Mother and Child: Pregnancy Exposures Can Have Unintended Effects in Later Life for Both Offspring and Mother

Two studies from the all-virtual ENDO 2021 focused on how pregnancy is impacted by endocrine-disrupting chemicals. From both ends of the umbilical cord, research shows that both mothers and offspring feel the effects of these chemicals, sometimes for generations to come.

In 2009, the Endocrine Society’s first Scientific Statement on endocrine-disrupting chemicals (EDCs) was considered a long overdue wake-up call to the scientific community about the impacts of EDCs on health and disease. As the years have passed, an even larger body of research has emerged further demonstrating the effects of these disruptors in both animals in humans — especially during pregnancy — and how they can have far-reaching consequences, not only in the development and growth of the offspring, but often in future generations to come.

Two new studies from ENDO 2021 specifically address the impacts of EDCs during pregnancy on both the mother and the unborn. In the session, “In Utero Exposure to 17α-Hydroxyprogesterone Caproate May Contribute to Increasing Incidence Rates of Early-Onset Cancer,” Caitlin Murphy, PhD, MPH, discussed the synthetic progesterone 17-OHPC and how it can double the cancer risk in the offspring of mothers who took it during pregnancy. Laura N. Vandenberg, PhD, presented her mouse research study on propylparaben exposure during pregnancy and lactation which was shown to cause adverse effects on the mother. The study, “Exposure to propylparaben during pregnancy and lactation induces long-term alterations to the mammary gland in mice,” was also published in Endocrinology in March.

Generation Cancer

Murphy, an assistant professor at the University of Texas Southwestern Medical Center in Dallas, Texas, presented her team’s research on 17-alpha hydroxyprogesterone caproate (17-OHPC). As a cancer epidemiologist, Murphy wanted to understand why rates of certain cancers like colorectal and prostate cancer, for example, are increasing, especially in adults younger than 50 years. “An important observation we’ve made is that incidence rates have increased over time, but they also increase successively across generations, so we see an elevated risk of cancer among people who were born in the 1960s, or generation X,” Murphy says. “That got me thinking about what was going on at that time, in particular in early life that may have contributed to this generation’s risk of cancer many decades later.”

Using data from participants in the Child Health and Development Studies, women who received prenatal care between June 1959 and June 1967 in the Kaiser Foundation Health Plan in Oakland, Calif., the team began to examine the drugs given to women in pregnancy in the 50s and 60s and fairly quickly zeroed in on 17-OHPC, a drug prescribed to treat a range of gynecologic and obstetric conditions, including in pregnancy to prevent miscarriage. “We know the naturally occurring hormone progesterone does a lot to support and strengthen a pregnancy, so the belief was that delivering a synthetic form of it might help improve pregnancy-related outcomes,” Murphy explains.

17-OHPC has a similar regulatory and controversial history as diethylstilbestrol (DES), the synthetic estrogen also given to women during pregnancy during the mid 1900s. DES has since been withdrawn from the market and contraindicated in pregnant women because it increased the risk of clear cell adenocarcinoma and other cancers in female offspring in addition to other health consequences in both male and female offspring. “DES set the precedent that exposure to synthetic hormones are endocrine-disrupting chemicals (EDCs) and have serious health consequences for adults exposed in utero,” Murphy says.

“An important observation we’ve made is that incidence rates have increased over time, but they also increase successively across generations, so we see an elevated risk of cancer among people who were born in the 1960s, or generation X. That got me thinking about what was going on at that time, in particular in early life that may have contributed to this generation’s risk of cancer many decades later.”– Caitlin Murphy, PhD, MPH, assistant professor, University of Texas Southwestern Medical Center

The researchers used the California Cancer Registry to identify cancers diagnosed in the adult children of the Child Health and Development Studies cohort through 2018. “Sure enough, we found that same phenomenon — that the synthetic hormone 17-OHPC seems to cause endocrine disruption during early fetal development that may lead to cancer later in life,” Murphy says. For colorectal cancer, the risk is particularly elevated, an increase of nearly five times higher for exposed individuals compared to non-exposed individuals. For prostate cancer, that risk is more than three times higher. All told, among more than 18,751 live births, 954 cancer diagnoses were made in offspring ages 18 to 58 years, and 181 women received OHPC during pregnancy.

Mixed Evidence

Murphy and team also found that the risk of any cancer is doubled in these generation X adults. “This is clearly not a targeted kind of mechanism happening for one particular type of cancer, but many different cancers, meaning many different organ systems are susceptible to exposure to this drug in the womb,” Murphy says. “Our study presents really compelling evidence that events and exposures that happen during critical periods of growth and development really matter for your risk of developing cancer many decades later.”

In the 1970s, the U.S. Food and Drug Administration (FDA) issued statements that evidence showed 17-OHPC increased the risk of birth defects in exposed offspring and removed all of the pregnancy-related indications. “By the year 2000, the manufacturer asked that the FDA withdraw their approval because 17-OHPC was no longer being marketed or used,” Murphy says. Then, in 2011, a randomized trial showed that the drug may have some benefit in reducing preterm birth.

