Ongoing research has revealed several insights into how fetal sex may influence not only the mother’s health during pregnancy and beyond, but also how it may influence the child’s health throughout life.
Four investigators reviewed the latest research related to Fetal Sex and Pregnancy Outcomes during a virtual symposium at the Scientific Sessions. The presentation can be viewed by registered meeting attendees at ADA2020.org through September 10, 2020. If you haven’t registered for the Virtual 80th Scientific Sessions, register today to access all of the valuable meeting content.
Samantha Ehrlich, PhD, Assistant Professor of Public Health at the University of Tennessee, studies the sex ratio of fetuses and infants, the various factors that may influence those ratios, and the role maternal diabetes may play.
“We’ve long seen a male bias at birth,” she said. “It’s remarkably consistent over time. In normal times, 51.3% of births are male.”
Research has shown the male bias at birth decreases when there are population level disruptions, including disasters and economic downturns, Dr. Ehrlich said. This phenomenon is known as the secondary sex ratio.
“There’s evidence to support that stressful experiences decrease the likelihood of delivering a male baby,” she said. “There are several mechanisms that have been put forward to explain the effect maternal stress has on the secondary sex ratio.”
Dr. Ehrlich shared results from a study looking at sex ratios at various stages of gestation. Researchers were able to estimate the sex ratio at conception, as well as the sex ratio trajectory across gestation.
“This study was unique in that it was among the first to suggest that the biased sex ratio we see at birth may result from an unbiased primary sex ratio at conception,” she said. “The data confirmed an unbiased 50/50 primary sex ratio at conception, so what happens in between to result in the male bias we see at birth? And where does maternal diabetes come in?”
Using a systematic review and metanalysis of 20 studies of almost 2.5 million mothers, Dr. Ehrlich reported that women carrying a boy have a 4% higher relative risk of gestational diabetes than those carrying a girl.
“However, a Lancet study from 1998 shows mothers that had insulin-dependent diabetes before conception had significant bias toward girls. Another study showed mothers with pre-pregnancy type 1 diabetes favored girls; however, mothers with pre-pregnancy type 2 had a sex ratio that favored boys,” said Dr. Ehrlich, noting that the data are in line with theories that suggest maternal stress at various points in gestation influence the sex ratio.
Building on the data Dr. Ehrlich shared, Claire Roberts, PhD, a placental biologist, reviewed research into how fetal sex influences maternal diabetes risk and other pregnancy complications, and the lifelong implications of those complications for the mother and child.
Dr. Roberts, Professor of Medicine and Public Health at Flinders University in Adelaide, Australia, said the first trimester placenta strongly influences pregnancy outcomes. At various times throughout gestation, the placenta can be influenced by environmental factors, she said. The placenta also makes the mother more insulin resistant in order to facilitate glucose transport.
“Pregnancy is a physiological stress test for the mother,” Dr. Roberts said. “It increases risk for blood clots, increases insulin resistance, increases inflammation, and increases weight gain. Every organ is affected.”
Dr. Roberts also reviewed data on maternal risk factors for adverse outcomes, including nonmodifiable factors such as fetal sex. The data show that the fetal genome affects outcomes.
“The conclusion is there is a higher cardiovascular and metabolic load for the mother carrying a male fetus. Male fetal sex was associated with term preeclampsia and with gestational diabetes,” she said.
“The placenta is more than just a conduit,” Dr. Roberts continued. “The complexity of its multiple functions and the myriad factors that influence it have made it difficult to understand the mechanisms by which the placenta programs the fetus and impacts maternal health. Clearly, fetal—hence placental—sex makes a difference to cardiovascular and metabolic adaptations in the mother that may have lifelong consequences, particularly in women already at high risk.”
Grace Huang, MD, MSc, Assistant Professor of Medicine at Harvard Medical School, reviewed data on the role of maternal androgens in adult metabolic syndrome.
“Based on our data, we found that higher levels of maternal bioactive androgens are associated with development of metabolic syndrome in adult offspring—an effect that was significant in female but not among male offspring,” she said.
Dr. Huang said of the five metabolic syndrome criteria, higher levels of maternal bioactive androgens were specifically associated with increased risk for hypertension among female but not male offspring.
“Our findings suggest that programming of adult cardiovascular risk by androgens may have early fetal origins that is sex-dependent,” she said. “Perhaps our data suggest that younger premenopausal women born to mothers with higher androgen levels may be a risk for cardiovascular disease and may be a key target for early screening and intervention.”
Susan Ozanne, PhD, Professor of Developmental Endocrinology at Cambridge University in Cambridge, United Kingdom, reviewed sex differences in metabolic programming by maternal obesity—specifically how the sex of the fetus may influence how it responds to an in utero obesogenic environment.
“The prevalence of obesity is not slowing down,” Dr. Ozanne said. “An estimated 35.6% to 47.9% of teenage girls in the United States are now obese. That’s a particular concern because we know the teenage girls of today will be the mothers of tomorrow.”
While it’s been known that obesity during pregnancy has immediate detrimental consequences for mother and baby, Dr. Ozanne said there’s now growing evidence of long-term effects in the offspring, including increased risk of obesity, cardiovascular disease, insulin resistance, and type 2 diabetes.
“There’s strong evidence to suggest that this transmission of poor cardiometabolic health from mother to child doesn’t simply reflect the transmission of obesogenic genes from mother to child but is related to epigenetic processes that arise in utero,” she said.
In addition, some data suggest male offspring may respond differently than female offspring to a suboptimal in utero environment.
“While there’s not evidence for sex differences in all outcomes we looked at, there is strong evidence that some parameters do differ in their response, particularly in relation to the glucose tolerance test,” Dr. Ozanne said. “Females may be better at protecting themselves from a suboptimal in utero environment. Males generally display a detrimental phenotype at a younger age compared to females.”
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