Review Examines Relationship Between Gestational Diabetes and Offspring Fertility

A review recently published in Endocrinology offers some new insights on how maternal obesity-associated gestational diabetes (GDM) affects the reproductive health of offspring, discussing possible mechanisms, the latest perceptions, and highlighting areas that need further investigation.

The review, by Niharika Sinha, PhD; Gretchen Lydia Walker; and Aritro Sen, PhD, all of Michigan State University in East Lansing, point out that women with obesity have a higher risk of developing GDM than normal-weight women, and that GDM affects 7% of pregnancies in the United States and 10% of pregnancies worldwide, and is becoming more prevalent as the obesity rate rises among women of reproductive age.

And while there has been a lot of focus on the effect of prenatal hyperglycemic environment and offspring health, specifically on the development of obesity, type 2 diabetes, and metabolic dysfunctions, there are very limited studies on the fertility and reproductive health of offspring born from women with hyperglycemia during pregnancy, the authors write. “Moreover, the understanding of how obesity and the GDM-associated adverse in utero prenatal environment reprograms the fetus (or fetal tissues) that predispose the offspring to various disease conditions is still poorly understood,” they continue. “Similarly, the underlying mechanism of the sexual dimorphism observed in GDM offspring with respect to manifestation of disease condition(s) later in life needs further investigation.”

For this review, the authors examined evidence from various animal models and human epidemiological studies to offer molecular insight and understanding of how epigenetic reprogramming of genes culminates in reproductive dysfunction and the development of subfertility or infertility later in adult life.

The review covers a lot, including the two-hit phenomenon, in which the adverse prenatal environment associated with GDM acts as the “first hit” that reprograms and sensitizes the offspring ovary (or the hypothalamus-pituitary-gonadal axis) to dietary (high-fat diet/high-fat, high-sugar) stress later in life. The HFD/HFHS diet acts as a “second-hit” later in life, accelerating and/or aggravating the reproductive dysfunction in the offspring. The authors write that animal studies of this phenomenon found that in utero programming can also have a transgenerational effect. “For example, studies have shown that subsequent generations of obese/hyperglycemic women are predisposed to metabolic diseases, even though they are not directly exposed to the metabolic insult,” they write. “Future studies are needed to establish whether similar transgenerational effects on reproductive health are associated with GDM.”

And again, the review points to areas that need further studies. For example, in the conclusion, the authors write that long-term prognosis of reproductive health of offspring from GDM pregnancy in human cohorts is needed to establish a connection between maternal health and sex-specific offspring, since reproductive dysfunction is a concern for men and women whose mothers experienced maternal hyperglycemia.

“Changes in epigenetic marks may be an early event in the pathogenesis and progression of various disorders,” they continue. “Thus, studies on mechanisms of epigenetic modifications can contribute to our understanding of long-term effects of in utero exposure and shed light on disease prevention/treatment.”

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