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.)

Clear and direct new Evidence that Autism begins during Pregnancy

New clues suggesting autism could be detected before birth

Researchers found new clues suggesting autism could be detected before birth ; their study gives clear and direct new evidence that autism begins during pregnancy. The researchers analyzed 25 genes in post-mortem brain tissue of children with and without autism. These included genes that serve as biomarkers for brain cell types in different layers of the cortex, genes implicated in autism and several control genes. Patches of unusual cell development was found in 10 samples.

More info and Videos
  • Video by UC San Diego Health System, Published on 26 Mar 2014.
  • In their small, explorative study – Patches of Disorganization in the Neocortex of Children with Autism – researchers found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism.
  • Read Patches of Cortical Layers Disrupted During Early Brain Development in Autism, University of California, San Diego, News Release March 26, 2014
  • Read Patches of Disorganization in the Neocortex of Children with Autism, N Engl J Med 2014; 370:1209-1219 March 27, 2014DOI: 10.1056/NEJMoa1307491
  • Watch more videos on our YouTube channel.

Cancer Risk among IVF Children before they reach 15 Years of Age

According to a recent cohort study, children who were conceived with in vitro fertilization IVF have no increase in the overall risk of #cancer – developed before 15 years of age – as those conceived naturally

Cancer Risk among Children Born after Assisted Conception
The New England Journal of Medicine is the world’s leading medical journal and website

Dr Alastair Sutcliffe – specialist in both general and adolescent paediatrics – and his team tracked more than 100,000 children conceived by IVF from 1992 to 2008 and compared the cancer rates in those children with those observed across the whole population of children in UK.

According to the cohort study, children who were conceived with in vitro fertilization have no increase in the overall risk of cancer – developed before 15 years of age – as those conceived naturally.

Study Abstract

METHODS
We linked data on all children born in Britain between 1992 and 2008 after assisted conception without donor involvement with data from the United Kingdom National Registry of Childhood Tumours to determine the number of children in whom cancer developed before 15 years of age. Cohort cancer rates were compared with population-based rates in Britain over the same period, with stratification for potential mediating and moderating factors, including sex, age at diagnosis, birth weight, singleton versus multiple birth, parity, parental age, type of assisted conception, and cause of parental infertility.
Full Text of Methods…

RESULTS
The cohort consisted of 106,013 children born after assisted conception (700,705 person-years of observation). The average duration of follow-up was 6.6 years. Overall, 108 cancers were identified, as compared with 109.7 expected cancers (standardized incidence ratio, 0.98; 95% confidence interval [CI], 0.81 to 1.19; P=0.87). Assisted conception was not associated with an increased risk of leukemia, neuroblastoma, retinoblastoma, central nervous system tumors, or renal or germ-cell tumors. It was associated with an increased risk of hepatoblastoma (standardized incidence ratio, 3.64; 95% CI, 1.34 to 7.93; P=0.02; absolute excess risk, 6.21 cases per 1 million person-years) and rhabdomyosarcoma (standardized incidence ratio, 2.62; 95% CI, 1.26 to 4.82; P=0.02; absolute excess risk, 8.82 cases per 1 million person-years), with hepatoblastoma developing in 6 children and rhabdomyosarcoma in 10 children. The excess risk of hepatoblastoma was associated with low birth weight.
Full Text of Results…

CONCLUSIONS
There was no increase in the overall risk of cancer among British children born after assisted conception during the 17-year study period. Increased risks of hepatoblastoma and rhabdomyosarcoma were detected, but the absolute risks were small. (Funded by Cancer Research UK and others.)

Cancer Monitoring by identifying tiny circulating Bits of Tumor DNA

Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Circulating Tumor DNA posted by Jamie ColbertWhat if instead of looking for circulating tumor surrogates, we actually tried to identify circulating bits of actual tumor?

One method to do this is to assay for pieces of circulating tumor DNA.

Read Circulating Tumor DNA posted by Jamie Colbert.

Abstract

BACKGROUND
The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.

METHODS
We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

RESULTS
Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

CONCLUSIONS
This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.)

Sources – the NEJM new proof-of-concept study:
Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer, March 28, 2013.

2011 DES Study Media Coverage

Covering DiEthylStilbestrol worldwide drug disaster

2011 DES study media coverage imageOver the past few days, there has been an unprecedented flurry of media attention on DES related health issues. This come after a long-awaited DES study was published on October 06th in the New England Journal of Medicine  (MEJM) which carefully documents elevated risk for women exposed to diethylstilbestrol (DES in short) for a host of medical problems including cancer, infertility, ectopic pregnancies, preterm labour, …. As yet, there has been no coverage from the UK press despite a call on UK journalists to make this information available to the public.

