Women with PCOS and T2D in pregnancy were at greater risk for high insulin requirements, excess weight gain, and worsening of pregestation hypertension if treated with metformin.
A study comparing pregnancy outcomes in women with type 2 diabetes (T2D) and polycystic ovary syndrome (PCOS) and those without PCOS found no significant differences in neonatal outcomes. However, PCOS in pregnant women with T2D was linked to high insulin requirements and excess weight gain.
Further, metformin treatment in this patient group was linked with an increase in extremely large-for-gestational-age infants as well as an increase in worsened pregestation maternal hypertension.
The findings appeared in Diabetes Metabolism Research and Review.
“We hypothesized that the additional presence of PCOS would be associated with an increase in adverse maternal and fetal outcomes, in the setting of T2D in pregnancy,” wrote investigators. “Secondly, we hypothesized that given the high insulin resistance present in women with PCOS, metformin treatment may be less effective in preventing these adverse maternal and fetal outcomes in individuals with PCOS as compared to those without PCOS in the setting of T2D in pregnancy.”
The retrospective cohort study analyzed data from a cohort of women with T2D in pregnancy who were treated with metformin. The group of 502 women were randomly assigned to receive either metformin or a placebo in addition to their usual insulin therapy. Eligible participants were between ages 18 to 45 years, were diagnosed with T2D before pregnancy or before 20 weeks’ gestation, were receiving insulin, had a live fetus confirmed by ultrasound, and had reached between 6 and 22 weeks plus 6 days’ gestation.
The diagnosis of PCOS was obtained through a self-reported questionnaire on baseline characteristics. There were 86 participants with PCOS and 396 without the condition.
Using linear and logistic regression to adjust for potential confounders, investigators compared differences in maternal and neonatal outcomes in patients with and without PCOS. They also examined any relative differences in the effect of metformin on pregnancy outcomes among these patients.
The study found that PCOS was significantly associated with higher excess gestational weight gain (unadjusted 12 vs 11.4 kg, adjusted mean difference of 2.1 kg; P = .021) and higher total insulin dose at 34 to 36 weeks (unadjusted 172 vs 124 units per day, unadjusted mean difference of 44 units; P = .004). However, no differences were seen in neonatal outcomes between patients with and without PCOS.
When researchers conducted a subgroup comparison of the effect of metformin in participants with and without PCOS, they found the agent associated with an increased risk of worsening chronic hypertension in the PCOS group (16.7% vs 4.5%; Pinteraction = .046). Moreover, the team reported that treatment with metformin vs placebo in the PCOS subgroup was associated with an increase in extremely large-for-gestational-age (LGA) infants (28.6% vs 14%; Pinteraction = .008). The metformin-treatment-related odds ratio (OR) for extreme LGA was significantly higher in the PCOS group than in the non-PCOS group (OR interaction 6.5 [1.7, 28.5], P = 0.008).
The findings showed that metformin use in individuals without PCOS was associated with a reduced risk of both of these outcomes.
Investigators called their fidings on the treatment effect of metformin "surprising," particularly as they had observed the opposite effect on gestational size in earlier analyses. “Interpreting this finding with caution, it can be stated that metformin may not be as protective against macrosomia in the setting of comorbid PCOS and T2DM than previously anticipated, and further research will be required to confirm this finding.”
The researchers acknowledged some limitations to the study, including the diagnosis of PCOS was self-reported, the dataset did not include information on the use of assisted reproductive technology, and not being able to detect rare adverse neonatal outcomes.
In their conclusion the team urged clinicians to be aware of the potential for adverse maternal outcomes among women with T2DM in pregnancy who also have PCOS, highlighting that higher insulin use may be required and that gestational weight gain may be pronounced. "Reassuringly, the presence of PCOS was not associated with an increase in adverse neonatal outcomes," the wrote. However, they caution, "metformin may be less protective against maternal weight gain and macrosomia than anticipated in this population."