Neonatal malformations and hormone therapy during pregnancy

Antenatal DES exposure and cardiovascular malformations

Abstract

The use of pharmacological treatment during pregnancy has always been extremely controversial, especially if the drugs involved are sex hormones, such as diethylstilbestrol.

The percentage of congenital malformations attributable to hormonal therapy during pregnancy is 3%; the period of maximum susceptibility to teratogenic agents is between the 3rd-10th week of gestation, or the period of organogenesis.

The 1st reported case of congenital malformation due to hormonal therapy during pregnancy goes back to 1957; since then the literature has published more on this subject.

One of the most important studies was done in 1977 by Heinonen on a group of 50,282 pregnant women; 1042 had been treated with sex hormones. 19 infants, or 18.2/1000, had cardiovascular defects. Among the remaining 49,240 patients there were 385 cardiovascular malformations, or 7.8/1000.

The problem is still far from being resolved; it is up to the individual physician to give the best possible advice, after careful consideration of the clinical situation of every pregnant patient.

Reference

  • Neonatal malformations and hormone therapy during pregnancy, Minerva ginecologica, NCNI PubMed, PMID: 7290498, 1981 Jul-Aug.
  • Featured image asianage.
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Cardiovascular birth defects and antenatal exposure to female sex hormones

The New England journal of medicine, 1977

Abstract

In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000).

Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000).

Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000).

After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.

Reference

  • Cardiovascular birth defects and antenatal exposure to female sex hormones, NCNI PubMed, PMID: 830309, 1977 Jan 13.
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Hysteroscopic enlargement metroplasty for T-shaped uterus

24 years’ experience at the Strasbourg Medico-Surgical and Obstetrical Centre (CMCO)

These T-shaped uteruses are most commonly observed in patients who were exposed in utero to diethylstilbestrol (DES). DES is a nonsteroidal synthetic oestrogen that was marketed in France between 1948 and 1977 and prescribed to almost 200,000 women to prevent various obstetrical complications. The number of female infants exposed in utero to DES in France is estimated at 80,000. It was shown to be ineffective for these obstetrical indications in 1953 but its prescription was banned in France only in 1977, long after it had been established that this treatment was harmful: it is associated with an increased risk of clear-cell adenocarcinoma of the vagina. In addition to its cancer-inducing risk, this treatment has been found to cause uterine malformations (in particular, T-shaped uterus) and Fallopian tube dysfunction, with a reduced fertility and increased risk of miscarriage and premature delivery.

Abstract

STUDY QUESTION
What is the impact of hysteroscopic enlargement metroplasty for T-shaped uterus on the live birth rate?

SUMMARY ANSWER
Performing enlargement metroplasty appears to improve the obstetrical prognosis and fertility in patients with a T-shaped uterus.

WHAT IS KNOWN ALREADY
T-shaped uterus is linked to an excess of myometrium in the uterine walls giving rise to a subcornual constriction ring which causes dysmorphism and hypoplasia of the uterine cavity. It is commonly associated with infertility or a sequence of repeated miscarriages.

STUDY DESIGN
Single-centre observational cohort study in 112 patients who underwent enlargement metroplasty for T-shaped uterus between 1992 and 2016 in a Strasbourg university hospital centre.

MAIN RESULTS
The mean age of patients was 33.2; they had been attempting to conceive on average for 56 months for subfertile patients and 42.2 months for infertile patients. Prior to surgery, patients had succeeded in becoming pregnant 161 times, i.e. a mean gravidity of 1.4 pregnancies. For subfertile patients the mean gravidity was 2.67. Mean parity was 0.04. In the overall population, one hundred pregnancies occurred following enlargement metroplasty. The live birth rate increased in a statistically significant manner following enlargement metroplasty: 4 (2.5%) vs. 60 (60%), p < 0.05. In parallel, the miscarriage rate was statistically reduced: 126 (78.3%) vs. 22 (22%), pnull< .05. Intraoperative complications were 1 case of cervical laceration (0.9%) and 1 case of false passage (0.9%). Subsequent pregnancies remained at risk of miscarriage (22%) and premature delivery (20%) but not extra uterine gestation. Delivery took place by Caesarean section in 61% of cases. In the subgroup of infertile patients, the live birth rate was also markedly increased and 49% of pregnancies which occurred were spontaneous.

LIMITATIONS
This study was descriptive and retrospective.

WIDER IMPLICATIONS
These results are consistent with those in the literature. Hysteroscopic enlargement metroplasty is now a well-established technique with few complications but which should nevertheless be reserved for symptomatic patients.

