Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

Massachusetts Medical Society, NEJM, 2017

Abstract

BACKGROUND
Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations.

METHODS
We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10−8) or an association with suggestive significance (P<1.0×10−6) in the discovery set.

RESULTS
In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome.

CONCLUSIONS
In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.)

Could taking Vitamin B3 prevent miscarriages and birth defects ?

Claims that niacin prevents miscarriages in humans grossly exaggerated

The “blockbuster breakthrough to prevent birth defects and miscarriages” releaseHistoric Discovery Promises to Prevent Miscarriages and Birth Defects Globally – describes a “double discovery” made by researchers at the Victor Chang Cardiac Research Institute in Australia that, theoretically, will greatly reduce the number of birth defects and miscarriages worldwide.

The premise rests on the discovery that genetic mutations causing a deficiency in one type of molecule (Nicotinamide adenine dinucleotide, or NAD) can lead to birth defects in humans. The researchers then tested the impact of vitamin B3 (or niacin) supplements on mouse models engineered to have the same mutations who were deficient in NAD. They found that the mice who had higher levels of niacin were less likely to have offspring with birth defects.

The news release hid the fact that the vitamin supplements (referring only to “preclinical models”) were tested in mice, and not humans. But most worrying was the use of extremely sensationalist language prevalent throughout the release. The language was so overblown that it could give false hope to women without properly describing the limits of the research.

continue reading Claims that niacin prevents miscarriages in humans grossly exaggerated, healthnewsreview, August 14, 2017.

  • NAD Deficiency, Congenital Malformations, and Niacin Supplementation, N Engl J Med 2017; 377:544-552, DOI: 10.1056/NEJMoa1616361, August 10, 2017.
  • Vitamin profile of 563 gravidas during trimesters of pregnancy, Journal of the American College of Nutrition, NCBI PubMed PMID: 11838885, 2002 Feb.
  • Featured image credit @HealthNewsRevu.

Endocrine disrupting chemicals and endometriosis

Endocrine disruptors and reproductive disorders

Abstract

Endometriosis is an estrogen dependent gynecologic disease with lasting implications for many women’s fertility, somatic health, and overall quality of life.

Growing evidence suggests that endocrine disrupting chemicals (EDCs) may be etiologically involved in the development and severity of disease.

We weigh the available human evidence focusing on EDCs and endometriosis, restricting to research that has individually quantified chemical concentrations for women, included a comparison group of unaffected women, and used multivariable analytic techniques.

Endocrine disrupting chemicals and endometriosis, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 959–966, September 15, 2016.

laparoscopic surgery for endometriosis: fuschia_foot.

Evidence supporting an environmental etiology for endometriosis includes metals/trace elements, dioxins, and other persistent organic pollutants, as well as nonpersistent chemicals, such as benzophenones and phthalates.

To address the equivocal findings for various EDCs, future research directions for filling data gaps include

  1. use of integrated clinical and population sampling frameworks allowing for incorporation of new diagnostic modalities;
  2. the collection of various biologic media, including target tissues for quantifying exposures;
  3. study designs that offer various comparison groups to assess potentially shared etiologies with other gynecologic disorders;
  4. and novel laboratory and statistical approaches that fully explore all measured EDCs for the assessment of mixtures and low dose effects and the use of directed acyclic graphs, and supporting causal analysis for empirically delineating relationships between EDCs and endometriosis.

Environmental exposure to endocrine-disrupting chemicals and miscarriage

The role of environmental toxins in reproduction

Abstract

Establishment of early pregnancy is the result of complex biochemical interactions between the decidua and blastocyst.

Any alteration in this chemical dialogue has the potential to result in adverse pregnancy outcomes including miscarriage.

Sporadic miscarriage is the most common complication of pregnancy and can be caused by multiple factors.

While the most common cause of miscarriage is genetic abnormalities in the fetus, other contributing factors certainly can play a role in early loss.

Environmental exposure to endocrine-disrupting chemicals and miscarriage, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 941–947, September 15, 2016.

Miscarriage Tattoo: stacylynn.

One such factor is environmental exposure, in particular to endocrine-disrupting chemicals, which has the potential to interfere with endogenous hormone action.

These effects can be deleterious, especially in early pregnancy when the hormonal milieu surrounding implantation is in delicate balance.

The purpose of this paper is to review the current evidence on the role of environmental toxins in reproduction.

Morphologic and molecular changes in the placenta: what we can learn from environmental exposures

Environmental exposures: pregnancy, placenta, and miscarriage

Abstract

In mammals, the extraembryonic tissues, which include the placenta, are crucial for embryonic development and growth.

Because the placenta is no longer needed for postnatal life, however, it has been relatively understudied as a tissue of interest in biomedical research.

Recently, increased efforts have been placed on understanding the placenta and how it may play a key role in human health and disease.

Morphologic and molecular changes in the placenta: what we can learn from environmental exposures, Fertility and Sterility, Volume 106, Issue 4, Pages Pages 930–940, September 15, 2016.

Pregnancy image: kulden.