MEDIA COVERAGE IN ENGLISH

Banned pregnancy drug impacts fetal immune system – Jerusalem Post, Oct 12, 2011

DES prescribed to women in the 1940s, 1950s, and 1960s to prevent miscarriages, had serious, untoward effects in daughters of these women, including the development of a rare type of cancer of the uterus. There has been renewed interest in light of a recent report in the New England Journal of Medicine documenting lifelong health complications facing daughters of women given DES.

Diethylstilbestrol in utero affects immune system of the fetus – News Medical, Oct 11, 2011

Reproductive tissues are not the only targets of DES. The immune system is also known to be a target for estrogens. Dr. S. Ansar Ahmed, professor of immunology at Virginia Tech, led a National Institutes of Health study in the 1990s on how exposure to DES in utero affects the immune system later in life using a mouse model.

Suit Claims Drug Leads To Breast Cancer, Victim Speaks Out – 10TV.com, Oct 10, 2011

One woman spoke out on Monday after learning a drug she was given before she was born had life threatening consequences for her as an adult.

Risky pregnancy drug raised daughters’ cancer odds – News Channel 9 ABC, Oct 10, 2011

A drug that millions of pregnant women took decades ago to prevent miscarriage and complications has put their daughters at higher risk for breast cancer and other health problems that are showing up now, a new federal study finds.

Pregnancy drug used decades ago raises cancer risk in offspring: studySouth Asia Mail

A drug that millions of pregnant women took decades ago to prevent miscarriage and complications has put their daughters at higher risk for breast cancer and other health problems that are showing up now, a new U.S. federal study finds.

Anti-miscarriage drug victim backs campaignTheMaitlandMecury.com.au, Oct 10, 2011

A woman given the anti-miscarriage drug diethylstilbestrol supports a call for a government-backed education campaign to highlight the dangers of exposure to the medication

Podcast 133: Over 50 years later, DES’ adverse effects continue
Oct 8, 2011 – Joe Elia – Audio interview with Dr Hoover, author of the NEJM DES Study

In a follow-up to the DES drug disaster, researchers (including one of the authors of the original reports in the early 1970s) have examined reproductive health in a large cohort of women exposed to DES in utero.  Their results were published last week in the New England Journal of Medicine, and they show that the health effects apparently continue beyond the reproductive years

Study adds to furor over pregnancy drug linked to daughter’s ailmentsThe Daily.com, Karen Keller – Oct 7, 2011

The DES breast cancer lawsuit, together with a bombshell New England Journal of Medicine article published yesterday — which suggests that infertility is twice as common and that breast cancer risk is nearly doubled in “DES daughters” — has ushered in a new awareness of the drug after decades when its lingering effects went under the radar.

Women Exposed to Synthetic Estrogen Diethylstilbestrol (DES) in the Womb Face Increased Cancer Risk, Study Finds
Science Daily – Oct 6, 2011 Hayden Donnell

A large study of the daughters of women who had been given DES, the first synthetic form of estrogen, during pregnancy has found that exposure to the drug while in the womb (in utero) is associated with many reproductive problems and an increased risk of certain cancers and pre-cancerous conditions.

Women exposed to diethylstilbestrol in the womb face increased cancer risk – EurekAlert (press release) – ‎Oct 5, 2011‎

Beginning in 1940, diethylstilbestrol, known as DES, was used clinically to prevent certain complications of pregnancy. In the 1950s, clinical studies showed DES was ineffective for this purpose. In the late 1960s, an unusual occurrence of a rare

Women Exposed To Hormone In Utero Face Lifelong Health Problems – NPR (blog) – Richard Knox – ‎Oct 5, 2011‎

Back in the 1940s, ’50s and ’60s, doctors prescribed a hormone called diethylstilbestrol, or DES, to millions of pregnant women in the unfounded belief it could prevent miscarriages. Smack in the middle of this period, the deformed thalidomide babies

Synthetic estrogen use leads to health problems
New Zealand Herald

Diethylstilbestrol was prescribed in the mistaken belief it could reduce pregnancy complications, but the daughters of the women who took it are still living with its effects

Health Risks for Women Exposed to DES in Utero
Doctors Lounge – HealthDay News – ‎Oct 5, 2011‎

Women who were exposed in utero to diethylstilbestrol have a higher lifetime risk for several adverse health outcomes, according to a study published in the Oct. 6 issue of the New England Journal of Medicine.