References

  • Hysteroscopic enlargement metroplasty for T-shaped uterus: 24 years’ experience at the Strasbourg Medico-Surgical and Obstetrical Centre (CMCO), European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed PMID: 29804025, 2018.
  • Image copyright © Pr P-J Weiller.
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Demographic, lifestyle, and reproductive risk factors for ectopic pregnancy

DES Daughters have a much higher risk of EP,
Fertility and sterility, 2018

Abstract

OBJECTIVE
To evaluate the relationship between demographic, lifestyle, and reproductive factors and the risk of ectopic pregnancy (EP).

DESIGN
Prospective cohort.

SETTING
United States.

PATIENT(S)
Nurses’ Health Study II cohort comprising 41,440 pregnancies from 22,356 women.

INTERVENTION(S)
Demographic, lifestyle, and reproductive factors self-reported in 1989 then updated every 2 years. Multivariable log-binomial regression models with generalized estimating equations were used to estimate adjusted risk ratios (aRR).

MAIN OUTCOME MEASURE(S)
Ectopic pregnancy.

RESULT(S)
Incident EP was reported in 411 (1.0%) pregnancies. Former and current smokers had 1.22 (95% confidence interval [CI], 0.97-1.55) and 1.73 (95% CI, 1.28-2.32) times, respectively, the risk of EP compared with never smokers. The risk of EP 10 years after quitting was similar to never smokers (aRR 0.90; 95% CI, 0.60-1.33). Women consuming ≥10 g/day of alcohol had 1.50 (95% CI, 1.08-2.09) times the risk of EP compared with never consumers. In utero exposure to diethylstilbestrol (aRR 3.55; 95% CI, 2.51-5.01), earlier initiation of oral contraceptives (aRR 2.64; 95% CI, 1.70-4.09 for <16 years vs. never), intrauterine device use (aRR 3.99; 95% CI, 2.06-7.72), or history of infertility (aRR 3.03; 95% CI, 2.48-3.71) or tubal ligation (aRR 16.27; 95% CI, 11.76-22.53) also were associated with a higher risk of EP.

CONCLUSION(S)
Women who were current or former smokers, consumed ≥10 g/day of alcohol, were exposed to diethylstilbestrol in utero, initiated oral contraceptives at earlier than age 16 years (which may be a marker of riskier sexual behaviors), and who had a history of infertility, intrauterine device use, or tubal ligation had a higher risk of EP.

Reference

  • Demographic, lifestyle, and reproductive risk factors for ectopic pregnancy, Fertility and sterility, NCBI PubMed PMID: 30503132, 2018 Dec.
  • Featured image : Transvaginal ultrasound images of an intrauterine pregnancy (IUP) and ectopic pregnancy. (A) An IUP at 6 weeks. The central dark area is the intrauterine gestational sac and within the sac is a circular ringed structure that is the yolk sac. The small oval structure below the yolk sac is the fetus. (B) An ectopic pregnancy. To the right of the image is the normal uterus and to the left of the uterus is the doughnut-shaped ectopic pregnancy – credit BMJ Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians & Gynaecologists.
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Possible links to the development of obesity

Diethylstilboestrol—A long-term legacy, School of Biosciences, 2012

Abstract

Obesity and type 2 diabetes levels have risen over the past century, the incidence being more marked in recent years. Both these conditions have adverse consequences and are significant public health issues. Even pets, laboratory animals and urban rats have increased in average body weight over the past decades. These trends in both humans and animals are not necessarily explicable by diet and exercise; prenatal exposure to environmental triggers (‘obesogens’), has been suggested as a possible factor, particularly to oestrogenic compounds such as DES, bisphenol A and phthalates.

Adipose tissue acts as an endocrine organ, releasing
hormones controlling appetite and energy metabolism and is a site for oestrogen synthesis. This mechanism, found in both animals and human beings, ensures a link between the food supply and the capacity to reproduce, since starvation and pregnancy are not a good combination. When low doses of DES were administered to mice pre- or neo-natally, the adult animals gained weight with altered expression of obesity-related genes and altered hormone levels. There was no difference in the number of fat cells but the cells already present increased in size.

Although it is not known at present whether DES acts as an obesogen in man, raised urinary concentrations of other environmental chemicals, such as phthalates, have been linked with the increased body weight and insulin resistance which lead to ‘metabolic syndrome’.

