Genetic Associations with Gestational Duration and Spontaneous Preterm Birth

Massachusetts Medical Society, NEJM, 2017


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.

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.

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.

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.)

Foxd1 specific gene found to have key role in recurrent miscarriages

Possible miscarriage gene found

Scientists said they had linked mutations in a specific gene with an increased risk of recurrent miscarriages, offering hopes of better diagnosis and treatment for affected women.


Recurrent spontaneous abortion (RSA) is a common cause of infertility, but previous attempts at identifying RSA causative genes have been relatively unsuccessful. Such failure to describe RSA aetiological genes might be explained by the fact that reproductive phenotypes should be considered as quantitative traits resulting from the intricate interaction of numerous genetic, epigenetic and environmental factors.

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans, The Royal Society Publishing, 19 October 2016.

Image James St. John.

Here, we studied an interspecific recombinant congenic strain (IRCS) of Mus musculus from the C57BL6/J strain of mice harbouring an approximate 5 Mb DNA fragment from chromosome 13 from Mus spretus mice (66H-MMU13 strain), with a high rate of embryonic resorption (ER). Transcriptome analyses of endometrial and placental tissues from these mice showed a deregulation of many genes associated with the coagulation and inflammatory response pathways. Bioinformatics approaches led us to select Foxd1 as a candidate gene potentially related to ER and RSA. Sequencing analysis of Foxd1 in the 66H-MMU13 strain, and in 556 women affected by RSA and 271 controls revealed non-synonymous sequence variants. In vitro assays revealed that some led to perturbations in FOXD1 transactivation properties on promoters of genes having key roles during implantation/placentation, suggesting a role of this gene in mammalian implantation processes.

Supplemental progesterone may not help for repeated miscarriage

Progesterone May Not Lower Risk of Repeated Miscarriage

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

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.

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.

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.

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.

Women who experienced a stillbirth almost five times more likely to suffer same tragedy again

Risk of recurrent stillbirth: systematic review and meta-analysis

Women who experience a stillbirth in their initial pregnancy have a higher risk of stillbirth in a subsequent pregnancy. Even after adjusting for potential confounding factors, the increased risk remains. Risk of recurrent unexplained stillbirth is largely unstudied,  evidence about this remains controversial. Roman Soto image.

2015 Study Abstract

To determine the risk of recurrent stillbirth.

Systematic review and meta-analysis of cohort and case-control studies.

Data sources
Embase, Medline, Cochrane Library, PubMed, CINAHL, and Scopus searched systematically with no restrictions on date, publication, or language to identify relevant studies. Supplementary efforts included searching relevant internet resources as well as hand searching the reference lists of included studies. Where published information was unclear or inadequate, corresponding authors were contacted for more information.

Study selection
Cohort and case-control studies from high income countries were potentially eligible if they investigated the association between stillbirth in an initial pregnancy and risk of stillbirth in a subsequent pregnancy. Stillbirth was defined as fetal death occurring at more than 20 weeks’ gestation or a birth weight of at least 400 g. Two reviewers independently screened titles to identify eligible studies based on inclusion and exclusion criteria agreed a priori, extracted data, and assessed the methodological quality using scoring criteria from the critical appraisal skills programme. Random effects meta-analyses were used to combine the results of the included studies. Subgroup analysis was performed on studies that examined unexplained stillbirth.

13 cohort studies and three case-control studies met the inclusion criteria and were included in the meta-analysis. Data were available on 3 412 079 women with pregnancies beyond 20 weeks duration, of who 3 387 538 (99.3%) had had a previous live birth and 24 541 (0.7%) a stillbirth. A total of 14 283 stillbirths occurred in subsequent pregnancies, 606/24 541 (2.5%) in women with a history of stillbirth and 13 677/3 387 538 (0.4%) among women with no such history (pooled odds ratio 4.83, 95% confidence interval 3.77 to 6.18). 12 studies specifically assessed the risk of stillbirth in second pregnancies. Compared with women who had a live birth in their first pregnancy, those who experienced a stillbirth were almost five times more likely to experience a stillbirth in their second pregnancy (odds ratio 4.77, 95% confidence interval 3.70 to 6.15). The pooled odds ratio using the adjusted effect measures from the primary studies was 3.38 (95% confidence interval 2.61 to 4.38). Four studies examined the risk of recurrent unexplained stillbirth. Methodological differences between these studies precluded pooling the results.