For an updated approval, the FDA required a confirmatory trial. Published in 2020, the PROLONG trial showed no reduction in neonatal morbidity or mortality. The FDA recommended withdrawing drug approval, but the drug sponsor appealed, and 17-OHPC was caught in regulatory limbo. In October 2020, the FDA proposed withdrawing the drug from the market, citing a lack of benefits. Nevertheless, under the trade name Makena, 17-OHPC continues to be prescribed and is marketed directly to women who have a history of preterm birth. In March 2021, The Lancet published a meta-analysis, “Role of progestogens in women at risk for spontaneous preterm birth: the final word?” showing that 17-OHPC reduced the risk of spontaneous preterm birth before 34 weeks for singleton pregnancies in women at high risk, and the questions surrounding this drug continue to swirl.

“There’s controversy in that some people are observing that this drug does have a benefit,” says Murphy, “but when we look at the randomized trials, clearly there is none. Something needs to be done to reconcile the mixed evidence.”

Propylparaben: Guilty Until Proven Innocent

While Murphy’s research focused on the offspring, Vandenberg’s study concentrates on the mother. An assistant professor at the School of Public Health, Division of Environmental Health Sciences, University of Massachusetts in Amherst, Mass., Vandenberg was intrigued by research done 20 years ago by Philippa Darbre who analyzed human breast tumor samples and found concentrations of parabens, especially near the axillae, suggesting a possible link between the chemical and cancer. Parabens are commonly used in personal care products like deodorant and have documented estrogenic effects.

What struck Vandenberg was that the logical next step was never taken — rodent studies. “We think of rodents as a sentinel species because they set up a warning sign,” she explains. “Breast cancer develops over decades, so to try to answer that question in humans is very complicated and very time intensive. It’s surprising that no one had even tried to look in rodents. In fact, I was shocked to realize how few studies from rodents have been done on propylparaben. We really are one of the first groups to be looking at it in the rodent and in the mammary gland in particular.”

“Part of the problem was, when do you look at the exposure and when do you look at the disease? What the rodent tells us is that we have to evaluate the exposure during the right period of life. What we are exposed to currently has nothing to do with what we may have been exposed to in utero — we’d have to ask our mothers.” – Laura N. Vandenberg, PhD, assistant professor, School of Public Health, Division of Environmental Health Sciences, University of Massachusetts, Amherst, Mass.

Although a clear association was not established with the Darbre series of studies between deodorant use and breast cancer, Vandenberg and team saw missed opportunities, not only with the use of rodents but also because they could control the period of exposure. “Part of the problem was, when do you look at the exposure and when do you look at the disease? What the rodent tells us is that we have to evaluate the exposure during the right period of life. What we are exposed to currently has nothing to do with what we may have been exposed to in utero — we’d have to ask our mothers,” Vandenberg says.

So, the team exposed mouse dams to a solution of propylparaben in corn oil in one of three doses: the lowest (20 µg/kg/day) approximated the intake of the 95th percentile of pregnant American women and the highest (10,000 µg/kg/day) represents the toxicological no-observed adverse-effect level for propylparaben. Exposures happened daily from pregnancy day 0 until lactation day 21. They were then untreated for five weeks to allow mammary gland involution. “Our question was, is propylparaben permanently changing the mammary gland? We endocrinologists expect the effects of hormones to be dependent on exposure to that hormone,” Vandenberg says. “When you take it away, the individual goes back to normal.”

That’s not what happened, however. After analyzing the mammary gland tissue from the euthanized mice, the researchers found that propylparaben exposure had impaired the remodeling of the mouse mammary gland that normally occurs during lactation and involution, reducing volume of mammary epithelium, thickness of periductal collagen, epithelial cell proliferation, and immune cell populations. In essence, propylparaben seemed to reverse the protective effects against breast cancer many believe to come from pregnancy.

“Mom Matters, Too”

This is yet another study building a body of evidence that EDCs are not behaving like normal hormones that can be “switched on or off.” And yet, as Vandenberg pointed out, the general public seems more concerned about the potential danger than the regulatory agencies. EDCs are extremely widely used in everything from personal care products and cosmetics to food packaging but have been comparatively poorly studied. The industry responded by labeling some products “paraben-free” so that individuals at least have an informed choice about what to put in their bodies.

“The regulatory agencies are almost sort of set up to say exposure isn’t a big deal until you prove that something is harmful, and I have a philosophical problem with that — that we treat chemicals as innocent until proven guilty,” Vandenberg says. Shouldn’t it be the opposite? Scientists will be the key to making this paradigm shift.

“From the endocrinology perspective, people are becoming really intrigued by this idea of how critical a period fetal development is during which EDCs can have unintended effects,” Vandenberg says. “Our study is expanding that vulnerable period to also really appreciate the fact that we can’t just worry about the fetus, we should also worry about the mom. We have not spent nearly enough attention thinking about how EDCs might affect their health. This study builds on work we have published in the last two or three years with some other chemicals that are saying exactly this: mom matters, too.”

Horvath is a freelance writer based in Baltimore, Md. She wrote about COVID-19’s impact on a variety of endocrine comorbidities in the June issue.