References

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Obesogenic endocrine disruptors and obesity

Myths and truths, Archives of Toxicology, 2017

Abstracts

Obesogenic endocrine disruptors, also known as obesogens, are chemicals potentially involved in weight gain by altering lipid homeostasis and promoting adipogenesis and lipid accumulation. They included compounds to which human population is exposed over daily life such as pesticides/herbicides, industrial and household products, plastics, detergents and personal care products.

The window of life during which the exposure happens could lead to different effects. A critical window is during utero and/or neonatal period in which the obesogens could cause subtle changes in gene expression and tissue organization or blunt other levels of biological organization leading to increased susceptibility to diseases in the adulthood.

“…the exposure to diethylstilbestrol (DES) during neonatal period resulted in increased body weight.
Interestingly, this efect was specifc for females and did not appear until 4–6 months. In male mice, the exposure to DES was accompanied by an increased number of adipocytes in the gonadal fat pad of mice.” …

… “…the prenatal exposure to DES resulted in childhood obesity at age of 7 and increased risk of adult obesity.”

Some of the reasons for this increased sensitivity include the lack of the protective mechanisms that are available in adult such as DNA repair mechanisms, a competent immune system, detoxifying enzymes, liver metabolism and the blood/brain barrier still not fully functional in the fetus or newborn.

The mechanisms of action of obesogens lay on their ability to increase the number and/or the size of the adipocytes and to alter appetite, satiety and food preferences.

The ability of obesogens to increase fat deposition results in an increased capacity for their own retention due to their lipophilic properties; thus prolonging the exposure and increasing the detrimental metabolic consequences.

References

  • Obesogenic endocrine disruptors and obesity: myths and truths, Archives of Toxicology, NCBI PubMed PMID: 28975368, 2017 Nov.
  • Image credit .
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Endocrine Disruptors and Obesity

DES exposure during the neonatal period predisposes to obesity in mice at 4–6 months of age

2017 Study Abstract

Purpose of Review
The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure.

Recent Findings
Recent findings demonstrate that such endocrine-disrupting chemicals, termed “obesogens”, can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period.

An especially sensitive time frame for exposure to obesogens has been found to be either prior to birth in utero or in the neonatal period. Neonatal mice exposed to the synthetic oestrogen DES have also been reported to have increased body weight. This featured image shows a representative photomicrograph at 4–6 months of age of control and neonatal DES-treated female mice: the mice were treated on days 1–5 of age with 1 μgDES/kg body weight/day, and obesity was evident by 4–6 months of age. This serves to demonstrate the obesogenic consequences of exposure to a potent oestrogen at an inappropriate developmental stage.

Summary
In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.

References

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Prenatal diethylstilbestrol exposure and risk of obesity in adult women

Journal of developmental origins of health and disease, 2015

Study Abstract

Diethylstilbestrol DES is a non-steroidal estrogen that was commonly prescribed during pregnancy from the late 1940s to 1971. A potent endocrine disruptor, prenatal DES exposure has been linked with reproductive tract malformations, adverse pregnancy outcomes, cancer, infertility and earlier menopause. DES was used for years as a growth promoter in animal production. Some animal studies suggest that prenatal DES exposure is associated with obesity and metabolic disturbances.

Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between DES and adult obesity, weight gain from age 20 to mid-life, central adiposity and height among 2871 prenatally exposed and 1352 unexposed women between 23 and 52 years of age(median 41.5) at baseline in 1994. DES exposure status was confirmed by prenatal medical record review. We used multivariable log-binomial models to calculate risk ratios (RRs) for obesity in 2006, and linear regression to calculate mean differences in body mass index, weight gain, waist circumference and height.

The adjusted RR for DES and obesity was 1.09 [95% confidence interval (CI): 0.97, 1.22],

  • and RRs were 1.23 (CI: 1.07, 1.42)
  • and 1.05 (CI: 0.91, 1.20) for low and high estimated total DES dose, respectively, compared with no exposure.
  • DES-exposed women gained slightly more weight than unexposed women [mean difference, 0.70 kg (CI: -0.27, 1.66)].

This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity.

From the “DES Follow-Up Study”

Some studies in animals suggest that prenatal DES exposure is linked to obesity and to abnormal metabolism of glucose. Using data from the National Cancer Institute DES Follow-Up Study, we evaluated the association between prenatal DES exposure and adult obesity. To do this, we looked at factors like weight gain, body mass index (BMI – a measure of body fatness) and waist circumference among 2,871 women exposed to DES before their birth and also among 1,352 who were not exposed to DES.

