Effect of Fertility on Perinatal Outcomes

Peter Kovacs, MD, PhD


July 01, 2015

Perinatal Outcomes Associated With Assisted Reproductive Technology: The Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART)

Declercq E, Luke B, Belanoff C, et al
Fertil Steril. 2015;103:888-895


In vitro fertilization (IVF) has a relatively short history. The first child conceived in vitro was born in 1978, but by 2006 more than 1 million cycles were performed worldwide.[1] In the developed world, up to 5% of children born are conceived in vitro.[2] The safety of the treatment has been questioned and studied since the birth of Louise Brown.

Risks such as ovarian hyperstimulation, thrombosis, injury during the retrieval, and infection may arise during the treatment and during the pregnancy itself as well as years after the treatment. Many studies have evaluated the short- and long-term maternal and offspring side effects.

A higher incidence of maternal problems during pregnancy, including hypertensive complications, gestational diabetes, and operative delivery, has been reported.[3] A higher risk for neonatal complications, primarily due to preterm delivery, has also been reported.[3]

These adverse outcomes are typically attributed to the use of assisted reproductive technology (ART). The impact of infertility itself is less often considered. The impact of ART in a fertile setting cannot be studied because otherwise fertile women cannot be randomly assigned to IVF treatment due to ethical concerns. Recent advances in technology, however, could present an opportunity. Couples with proven fertility may elect to undergo preimplantation genetic testing, and the perinatal outcome of these pregnancies could be used to evaluate an unstudied group: fertile women utilizing ART. An adverse impact observed among them could represent the adverse impact of ART itself.

In the meanwhile, it is important to assess the contribution of infertility and subfertility itself to adverse perinatal outcomes.

The Study

This study has linked information on ART treatments with live birth and fetal death data recorded in the Massachusetts Pregnancy to Early Life Longitudinal (PELL) data system. The combination of these various datasets resulted in the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART) database. In total, the PELL database included 282,971 women delivering singletons or twins, and their outcomes were linked to the pregnancy outcomes of 18,439 women undergoing 42,649 ART cycles. In addition to the ART group and the fertile control group, a third group of patients was included. These were women whose histories (hospital records or personal history of past ART use) indicated subfertility but whose index pregnancy was conceived spontaneously. The subfertile group consisted of women who at some point attended infertility clinics but eventually conceived on their own.

Four parameters were compared among the three groups: preterm birth (<37 weeks), low birth weight (<2500 g), small for gestation (SGA; weight <10th percentile), and perinatal death. Maternal age, race, marital status, level of education, insurance availability, smoking, parity, chronic hypertension, sex of the neonate, and prenatal care were controlled for during multivariable analysis. Mothers in the ART group were older, had a higher level of education, were more likely to be nulliparous, were more likely to have private insurance, were more often diagnosed with hypertension during pregnancy, and were more likely to deliver by Cesarean section.

When compared with the fertile controls, the risk for preterm delivery of singletons was higher in the subfertile (adjusted odds ratio [OR]: 1.24; 95% confidence interval [CI], 1.12-1.38) and ART (adjusted OR: 1.53; 95% CI, 1.40-1.67) groups. The risk for low birth weight of singletons was also increased in subfertile women (adjusted OR: 1.20; 95% CI, 1.06-1.36) and ART women (adjusted OR: 1.51; 95% CI, 1.37-1.67). The risk for SGA of singletons did not differ significantly in the three groups. The risk for perinatal death was increased in the subfertile group (adjusted OR: 1.51; 95% CI, 1.05-2.17) but not in the ART group when compared with fertile controls. Furthermore, the risk for preterm birth of singletons was increased in the ART group when compared with the subfertile group (adjusted OR: 1.23; 95% CI, 1.08-1.41) and the risk for low birth weight was also increased in the ART group when compared with the subfertile group (adjusted OR: 1.26; 95% CI, 1.08-1.47).

The risk for preterm delivery of twins or low birth weight of twins was not increased in the ART or subfertile groups when compared with the fertile controls. The risk for SGA was significantly lower in the ART and subfertile groups, while the risk for perinatal death was lower in the ART group and higher in the subfertile and fertile groups.

The authors have concluded that perinatal outcome is less favorable in subfertile women who conceive spontaneously and in infertile women undergoing ART when compared with fertile controls.


It has been shown in multiple studies that perinatal outcome is less ideal following the use of ART.[4,5] The adverse impact of the treatment itself can only be partially explained by the higher incidence of multiple gestations in the ART group.[4,5] Subsequent studies have shown that even singletons are affected, and the perinatal outcome in their case is less ideal.[5,6] It has to be emphasized that we are talking about relative risks, and the absolute risk is overall small.

The epidemiologic studies are not randomized trials; therefore, one has to carefully control for confounding factors such as maternal age, ethnicity, chronic medical problems, the plurality of pregnancy, parity, level of education, level of prenatal care, etc.

Several meta-analyses on this topic have shown that ART singletons are more likely to be delivered preterm and be affected by low birth weight, very low birth weight, or SGA when compared with naturally conceived singletons.[4,5]

The review by Pinborg and colleagues has shown that subfertile women (time to spontaneous pregnancy >1 year) were at an increased risk for preterm delivery.[6] A similar conclusion was drawn based on the meta-analysis of 14 studies by Messerlian and colleagues.[7]

A potential explanation for the increased risk for adverse perinatal outcome is the phenomenon of spontaneous reduction (vanishing twin). The review by Pinborg and colleagues[8] has shown that singletons with a "vanishing co-twin" were at an increased risk for preterm birth compared with singletons that have not undergone spontaneous reduction. The risks for low birth weight and very low birth weight were also higher in those singletons that originated from a twin pregnancy.[8]

During IVF, the endometrium is exposed to excessive hormonal stimulation as a result of multifollicular development. This could have an adverse impact on placenta formation and, therefore, could affect birth weight and gestational age at delivery. This is supported by observation that frozen embryo transfer cycles with a more physiologic hormonal profile are associated with improved perinatal outcome (fewer preterm deliveries, higher birth weight) when compared with singletons conceived in fresh IVF cycles.[6,9]

Finally, we should not rule out the possibility of iatrogenic preterm deliveries. Sometimes providers consider ART pregnancies more precious, which may affect the tests ordered during pregnancy.[10] More is not always better; the results of extra tests could result in earlier inductions and Cesarean sections.

Perinatal outcome seems to be affected by the mode of conception. The use of ART, however, does not fully explain the excess relative risk. Subfertile and infertile women differ from the fertile population, and these differences explain some of the adverse perinatal outcomes alone. Better understanding of the mechanisms responsible for preterm delivery or low birth weight may affect the way ART will be practiced in the future. The utilization of single embryo transfer will likely be more common to avoid multiple gestations. As the cryopreservation technology improves, we may turn to elective cryopreservation and subsequent transfer in natural cycles to avoid the endometrial effects of stimulation. Furthermore, we may identify important and correctable factors associated with infertility itself that could affect perinatal outcome.



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