The risk of stillbirth in subsequent pregnancies is higher in women who experience a stillbirth in their first pregnancy. This increased risk remained after adjusted analysis. Evidence surrounding the recurrence risk of unexplained stillbirth remains controversial.

Sources and more information
  • Risk of recurrent stillbirth: systematic review and meta-analysis, thebmj, 2015;350:h3080, 24 June 2015.
  • Women with history of stillbirth at ‘high risk of another’, NHS News, June 26 2015.

Pregnancy Apps: where is the Reset Option for Miscarriages?

A plethora of pregnancy apps promise answers and support during this life-changing time…

I was preparing a post overview about pregnancy apps, when I came across a review that I found of circumstance for DES Daughters and DES Grand Daughters:

Pregnant_woman_cell_phone image
A plethora of pregnancy apps promise answers and support during this life-changing time…
Okay, sounds great, but where is the reset option for miscarriages?

It was an awesome app while I was pregnant but at 10 weeks 3 days at our first US we found out I am miscarrying. This is very emotionally painful for anyone who has to go through this. This app just made it worse, there is no “report a miscarriage” button or even a reset button. When I tried to erase this pregnancy the app even pops up a message saying “you must have at least one baby entered in the app” this message alone made me tear up and say “well thanks, ya I know I don’t have a baby anymore thanks a lot webmd” now I’ll just have to wait for the continued email update of my pregnancy and opt out that way, causing more pain. please make some changes to the app to make this an easier transition for moms who experience miscarriages. Thanks

Many DES-exposed women have experienced miscarriages, and even recurrent miscarriages… Some of us want to have kids but are struggling or unable to…
Sadly for many DES daughters having their own children is not possible!
Read more about DES pregnancy risks and studies about DES and pregnancy.

Blog Post Sources

The Big Lie

Fertility, Motherhood and the Reality of the Biological Clock

A candid assessment of the pros and cons of delayed motherhood

The-Big-Lie book cover image
Watch @DES_Journal diaporama and health books album on Flickr.  The Big Lie, a candid assessment of the pros and cons of delayed motherhood

Biology does not bend to feminist ideals and science does not work miracles. That is the message of this eye-opening discussion of the consequences of delayed motherhood. Part personal account, part manifesto, Tanya Selvaratnam recounts her emotional journey through multiple miscarriages after the age of 37. Her doctor told her she still “had time,” but Selvaratnam found little reliable and often conflicting information about a mature woman’s biological ability (or inability) to conceive.

Beyond her personal story, the author speaks to women in similar situations around the country, as well as fertility doctors, adoption counselors, reproductive health professionals, celebrities, feminists, journalists, and sociologists. Through in-depth reporting and her own experience, Tanya Selvaratnam urges more widespread education and open discussion about delayed motherhood in the hope that long-lasting solutions can take effect. The result is a book full of valuable information that will enable women to make smarter choices about their reproductive futures and to strike a more realistic balance between science, society and personal goals.

More information
On Flickr®

When a Mom becomes her own Daughter’s Surrogate at 58 Years Old

Julia is carrying her daughter’s daughter!

I'm carrying my daughter's daughter! Grandmother, 58, is 32-year-old daughter's surrogate after she suffered a DOZEN failed pregnancies
Personal Stories

A Utah grandmother became a surrogate mother to give her daughter and son-in-law the baby they so desperately wanted.
Julia Navarro, the 58-year-old grandmother, is carrying her granddaughter for her 32-year-old daughter Lorena McKinnon who struggled through three years of failed pregnancies.

When one potential surrogate dropped out, Lorena’s mother Julia Navarro stepped up to volunteer.

At 58, she had to go through three months of hormone treatment to get her body ready for baby. The embryo took on first try and Julia is now just weeks away from being a grandmother for the first time.

Read I’m carrying my daughter’s daughter! Grandmother, 58, is 32-year-old daughter’s surrogate after she suffered a DOZEN failed pregnancies, The Daily Mail, 7 January 2014.  Find out more about Fertility – IVF – Pregnancy – Recurrent Miscarriages – Surrogacy.