DES Exposure Linked to Lifetime Risk of Adverse Outcomes
Family Practice News Digital Network – Mary Ann Moon – ‎Oct 5, 2011‎

In-utero exposure to diethylstilbestrol was associated with a high lifetime risk of a broad spectrum of adverse outcomes in a follow-up study of patients now in their 40s, 50s, and 60s, according to a report in the Oct. 6 issue of the New England

Effects of DES Exposure Follow Women for Decades
MedPage Today – Charles Bankhead – ‎Oct 5, 2011‎

Explain that the teratogenic effects of diethylstilbestrol have continued to exact a heavy toll throughout the lifetime of women who were exposed to the drug in utero. Point out that DES-exposed women

Pregnancy Drug is Causing Grown Daughters to Face Risk of Cancer, Infertility – AboutLawsuits.com

The daughters of women given diethylstilbestrol (DES), a drug commonly used decades ago to prevent miscarriages and birth defects, are showing high rates of breast cancer and infertility problems, according to recent research.

DES daughters (and bummmer, I’m one) have some raised health risks – Los Angeles Times – ‎Oct 5, 2011‎

Millions of women alive today were exposed to a chemical called DES – diethylstilbestrol – in their mother’s uterus. The chemical, an early synthetic estrogen, was administered to some pregnant women before 1971 to help reduce risk of miscarriages and

Prenatal exposure to synthetic estrogen ups cancer risk in daughters – TruthDive

Washington, Sept 06 (ANI): Daughters of women who took a synthetic estrogen called diethylstilbestrol (DES) while pregnant decades ago are now facing a greater chance of being infertile and developing cancer, according to a large study by the National

Pregnancy drug found to cause fertility woes, cancers
Vancouver Sun

The study in Thursday’s New England Journal of Medicine examines the daughters of females exposed in the womb to diethylstilbestrol (DES), which was prescribed in the mistaken belief it could reduce certain complications of pregnancy.

Anti-miscarriage drug DES causes multi-generational health problems – Macleans.ca

by macleans.ca on Thursday, October 6, 2011 12:56pm – 0 Comments DES (or diethylstilbestrol), an anti-miscarriage drug widely used between 1940 and 1970, has been linked to health problems—including breast cancer, infertility, difficult pregnancies and

“DES” increases women infertility and cancers
Empowered News

DES or diethylstilbestrol have been prescribed to pregnant women for the belief that it will reduce complications during pregnancy. The National Cancer Institute researchers and scientists have been following about 6500 women including those exposed to

Health Woes Still Strike Women Exposed to Banned Pregnancy Drug – U.S. News & World Report – ‎Oct 5, 2011‎

Women whose mothers were given the drug diethylstilbestrol (DES) during pregnancy are at increased risk for fertility problems and cancer as they age, new research shows. This study from the US National Cancer

DES cancer link sparks campaign call
Sydney Morning Herald – ‎Oct 5, 2011‎

A study published by the New England Journal of Medicine on Thursday found daughters of women who took diethylstilbestrol (DES) while pregnant face a greater chance of being infertile and developing a rare vaginal cancer.

DES linked to cancer, infertility
Sydney Morning Herald – ‎Oct 5, 2011‎

A study appearing in Thursday’s New England Journal of Medicine examines women exposed in the womb to diethylstilbestrol (DES), which was prescribed in the mistaken belief it could reduce certain complications of pregnancy. Researchers at the National

In Utero DES Exposure Hurt Daughters’ Health
CalorieLab Calorie Counter News – ‎Oct 5, 2011‎

A comprehensive study looking at the drug diethylstilbestrol (DES) that was widely used by pregnant women in Europe and the United States to prevent problems in pregnancy such as miscarriage and premature birth from the 1940s until the 1960s suggests

Fake Hormone For Pregnant Women Causes Real Cancer In Their Daughters – Jezebel

The Associated Press reports that the drug, an artificial form of estrogen called DES (diethylstilbestrol), was often prescribed to pregnant women in pill or cream form between 1940 and 1960. When it was discovered that the teenage daughters of women

DES Daughters: Banned Pregnancy Drug Linked to Infertility, Prematurity and Cancer – TIME – Bonnie Rochman

That drug was DES, or diethylstilbestrol, which was widely prescribed in the US beginning in 1940 to help stave off miscarriage — until 1971, when the US Food and Drug Administration decided that the drug doesn’t work and that it causes cancer.

Risky pregnancy drug raised daughters’ cancer odds
Coshocton Tribune

Diethylstilbestrol, or DES, widely was used in the United States, Europe and elsewhere from the 1940s through the 1960s to prevent miscarriage, premature birth, bleeding and other problems. Many companies made it as pills and creams.