We conducted statistical analyses to see if exposed women had a higher risk of being obese, and whether there were differences between exposed and unexposed women in BMI, weight gain, waist circumference and height. Other factors possibly related to obesity such as age, educational level and whether the woman smoked, were accounted for in the analysis. We also considered whether the mother smoked during the pregnancy with the daughter, the daughter’s use of postmenopausal hormones, her menopausal status, and how many children she had.

DES-exposed women had a 9% greater overall risk of being obese compared with unexposed women, but these findings could have been due to chance. Compared with unexposed women, the risk of obesity was 23% greater for women who were exposed prenatally to a low DES dose and 5% greater for women exposed to a high dose. Overall, most women gained around 30 pounds between the ages of 20 and the mid-fifties, and DES-exposed women gained slightly more (about 1.5 pounds) than those not exposed, although this was not statistically significant. Height and waist circumference were very similar among DES- exposed and unexposed women. This study suggests that prenatal DES exposure may be associated with a small increase in adult obesity but not the larger differences that have been observed in some animal studies.

References

  • Prenatal diethylstilbestrol exposure and risk of obesity in adult women, Journal of developmental origins of health and disease, NCBI PobMed 25697972, 2015 Jun.
  • Image credit Sandra Cohen-Rose and Colin Rose..
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Etiology of obesity : Environmental Estrogen DES

DES exposure effects in mouse models replicate human findings

Abstract from “EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals”, 2015

Obesity requires eating more food and/or consuming less energy. To date, most of the obesity studies in animals are based in the observation that EDC exposures induce weight increases and changes in adiposity, as well as affecting hormones and adipokines involved in the regulation of food intake and energy expenditure. There are fewer studies related to how EDCs disrupt energy balance. Therefore, more studies are necessary to gain mechanistic insights into the role that EDCs play in the etiology of obesity.

Studies of rodents that were prenatally, neonatally, or perinatally exposed to EDCs support the obesogen hypothesis. For example, DES exposure effects in mouse models replicate human findings. DES is an estrogenic chemical that binds with high affinity to the ERs, ERα and ERβ, which play an important role in adiposity regulation as well as central and peripheral energy balance. Developmental exposure to DES in mice induced adipogenesis and caused mice to become obese or overweight.

Other chemicals classified as environmental estrogens, particularly BPA, produced similar effects. Perinatal exposure to low doses of BPA caused increased body weight; adiposity; alterations in blood levels of insulin, leptin, and adiponectin; as well as a decrease in glucose tolerance and insulin sensitivity in an age-dependent manner.

References

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Environmental Estrogens, Obesity, and Metabolism

Perinatal exposure to DES and latent development of high body weight and obesity

Abstract from “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement”, 2009

White adipose tissue metabolism is under the control of the sympathetic nervous system and is modulated by hormones including sex steroids. The impact of environmental estrogens on adipose tissue may be through direct modulation of lipogenesis, lipolysis, and adipogenesis, or indirect by affecting food consumption and leptin secretion targeting the central nervous system or lipid homeostasis in liver.

The estrogenic pharmaceutical chemical DES illuminates the relationship between perinatal exposures and latent development of high body weight and obesity. Moreover, there is a complex relationship between the concentration of estrogen to which pregnant animals are exposed and the weight of the offspring in adulthood. Specifically, according to a recent experiment by Newbold et al., mice neonatally exposed to DES experience increased body weight in adulthood associated with excess abdominal body fat. Interestingly, the dose of DES determines the chronic manifestation of the observed alterations, with high doses leading to initially decreased body weight and a peripubertal “catch-up” and low doses causing an increase in weight detectable only in adulthood. Moreover, the timing is important because gestational administration in rodents results in the offspring’s low birth weight, an unchanged metabolic characteristic throughout life. Along with an increase in body fat stores, the adipokines leptin and adiponectin, IL-6 (an inflammatory marker), and triglycerides were all elevated in DES-exposed mice.

An in vitro study using a culture system of 3T3-L1 preadipocytes showed that 4-nonylphenol and BPA stimulated lipid accumulation, accelerating their differentiation to mature adipocytes in a time- and concentration-dependent way. The underlying mechanism appeared to involve up-regulation of gene expression involved in lipid metabolism and adipocyte differentiation. In the second part of the experiment, fat accumulation was observed in human hepatocellular carcinoma cell lines exposed to those endocrine disruptors. These findings are consistent with previous in vitro studies using mouse fibroblast cell lines in which a link between environmental chemicals including nonylphenol, BPA, and genistein in the development of body weight imbalance was suggested.

References

  • Full study (free access) : Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, Endocrine Society endocrine reviews, PMC2726844, 2009 Jun.
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