Discussion
Main Findings
When the pregnancy began, there was a significantly higher rate of late
pregnancy loss among the PCOS population, without an increase in the
rate of early clinical pregnancy loss. However, in the final adjusted
model, PCOS was no longer associated with increased risk of late
pregnancy loss. Adverse pregnancy outcome in PCOS may be influenced by
increased BMI and underlying medical conditions rather than an
independent effect of PCOS.
Strengths and limitations
There are some limitations to acknowledge. First, due to the
retrospective character, information about preexisting conditions and
gestation-related health issues could be incomplete and underreporting.
Insulin concentrations were measured in only a few of the PCOS cases, we
did not explore the correlation between the pregnancy insulin resistance
and the occurrence of GDM. Secondary, the lines between spontaneous and
induced abortion was not clearly distinguished. However, the proportion
of induced abortion in this study is negligible, because women are
conceived by ART thus artificial abortion is performed very seldom, and
only on maternal medical indication. Finally, as we restricted our
analyses to pregnancies conceived by ART, our results may not be
generalizable to women with natural pregnancies. To draw firm
conclusions on the risk of pregnancy loss in PCOS cases, multi- center
studies cross country is needed.
The major strength of our study is in its real-world based data with a
large sample size of women. Unlike most previous studies, we were able
to distinguish between early and late pregnancy loss. Evaluating risk of
pregnancy loss at different gestational ages is critical in
understanding its etiology and in counseling pregnant women about their
possibility of pregnancy loss. Additionally, we also calculated the risk
for pregnancy loss stratified by plurality of the pregnancy sac on early
ultrasound, which strengthens our findings.
Interpretation
While previous studies have shown that women with PCOS are more prone to
suffer from early pregnancy loss,19-22 we show here,
as Sterling et al.23 suggested, that risk of early
pregnancy loss did not differ markedly between PCOS cases and controls.
Furthermore, findings in the current study extended upon previous
literature. PCOS cases in the previous study were within the normal
range of BMI which does not therefore represent the whole spectrum of
PCOS. They studied pregnancy outcomes after fresh embryo transfer only,
whereas pregnancy losses in subsequent frozen embryo transfer were also
included in our study.
An important finding of the present study was that late pregnancy loss
appeared to have stronger associations with PCOS than early pregnancy
loss. After 13 weeks of gestation, women with PCOS have been shown to be
at higher risk of pregnancy loss, regardless the plurality of the
pregnancy. In the adjusted model 1, late pregnancy loss was associated
with the diagnosis of PCOS. The retrospective nature of our study design
makes it difficult to elucidate the reasons for this finding. This may
reflect the hypothesis of a different etiology of pregnancy loss in
first and second trimester.
Some authors have argued that the risk of pregnancy loss is more related
to the elevated BMI which is known to be associated with an increased
risk other than PCOS status.24-26 This is in
congruence with the findings of this study. Although the cause of this
association between PCOS and obesity remains unknown, overweight is
present in 30%~50%.27-29 and in the
present study 33.7% had BMI ≥25 kg/m2 and 9.2% with
BMI ≥30 kg/m2. We noticed that the potential negative
impact of PCOS was eliminated once BMI were taken into account in the
fully adjusted Model 2. In line with our results, Joham et
al,3 suggested that PCOS was not independently
predicts higher risk of a pregnancy loss. However, as overweight and
obesity often coexisting with PCOS,27-30 it is
debatable whether data should be controlled for BMI.
Significant differences were found in maternal preexisting medical
conditions with a markedly increased risks of hypertension and diabetes
were noted in women with PCOS compare with women with non-PCOS, which
was supported by other researches.30-33 A recent
review of PCOS patients, derived from a UK general practitioner research
database with a mean age of 27 years followed for a median period of 4.7
years, demonstrated that women with PCOS had a higher systolic blood
pressure.30 Reports suggest that a woman with PCOS may
have a fourfold increased risk of developing diabetes, and a 33% risk
of impaired glucose tolerance.33 Though overweight
seems to be the most important predictor, the effect of comorbidities
also remained statistically significant after multivariable analysis
(Table 4 model 2)
Women with PCOS are prone to undergo ART, with its higher frequency of
twins and multiple pregnancy. The loss of pregnancy due to multiple
pregnancies have been evaluated in PCOS patients. Mikola et
al.34 found that the higher incidence of poor
obstetric outcomes of PCOS pregnancies could partly explained by the
increased number multiple pregnancies. As double-embryo transfer is
still common, we here, subdivided the pregnancy loss rate according to
the numbers of gestational sac in early ultrasound. Our results here do
not suggest that the number of embryos transferred or multiple
pregnancies alone increases the risk the pregnancy loss among patients
with PCOS (Table 2 and Table 3). But the results should not be taken as
a plea for DET or twin pregnancies for those with PCOS. On the contrary,
higher rate of late pregnancy loss was observed when DET was performed
in both of the two groups, confirming that SET is a logical
practice.35 In line with previous
studies,36 we found that 25.8% percent of multi
gestational pregnancies that progressed to a livebirth delivery
experienced loss of at least one fetus during the pregnancy. More
worryingly, spontaneous reductions in IVF/ICSI twin pregnancies have
been suggested to be a possible cause of the increased morbidity in IVF
singletons.36-38 Message above is critical for the
whole cohort of infertility patients since they frequently ask for more
embryos to be transferred to secure a maximum chance of success.
In the present study we found women with PCOS were slightly younger than
women without the diagnosis. PCOS women frequently exhibit menstrual
irregularities such as oligomenorrhea, hence are more likely to require
medical assistance. With the awareness of the potentially reduced
fertility, they could have started trying to conceive earlier. This
hypothesis is supported by an observational study, which reported that
women with PCOS are also more likely to have had their first pregnancy
at a younger age.33 Advanced maternal age is strongly
correlated with early pregnancy loss in the study (Table 3), although we
adjusted for maternal age in the multivariate analysis, a residual
effect could still be possible. However, there was no association with
maternal age and late pregnancy loss in PCOS or non-PCOS cases, before
and after multivariable analysis (Table 4). These findings need to be
confirmed in future studies.
Various studies suggested that females with PCOS who conceive might
suffer from pregnancy-related complications such as gestational
diabetes,39 pregnancy induced hypertension39,40 to a higher extent in comparison to controls.
Varies studies have shown that infants born to women with PCOS are also
predisposed to many adverse health outcomes.2,23,40 We
have consistently reported an increase in maternal and neonatal
complications for women with PCOS, even analysis was restricted to
singletons. But we failed to find a correlation between PCOS and risk of
caesarean section, which does not correspond with the findings of other
studies. Differences can probably be explained by the high incidence of
caesarean section in China, either caused by social or clinical factors,
particular when women undergoing ART.