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Prepregnancy insulin resistance was associated with impaired fertility and increased pregnancy complications such as preeclampsia for women with polycystic ovary syndrome (PCOS), according to recent research. However, addressing insulin resistance through medications and lifestyle modifications before pregnancy might have improved reproductive success and reduced obstetric risks for women with PCOS.

PCOS was recently renamed as polyendocrine metabolic ovarian syndrome (PMOS).

A secondary analysis of data from the multicenter PPCOS II study showed that in 746 women with PMOS, higher prepregnancy insulin resistance was associated with decreased ovulation, lower pregnancy and live birth rates, and higher risk for gestational diabetes. But improvements in insulin resistance measures during treatment were associated with increased odds of clinical pregnancy and a 78% reduced risk for preeclampsia.

These results were published online in Obstetrics & Gynecology.

“It’s the first study that showed that if you decrease insulin resistance before pregnancy, there was less preeclampsia,” said senior study author Veronica Gomez-Lobo, MD, director of pediatric and adolescent gynecology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, in Bethesda, Maryland.

“The fact that it decreased preeclampsia, which is a huge problem in pregnancy and can have really significant morbidity and mortality, is really important to know, especially since we now have medications and things that can decrease insulin resistance,” she said, noting that clinicians generally are not routinely measuring insulin resistance but should be.

Researchers reviewed data from PPCOS II, a multicenter, double-blinded, randomized clinical trial that compared clomiphene citrate and letrozole for infertility treatment in women with PMOS. Insulin resistance was assessed at screening and end-of-treatment visits using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), the quantitative insulin sensitivity check index, and the glucose to insulin ratio. The primary outcome was clinical pregnancy, with secondary outcomes including gestational diabetes, preeclampsia, and preterm delivery.

Participants were stratified by HOMA-IR quartiles as follows: Q1 was up to the 25th percentile, Q2 was 26th-50th percentile, Q3 was 51st-75th percentile, and Q4 was above the 75th percentile.

In the 746 women whose data were analyzed (mean age, 28.9 years), baseline characteristics varied significantly across HOMA-IR quartiles. Those in higher quartiles had longer durations of infertility (median, 36 vs 18.5-24 months; P < .001) than women in lower quartiles. Participants who achieved clinical pregnancy had lower BMI, waist circumference, fasting glucose, and fasting insulin levels than those who did not conceive.

Fertility outcomes showed a significant inverse association with insulin resistance severity. Women in the HOMA-IR Q4 had significantly lower ovulation rates (73.8% vs 93.5%; P < .001), more delayed first ovulation (mean, 1.9 vs 1.5 cycles; P = .005), and lower clinical pregnancy rates (26.5% vs 36%; P < .001) than those in Q1. Live birth rates decreased progressively across quartiles, from 35.5% in the first quartile to 18.2% in the fourth. Miscarriage rates were similar across quartiles.

Neonatal birth weight did not differ significantly but showed a decreasing trend with increasing HOMA-IR quartiles. Preterm delivery (7.6% for Q1, 29.4% for Q4; P = .04), preeclampsia (7.6% for Q1, 22.9% for Q4; P =.06), and gestational diabetes (13.8% for Q1, 45.7% for Q4; P = .002) increased linearly across quartiles.

After adjusting for confounders, improvement in the HOMA-IR during treatment was associated with nearly a twofold increase in clinical pregnancy rates (adjusted odds ratio [aOR], 1.83; 95% CI, 1.13-2.96; P = .014). The fourth quartile of HOMA-IR at screening was associated with a higher risk for gestational diabetes (aOR, 5.24; 95% CI, 1.99-13.80; P < .001). Prepregnancy fasting glucose level at or above 110 mg/dL was a strong predictor of gestational diabetes (aOR, 40.07; 95% CI, 4.89-327.96; P < .001).

Improvement in the HOMA-IR also was associated with a reduced risk for preeclampsia (aOR, 0.21; 95% CI, 0.06-0.73; P = .01).

The study suggests that insulin resistance is a modifiable risk factor with “meaningful clinical implications,” Gomez-Lobo and colleagues wrote. “From a clinical perspective, these data support the incorporation of metabolic optimization into prepregnancy care rather than deferring intervention until pregnancy is achieved.”

Most physicians don’t use the HOMA-IR because it is complicated, said Gomez-Lobo. “It’s really done more for research purposes.” But clinicians can easily check patients’ fasting glucose and insulin, “and that can give you a hint as to whether there’s insulin resistance,” she said.

“What I like about this study is it mimics something that I’ve advocated for some time, which is that we should be looking at preclinical insulin resistance, not waiting until somebody has hemoglobin A1c in the prediabetic range,” said Basma Faris, MD, an ob/gyn and an assistant professor in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology and Reproductive Science at the Icahn School of Medicine at Mount Sinai in New York City, who was not involved with the study.

The research validates the use of HOMA-IR as a clinical tool to identify those who are at risk, Faris said. Although the study did not provide cutoff numbers to indicate who has insulin resistance, “it came up with some really important conclusions, which are that prepregnancy insulin resistance is associated with fertility challenges and also pregnancy complications, but if you actually can intervene and improve the insulin sensitivity, you may actually have better success in terms of fertility treatment and decrease pregnancy risks.”

Faris, whose practice is focused on patients with PMOS, said patients with a new diagnosis of PMOS should have a HOMA-IR, which can be revisited periodically as interventions are made. Her practice uses “all the tools in the toolbox,” including nutrition and lifestyle changes and insulin-sensitizing medications such as metformin. Exercise can lower the amount of insulin produced and improve insulin sensitivity in skeletal muscles, she said.

“There’s a short-term benefit of exercise. There’s also a long-term benefit of exercise, and it’s one of the most powerful ways that we can improve insulin sensitivity,” she said.

Gomez-Lobo and Faris reported having no relevant financial disclosures.

Karen Blum is a freelance medical/science writer in the Baltimore area.