Could Metformin Before Conception Be the Answer in PCOS?

Marlene Busko

April 10, 2019

Among pregnant women with polycystic ovary syndrome (PCOS), metformin treatment may up the odds of delivering a full-term baby — but the offspring are also more likely to be overweight as toddlers, and remarkably, metformin had no effect on gestational diabetes.

These findings from PregMet2 were published in Lancet Diabetes & Endocrinology. They follow topline results from the trial, presented last year, at ENDO 2018: the Endocrine Society annual meeting.

However, buried in the appendix, the findings also hint that women with PCOS might benefit most from pre-pregnancy metformin, according to an editorial published with the article.

Two Decades of Research: NNT Is 18 With Metformin

The work is the culmination of two decades of research and three randomized controlled trials — a pilot study, PregMet, and now PregMet2 — by Ester Vanky, MD, PhD, and colleagues, from the Norwegian University of Science and Technology, Trondheim.

"Our findings suggest that metformin might reduce late miscarriage and preterm birth in pregnant women with PCOS," doctoral student Tone S. Løvvik, the lead author, and colleagues conclude.

"Metformin is cheap, tolerable, and widely available," they note. "However, the possible benefit of metformin on pregnancy outcomes should be balanced by recent findings of overweight among in utero metformin-exposed offspring at age 4 years," they caution.

Moreover, as previously reported, metformin did not reduce the development of gestational diabetes (which was about 25% in this cohort), but it was associated with lower weight gain than with placebo.

The pooled analysis of the three trials shows that in pregnant women with PCOS, the number needed to treat was 18.4 to prevent miscarriage or preterm birth, Lourdes Ibáñez, MD, PhD, University of Barcelona, Spain, and Francis de Zegher, MD, PhD, University of Leuven, Belgium, calculate in their editorial.

"This finding is a remarkable achievement, crowning almost two decades of relatively solitary exploration by this group of investigators," they write.

These latest results "provide an obvious wealth of knowledge, but also a potential pearl of wisdom somewhat hidden in the study appendix," Ibáñez and de Zegher continue.

"Finding that exclusive pre-study treatment [with metformin] seemed as effective as gestational treatment," they note, "suggests the possibility that metformin treatment before pregnancy might be an alternative to treatment during pregnancy."

"An exclusive preconception strategy" would remove concerns about potential lifelong consequences in the offspring stemming from fetal exposure to metformin, they emphasize.

However, this finding from an unspecified post-hoc analysis in a nonrandomized subset of patients "should be treated with caution," they stress.

800 Pregnant Nordic Women With PCOS

A pooled analysis of the pilot study (in 40 women, conducted in 2000-2004) and PregMet (in 273 women in 2005-2009) suggested that among women with PCOS, those who received metformin during pregnancy were less likely to have a late miscarriage (between gestational week 13 and week 22 and 6 days) or a preterm delivery (between gestational week 23 and week 36 and 6 days).

PregMet 2 aimed to test this hypothesis in a third randomized trial.

Between 2012 and 2017, PregMet2 randomized 487 pregnant women with PCOS in 14 hospitals in Norway, Sweden, and Iceland to metformin (500 mg twice daily for 1 week then 1000 mg twice daily) or matching placebo from the third trimester until delivery.

Almost all of the women were white; they were a mean age of 29 years and 29% had a university education.

The primary outcome of late miscarriage and preterm birth occurred in fewer women who received metformin (12 of 238 women, 5%) versus placebo (23 of 240 women, 10%), but this was not significant (odds ratio [OR], 0.50; 95% CI, 0.22 - 1.08; P = .08).

However, in the larger post-hoc pooled analysis of all three trials, late miscarriage and preterm birth occurred in significantly fewer women who received metformin (18 of 397 women, 5%) versus placebo (40 of 399 women, 10%) (OR, 0.43; 95% CI, 0.23 - 0.79; P = .004).

Pre-pregnancy Metformin for Women With PCOS Trying to Conceive?

And the editorialists note differences in the 222 women (28%) who were already receiving metformin versus the other women.  

Data "hidden" in the appendix suggest that "gestational metformin treatment reduced the incidence of late miscarriage and preterm delivery when given in the absence of pre-study metformin treatment (OR, 0.33; P = .001), but not in the presence of pre-study metformin treatment (1.00, 0.29 - 3.46; P = 1.00)," Ibáñez and de Zegher write.    

However, this observation would need to be confirmed.

Metformin had no effect on pre-eclampsia, pregnancy-induced hypertension, or the newborn's need for intensive care. 

There were also no substantial between-group differences in adverse events in the women or their offspring, and no serious adverse events were associated with metformin.

But No Effect of Metformin on Gestational Diabetes in Those With PCOS

"Perhaps the most remarkable finding was that metformin" — which in some countries is regarded as equivalent to insulin as a first-line therapy for gestational diabetes — "had no effect whatsoever on either the incidence or severity of gestational diabetes," Vanky said in a statement issued by the university.

So "there is no evidence to recommend metformin as prevention or treatment for gestational diabetes in women with PCOS," she said, although "it did reduce late miscarriage and preterm birth," the researchers summarize.

The study was funded by the Norwegian Research Council, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology. Authors Løvvik and Vanky and editorialists Ibáñez and de Zegher have reported no relevant financial disclosures. Disclosures of the other authors are listed with the article.

Lancet Diabetes Endocrinol. 2019;7:256-266, 242-243. Abstract, Commentary

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