Intergenerational effects— causation or confounding?

One can get a glimpse into the early origins of long-term reproductive health by assessing pubertal onset. Studies of pubertal development not only provide insight into reproductive health but may also have broader implications. Reproductive health outcomes and infertility in both men and women have come to be recognized as a window into the overall health of an individual—shedding light on risk for later chronic health outcomes. For example, semen quality in men is predictive of mortality and general health, and gynecologic conditions in women have been linked to metabolic disorders and cardiovascular disease. As such, it is vital that large prospective, intergenerational studies are conducted to identify early determinants of pubertal timing.

In this issue of Fertility and Sterility, Lauridsen et al. show an earlier pubertal onset among daughters, but not sons, born to mothers with gestational diabetes (GDM) (1). This is part of a growing body of evidence showing the importance of intrauterine exposures on offspring health and the potential for developmental programming to increase chronic disease risk throughout life. The results are intriguing and particularly relevant given the increasing prevalence of GDM and obesity. With the potentially large impact on population health it becomes even more imperative to figure out what these results mean, whether they represent true biologic effects or are artifacts of measurement issues or confounding, and how we can move forward to understand the role of intrauterine exposures on offspring health.

Confounding is always a concern in observational research, but for identifying intergenerational effects it is paramount given the long amount of time passing between conception and puberty and the multiple opportunities for exposures during childhood to influence pubertal timing. The authors importantly adjust for maternal prepregnancy body mass index and maternal age at menarche, as well as socioeconomic factors. However, the results were not adjusted for other comorbidities, such as maternal hypertensive disorders, or the shared environment of mothers and their offspring. Family dietary habits as well as exposure to hormones in milk products (2) may be relevant factors that could partially explain the earlier pubertal timing. Exposure to endocrine-disrupting chemicals may also be an important shared lifestyle factor as they have been shown to be associated with both early puberty and GDM. In the absence of data on these important confounders, sensitivity analysis techniques are available to evaluate the potential role of unmeasured confounding to provide some assessment of the robustness of the findings (3). Thorough and realistic sensitivity analyses can bolster causal inference of intergenerational effects and are needed to move the field forward.

Interestingly, in this study the differences in pubertal timing were only observed among daughters. Although the biologic rationale for an association in only one sex remains unclear, some suggestive evidence includes placentation differences and differences that sex hormones may play in regulating insulin. However, in this study the observed sex-specific findings by Lauridsen et al. could also be due to issues with measurement of puberty (1). Although self-assessment of sexual maturation may be necessary in large population-based studies, some researchers have noted less validity of this approach for assessment in boys, which may require physician assessment of testicular growth (4). In addition, while the children in this study were followed biannually through the end of puberty or the age of 18, beginning assessment at 11 years of age may be too late to fully capture initiation and duration of puberty given that puberty is starting earlier. In fact, the authors note that over half of the children had already started puberty before enrollment. Further, studies that start earlier in childhood and include biomarkers such as antimüllerian hormone (a marker of ovarian reserve), sex hormone–binding globulin (a marker associated with obesity and insulin resistance and also linked to early puberty and metabolic syndrome), and leptin (a factor hypothesized to be important for the initiation of puberty for both boys and girls) may clarify biologic relationships.

The authors also observed differences in findings between GDM and type 1 and type 2 maternal diabetes. It is unclear whether this is due to lack of power in the subgroups or biologic differences. Indeed, the authors suggested that the prodromal phases of type 1 and type 2 diabetes before pregnancy led to better glucose control and therefore potentially explain the lack of observed associations. However, some borderline associations with maternal type 2 diabetes on daughter’s pubertal timing were observed. Since there is shared etiology between GDM and type 2 diabetes, with pregnancy sometimes regarded as an unmasking of underlying beta cell function or susceptibility, future studies should also consider the effects of medication use and longitudinally measured prenatal biomarkers to further investigate the effects of maternal diabetes on offspring health.

Understanding the potential downstream effects of GDM on both the mothers and the offspring is becoming increasingly important as the prevalence of obesity and GDM continue to rise. Large longitudinal cohorts afford an incredible opportunity to evaluate hypotheses of intergenerational effects, although not without challenges. In the present context it is difficult to know whether the observed effects of GDM on pubertal development in girls are true biologic effects or are due to measurement error and confounding. Pubertal timing could potentially be an early marker of long-term reproductive and overall health, underscoring the need for careful and thoughtful analyses of intergenerational effects.