Polycystic ovary syndrome and preterm birth – what’s going on?

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders worldwide and a leading cause of female infertility. With the advent and increasing usage of assisted reproductive technologies (ART), women with PCOS are having children at a similar rate to women without PCOS. However, a PCOS diagnosis and ART treatment have each been associated with adverse maternal and neonatal outcomes. Teasing out the associations specific to PCOS from those specific to treatment processes is difficult in a population-setting.

In “The neonatal outcomes in women with polycystic ovary syndrome following the frozen-thawed embryo transfers,” the authors look at a unique population to try to isolate the effect of maternal PCOS on child birthweight and gestational age (1). All 11,162 women in this study, including 1,167 women diagnosed with PCOS using the Rotterdam criteria, underwent a frozen embryo transfer (FET). Thus, the effect of FET is controlled for in this study. Additionally, these women were all treated in one center which minimizes potential variations in the FET procedures. Among the findings was that the odds of preterm birth was higher in women with PCOS compared to women without PCOS (Odds Ratio 1.53, 95% CI 1.23–1.91) and the association was similar in a subpopulation of women with normal body mass index (BMI 18.5–24.9 kg/m²) (Odds Ratio 1.62, 1.25–2.10).

Preterm birth remains a major cause of child morbidity and mortality worldwide, and thus this finding is of public health importance. A strength of examining this question in an ART setting is that gestational age is unquestioningly accurate given knowledge of the exact date of fertilization and of embryo transfer. On the other hand, generalizability may be limited due to use of a control group with other fertility factors and the selection of a PCOS phenotype severe enough to require ART. Nevertheless, similar results have been seen in a large retrospective cohort study with millions of participants in the United States (2) where PCOS was related to preterm birth but not associated with small for gestational age, while controlling for in vitro fertilization use. Notably, large population-based studies often rely on the accuracy of registries or self-report of PCOS and its sequalae which may not have high sensitivity.

That said, despite limitations inherent to observational studies, PCOS has been consistently related to preterm birth in different research settings. This association is somewhat surprising since PCOS is a rather unspecific diagnosis. Using the Rotterdam criteria, PCOS is diagnosed by having at least two of the following conditions: hyperandrogenism, oligo- or anovulation, and polycystic ovaries confirmed by ultrasound. In adult women, a PCOS diagnosis is associated with obesity, type II diabetes, and gestational diabetes in pregnancy. Both the metabolic and endocrine conditions commonly present in women with PCOS may relate to birth outcomes. Indeed, large randomized controlled trials of metformin treatment during pregnancy versus placebo have shown promising reductions in preterm delivery (Risk Ratio, 0.46; Risk Difference 4.18% for metformin treatment versus placebo) (3). Metformin is an antidiabetic medication commonly prescribed in PCOS which increases insulin sensitivity and, through this pathway, indirectly reduces circulating androgen concentrations. Long-term follow-up of these trials to investigate child metabolic, behavioral, and neurologic outcomes is ongoing with varying results.

Emerging technologies can also enhance the study of mechanisms of this association in epidemiologic research. For instance, recent studies of term placentas have noted macro- and microscopic differences in the placentas of women with versus without PCOS (4). Epigenetic contributions are increasingly being examined as an underlying mechanism related to pregnancy complications. These include modifications to DNA methylation and noncoding RNAs which can alter gene expression. In addition, we are now able to isolate and investigate the role of smaller components of circulating biofluids – extracellular vesicles. Extracellular vesicles are small nanoparticles secreted from various tissues which have been recognized as facilitators of intracellular communication. They vary in size, concentration, and content. Placental-derived extracellular vesicles may mediate associations between markers of disease states (e.g., maternal obesity, PCOS, etc.) and obstetric/neonatal outcomes. These new technologies, once standardized (5), could help determine molecular mechanisms driving the association of PCOS with preterm birth and, potentially, identify more specific targets for intervention.

In summary, the study put forth by Lin et. al (1) reaffirms a well-documented association – that maternal PCOS is positively associated with preterm birth – in a previously underexamined population of women undergoing FET. Well-designed, comprehensive pregnancy cohort studies combined with new technologies which can interrogate biological mechanisms are now needed to pinpoint what it is about a PCOS diagnosis that relates to preterm birth and identify potential treatments for women with PCOS which could mitigate their risk of delivering preterm.