In this review, we discuss two very different types of environmental exposures: assisted reproductive technologies and in utero exposure to endocrine-disrupting chemicals.

We summarize the current literature on their effects on placental development in both rodent and human, and comment on the potential use of placental biomarkers as predictors of offspring health outcomes.

Environmental influences on reproductive health: the importance of chemical exposures

Environmental exposures: pregnancy, placenta, and miscarriage

Abstract

Chemical exposures during pregnancy can have a profound and life-long impact on human health.

Because of the omnipresence of chemicals in our daily life, there is continuous contact with chemicals in food, water, air, and consumer products.

Consequently, human biomonitoring studies show that pregnant women around the globe are exposed to a variety of chemicals.

In this review we provide a summary of current data on maternal and fetal exposure, as well as health consequences from these exposures.

Environmental influences on reproductive health: the importance of chemical exposures, Fertility and Sterility, Volume 106, Issue 4, Pages 905–929, September 15, 2016.

Pregnancy image: Stefan Pasch.

We review several chemical classes, including polychlorinated biphenyls, perfluoroalkyl substances, polybrominated diphenyl ethers, phenols, phthalates, pesticides, and metals.

Additionally, we discuss environmental disparities and vulnerable populations, and future research directions.

We conclude by providing some recommendations for prevention of chemical exposure and its adverse reproductive health consequences.

Outdoor air pollution and human infertility

Outdoor air pollution and reproduction, 2016

Abstract

Air pollution is a current research priority because of its adverse effects on human health, including on fertility.

However, the mechanisms through which air pollution impairs fertility remain unclear.

In this article, we perform a systematic review to evaluate currently available evidence on the impact of air pollution on fertility in humans.

Several studies have assessed the impact of air pollutants on the general population, and have found reduced fertility rates and increased risk of miscarriage.

Outdoor air pollution and human infertility: a systematic review, Fertility and Sterility, Volume 106, Issue 4, Pages 897–904, September 15, 2016.

Image: Environmental Research Group, King’s College London, London Air Quality Network.

In subfertile patients, women exposed to higher concentrations of air pollutants while undergoing IVF showed lower live birth rates and higher rates of miscarriage.

After exposure to similar levels of air pollutants, comparable results have been found regardless of the mode of conception (IVF versus spontaneous conception), suggesting that infertile women are not more susceptible to the effects of pollutants than the general population.

In addition, previous studies have not observed impaired embryo quality after exposure to air pollution, although evidence for this question is sparse.

Stillbirth: the overall trend masks big variations in rates across the UK

Fifteen babies a day in UK are stillborn or die within month of birth

Fifteen babies are dying every day in the UK from stillbirth, during labour or within four weeks of being born, according to a new report.

Perinatal Mortality Surveillance Reports for UK Births, MBRRACE-UK.

There has been slight fall in the rates of stillbirths and neonatal deaths in the UK compared with rates in 2013 which continues the downward trend in rates from 2003 onwards. However, the overall trend masks big variations in death rates across the UK from 4.1 to 7.1 per 1,000 births. Women from the poorest backgrounds and black and Asian mothers run a higher risk than others that their baby will die in the womb or soon after birth.

Fifteen babies a day in UK are stillborn or die within month of birth, the Guardian, 17 May 2016.

These variations remain despite the fact that a novel method of analysis introduced by MBRRACE-UK has been used to take into account aspects of case-mix to allow ‘fairer’ comparisons of mortality rates between services provided for high risk and low risk pregnancies. The new analytical method which divides the figures for Trusts and Health Boards into five groups based on the services they deliver, also takes into account the random variation in rates which can occur because of the small number of births which occur in some areas.

Talking Toxic Chemicals: EDCs Expert Scientists urge Prevention

A global problem that need a global solution: time to act on a global scale

Video published on 1 Dec 2015 by PRHE UCSF‘s channel

Exposure to toxic environmental chemicals among women and men of reproductive age is ubiquitous and threatens healthy human reproduction.

The International Federation of Gynecology and Obstetrics (FIGO) World Congress attendees learned more about the science that links exposure to toxic environmental chemicals to poor health outcomes and what physicians and health care providers can do to prevent harm

More information

Supplemental progesterone may not help for repeated miscarriage

Progesterone May Not Lower Risk of Repeated Miscarriage

progesterone-and-placebo
Distribution of gestational age according to study group assignment. Image @NEJM.
Giving progesterone to women who have had three or more miscarriages does not increase their chances of carrying a pregnancy to term, according to a new study.

2015 Study Abstract

BACKGROUND
Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain.

METHODS
We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation.

RESULTS
A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.

CONCLUSIONS
Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages.

Sources and more information
  • Progesterone May Not Help Women With History of Miscarriages, Study Finds, NYtimes, NOV. 25, 2015.
  • A Randomized Trial of Progesterone in Women with Recurrent Miscarriages, The New England Journal of Medicine, DOI: 10.1056/NEJMoa1504927, November 26, 2015.
  • Progesterone May Not Lower Risk of Repeated Miscarriage, livescience, NOV. 25, 2015.