Sadly for many DES daughters having their own children is not possible! Many of us who have experienced miscarriages, want to have kids but are struggling or unable to…

What is recurrent pregnancy loss (RPL)?

2016: ASRM has updated their fact sheet to include DES as a cause of recurrent pregnancy loss

Recurrent Pregnancy Loss PATIENT’S FACT SHEET
ASRM is a non-profit organization devoted to advancing knowledge and expertise in reproductive medicine including infertility, menopause, and sexuality

Recurrent pregnancy loss is a disease distinct from infertility, defined by two or more failed pregnancies. When the cause is unknown, each pregnancy loss merits careful review to determine whether specific evaluation may be appropriate. After three or more losses, a thorough evaluation is warranted. Although approximately 25% of all recognized pregnancies result in miscarriage, less than 5% of women will experience two consecutive miscarriages, and only 1% experience three or more. Couples who experience recurrent pregnancy loss may benefit from a medical evaluation and psychological support.

The American Society for Reproductive Medicine includes:

  • Genetic/Chromosomal Causes
  • Age
  • Hormonal Abnormalities
  • Metabolic Abnormalities
  • Uterine Abnormalities
  • Antiphospholipid Syndrome
  • Thrombophilias
  • Male factor
  • Unexplained

No explanation is found in 50% to 75% of couples with recurrent pregnancy losses. Here’s an explanation: the chance of miscarriages increases if a women has been exposed to DES, synthetic estrogens, BPA, Endocrine Disruptors…  ! ! !

A problem with the shape of a woman’s uterus might be a cause for pregnancy loss. Causes for abnormal shape of the uterus can be genetic or exposure before birth to medications such as diethylstilbestrol (DES).

The American Society for Reproductive Medicine, Revised 2016.
Full Patient Fact Sheet: What is recurrent pregnancy loss (RPL)?

Related posts

DES Daughters

DES daughters have a higher risk of recurrent miscarriages.
If you know or think you may have been exposed to DES it’s important to inform your doctor and gynaecologist.

More DES DiEthylStilbestrol Resources

Women with Recurrent Miscarriages

Endometrial Stromal Cells of Women with Recurrent Miscarriage Fail to Discriminate between High- and Low-Quality Human Embryos

Endometrial Stromal Cells of Women with Recurrent Miscarriage Fail to Discriminate between High- and Low-Quality Human Embryos
PLOSmedicine, the leading weekly Open-Access medical journal

More than ten percent of clinical pregnancies end in miscarriage. Recurrent miscarriages (RM), defined as three or more consecutive miscarriages, is experienced by 1–2% of couples that try to conceive. Since the prevalence of RM is higher than what would be expected by probability alone, it is likely to indicate specific aetiologies in affected women. Known causes include fetal genetic abnormalities, uterine abnormalities, antiphospholipid syndrome and thrombophilic disorders. However, in more than 50% of cases, no cause is identified.

Increasing evidence suggests that some women may experience RM when ‘super-receptive’ endometrium allows embryos of low viability to implant, presenting as a clinical pregnancy before miscarrying.

Full study: Endometrial Stromal Cells of Women with Recurrent Miscarriage Fail to Discriminate between High- and Low-Quality Human Embryos, PLOSone, 25 July 2012

Analysis: Super-Fertile Women May Have More Miscarriages
LiveScience, 27 August 2012

Related: Understanding why some Women have repeated Miscarriages

DES daughters have a higher risk of recurrent miscarriages.
If you know or think you may have been exposed to DES it’s important to inform your doctor and gynaecologist.

More DES DiEthylStilbestrol Resources

Understanding why some Women have repeated Miscarriages

“Crucial” new recurrent miscarriage insight

'Crucial' new recurrent miscarriage insight
Losing several pregnancies in a row causes incredible psychological distress and anguish

Fertility scientists say they have made a “crucial breakthrough” – that “steroids shouldn’t be given to all” – in understanding why some women have repeated miscarriages.

Read Crucial’ new recurrent miscarriage insight
by James Gallagher, BBC News Health and Science, 12 Sept 2013.

DES daughters have a higher risk of recurrent miscarriages.
If you know or think you may have been exposed to DES it’s important to inform your doctor and gynaecologist.

More about DES pregnancy risks – read DES studies on fertility and pregnancy.