes. Ovulatory disorders are a common cause of sterility. These patients may exhibit serious endocrine disorders, such as insulin resistance, and carry high risk factors for obstetrical diseases. Some infertile patients have uterine damage due to uterine cavity operations. Some ART patients have infertility caused by endometriosis. A meta – analysis revealed that endometriosis is associated with an increased risk of placenta previa in pregnancies achieved through ART.
ART Technology
With the rapid development of ART technology, many new technologies have been born. In our study, differences became insignificant when comparing the incidence between the IVF and ICSI groups, except for PROM. There is only one insignificant difference between the FET and ET groups, which is placental abruption. Our results in part complement a recent publication. According to our study, we suggested that there is no significant difference in pregnancy outcomes between different ART techniques. Clinicians can flexibly adopt various ART techniques according to the actual situation of the patients.
Limitations
There are several limitations to our study. First, due to the retrospective study design, data were extracted from the medical record system at a single center. The sample number is still relatively small. Second, since no data were collected on the particular cause of infertility, baseline endocrine level, as well as serum hormone levels during ovarian stimulation, we cannot analyze how these different factors may affect maternal and neonatal outcomes. The intrauterine insemination (IUI) is a relatively less invasive form of ART. However, the records of IUI outcomes are lacked in our database, and not included in the present study, which would lead to bias.
Conclusion
This retrospective cohort study demonstrated that patients who underwent ART were at increased risk of several adverse pregnancy outcomes compared with women who conceived spontaneously. These complications may be attributed in part to the relatively high multiple pregnancy rate after ART. Elective single embryo transfer should be promoted in China to reduce the obstetrical risks of ART pregnancy. Singletons of ART pregnancy exhibited increased maternal and neonatal complications as well, suggesting that underlying infertility or other maternal or parental factors may contribute to the adverse outcomes. Further studies about how the cause of sterility affects the pregnancy outcome of ART are deserved.
doi: 10.1097/CM9.0000000000000484
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