Moms who took miscarriage drug DES have daughters with higher risk for breast … – New York Daily News

DES, or diethylstilbestrol, was widely used in the United States, Europe and elsewhere from the 1940s through the 1960s to prevent miscarriage, premature birth, bleeding and other problems. Many companies made and sold it as pills, creams and other

Prenatal exposure to synthetic estrogen ups cancer risk in daughters – BioScholar News

Daughters of women who took a synthetic estrogen called diethylstilbestrol (DES) while pregnant decades ago are now facing a greater chance of being infertile and developing cancer, according to a large study by the National Cancer Institute in the

Pregnancy drug raised daughters’cancer odds
Post-Tribune – Marilynn Marchione – ‎Oct 5, 2011‎

Risks for other health problems vary. DES, or diethylstilbestrol, was widely used in the United States, Europe and elsewhere from the 1940s through the 1960s to prevent miscarriage, premature birth, bleeding and other problems.

Pregnancy drug raised daughters’ cancer odds
Salt Lake Tribune – Marilynn Marchione – ‎Oct 5, 2011‎

AP A drug that millions of pregnant women took decades ago to prevent miscarriage and complications has put their daughters at higher risk for breast cancer and other health problems that are showing up now, a new federal study

Pregnancy Drug proving a risk for children – WREG

Millions of women in the 1940s, 50s, and 60s who wanted to make sure they had safe pregnancies, took a drug called DES. The women likely didn`t know it then, but that drug came with side effects that are surfacing 50 plus years later in their children.

Today’s Top Medical Stories for October 6, 2011
OzarksFirst.com – ‎Oct 6, 2011‎

Millions of women exposed to the first synthetic form of estrogen are at risk of cancer . A National Institutes of Health study followed daughters of pregnant women given synthetic estrogen called DES from the 1940’s to the 1970s.

Drugs women took years ago may affect daughters
WNDU-TV

A drug millions of pregnant women took decades ago may increase health risks among their daughters. An estimated four million Americans were exposed to DES, a synthetic estrogen prescribed to prevent miscarriages and pregnancy complications,

Risky pregnancy drug raised daughters’ cancer odds
KTUU – ‎Oct 5, 2011‎

A new federal study finds that a drug that millions of pregnant women took decades ago to prevent miscarriage and complications has put their daughters at higher risk for breast cancer. Cancer and other health problems are showing

Drug To Prevent Miscarriage Increases Odds for Breast Cancer
Heal Blog (blog) – ‎Oct 5, 2011

by Art Writ, October 6th, 2011 Decades ago, women have taken a certain drug that lessens the risk of miscarriage. However, just recently, researchers have found out that the complications and side effects of this drug has placed their daughters at

MEDIA COVERAGE IN FRENCH

L’exposition fœtale au Distilbène accroît les risques de certains cancers – Le Monde – ‎6 oct. 2011‎

Les femmes exposées dans le ventre de leur mère au Distilbène, premier œstrogène de synthèse utilisé dès 1940, souffrent de nombreux problèmes de reproduction et sont soumises à un net accroissement du risque de certains cancers, selon une vaste étude

Distilbène : de nouveaux risques de cancers identifiés
Magic Maman – ‎6 oct. 2011‎

Une étude menée par les chercheurs de l’Institut National du Cancer américain publiée aujourd’hui dans le New England Journal of Medecine révèle de nouveaux effets négatifs liés à l’exposition intra-utérine au distilbène. En cause : des risques accrus

Les femmes exposées au Distilbène au stade foetal ont plus de problèmes de santé – Maxisciences – ‎6 oct. 2011‎

Une étude menée par des chercheurs de l’Institut national américain du cancer (NCI) montre que des femmes exposées au stade fœtal au Distilbène, un œstrogène de synthèse, souffrent aujourd’hui de problèmes de reproduction et sont davantage sujettes à

Filles du Distilbène : un risque accru de cancers
Terrafemina – ‎6 oct. 2011‎

Les résultats d’une vaste étude publiée aujourd’hui dans le New England of Medicine révèlent que les femmes exposées au Distilbène dans le ventre de leur mère sont soumises à un risque accru de cancer. Entre 1948 et 1976, 200 000 femmes ont été

Reproductive tissues are not the only targets of DES. The immune system is also known to be a target for estrogens. Dr. S. Ansar Ahmed, professor of immunology at Virginia Tech, led a National Institutes of Health study in the 1990s on how exposure to DES in utero affects the immune system later in life using a mouse model.

More DES DiEthylStilbestrol Resources