Ambient air pollution and the risk of pregnancy loss

Air pollution exposure in early pregnancy linked to miscarriage

Exposure to common air pollutants, such as ozone and fine particles, may increase the risk of early pregnancy loss, according to a new study.

2017 Study Abstract

Objective
To estimate the association of pregnancy loss with common air pollutant exposure. Ambient air pollution exposure has been linked to adverse pregnancy outcomes, but few studies have investigated its relationship with pregnancy loss.

Design
Prospective cohort study.

Setting
Not applicable.

Patient(s)
A total of 343 singleton pregnancies in a multisite prospective cohort study with detailed protocols for ovulation and pregnancy testing.

Intervention(s)
None.

Main Outcome Measure(s)
Timing of incident pregnancy loss (from ovulation).

Result(s)
The incidence of pregnancy loss was 28% (n = 98). Pollutant levels at women’s residences were estimated using modified Community Multiscale Air Quality models and averaged during the past 2 weeks (acute) and the whole pregnancy (chronic). Adjusted Cox proportional hazards models showed that an interquartile range increase in average whole pregnancy ozone (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.07–1.17) and particulate matter <2.5 μm (HR 1.13, 95% CI 1.03–1.24) concentrations were associated with faster time to pregnancy loss. Sulfate compounds also appeared to increase risk (HR 1.58, 95% CI 1.07–2.34). Last 2 weeks of exposures were not associated with loss.

Conclusion(s)
In a prospective cohort of couples trying to conceive, we found evidence that exposure to air pollution throughout pregnancy was associated with loss, but delineating specific periods of heightened vulnerability await larger preconception cohort studies with daily measured air quality.

More Information

  • Ambient air pollution and the risk of pregnancy loss: a prospective cohort study, Fertility and Sterility, dx.doi.org/10.1016/j.fertnstert.2017.09.037, November 16, 2017.
  • Air pollution exposure in early pregnancy linked to miscarriage, NIH study suggests, National Institutes of Health, news-releases, November 16, 2017.
  • Pregnancy loss featured image credit Heather Kittredge

IVF treatment : a healthy singleton delivery is best achieved by SET

Single-embryo transfer point – it is the way forward

In vitro fertilization (IVF) treatment in the United States is complicated by a high rate of multiple-gestation pregnancies. In 2014, the Society for Assisted Reproductive Technology reported that 23% of women <38 years of age with a pregnancy from their IVF treatment had a twin-gestation pregnancy. Although this is an improvement over past years, it remains an unacceptably high rate of twins, considering the medical risks and financial burdens associated with such pregnancies.

In this issue of Fertility and Sterility, Mersereau et al. have added strong support to the conclusion that single-embryo transfer (SET) is highly effective at reducing multiple-gestation birth rates: a 47% decrease with the use of SET compared with double-embryo transfer (DET). Furthermore, using data from their study and others, Mersereau’s team has led a revision of American Society for Reproductive Medicine committee opinion guidelines to unambiguously call for SET for women under the age of 38 years with a favorable prognosis for pregnancy. With the increasing weight of evidence and explicit professional guidelines, why is DET still so common in the United States?

In their article, Mersereau et al. report a comprehensive analysis of 10 years of national SET data, finding a 10%–15% reduction in live birth rate (LBR) with the use of SET. This reduction is not attractive to either physicians or patients, for whom IVF pregnancy rates matter a great deal. Indeed, we have shown that, despite education about the risks of twins after DET, most patients would still choose this option over SET, even with as little as a 10% drop in the LBR.

Yet we think that the 10%–15% difference in LBR may be an overestimate of the negative effect of SET on LBR, considering trends in current clinical IVF care. As reported, blastocyst transfers are becoming increasingly common, and SET live birth rates are higher with blastocysts than with cleavage-stage embryo. In fact, the LBR differences between DET and SET were still reduced, but only in the 6%–8% range, when looking at fresh blastocyst transfers in a first or second cycle. Even this may be an overestimate of the true difference between DET and SET, because higher pregnancy rates are seen when the single transferred embryo comes from a larger cohort of available embryos.

Thus, it is likely a false comparison to judge the success of SET with one or more embryos cryopreserved (at least two embryos in the cohort) against DET with one or more embryos cryopreserved (at least 3 embryos in the cohort). In a recent analysis of national IVF outcomes data, we strictly controlled for the size of the available cohort and found very similar pregnancy rates in younger good-prognosis patients undergoing elective SET versus DET on day 5–6.

We think that this trend of increasing blastocyst transfers combined with improvements in embryo selection techniques (such as preimplantation genetic screening) will result in further increases in SET pregnancy rates and allow clinics to more confidently offer SET with little to no impact on their clinic-specific pregnancy outcome. Despite continuing technical advances, however, it is likely that small but potentially significant LBR differences will persist between SET and DET if as a field we continue to report and emphasize pregnancy rates per transfer instead of cumulative pregnancy rates per fresh IVF cycle. As mentioned in Mersereau et al.’s paper, predictive models suggest that cumulative LBRs with the use of sequential SET are equal or superior to DET.

Further studies confirming this prediction will help to convince physicians, patients, and insurance providers of the benefits and feasibility of SET, even if this strategy requires additional transfers and a slightly longer time to pregnancy. A healthy singleton delivery should be the goal of all IVF cycles, and this is best achieved by SET.

The IUD (intrauterine device) would reduce the risk of cervical cancer

Intrauterine Device Use and Cervical Cancer Risk : A Systematic Review and Meta-analysis

A study shows that the possibility of developing cervical cancer could be reduced by a third by wearing the IUD. Image credit @magicmaman_com.

2017 Study Abstract

OBJECTIVE
To estimate the association between use of an intrauterine device (IUD) and risk of cervical cancer by subjecting existing data to critical review, quantitative synthesis, and interpretation.

DATA SOURCES
We searched PubMed, Web of Science, ClinicalTrials.gov, and catalogs of scientific meetings and abstracts, theses, and dissertations queried from inception through July 2016.

METHODS OF STUDY SELECTION
Examination of abstracts from 225 reports identified 34 studies with individual-level measures of use of an IUD and incident cervical cancer. By critically assessing the full text of these reports, independent reviewers identified 17 studies conducted without recognized sources of systematic error, of which 16 could be harmonized for meta-analysis.

TABULATION, INTEGRATION, AND RESULTS
Point and interval estimates of the association between use of an IUD and incident cervical cancer were extracted from original reports into a structured database along with key features of study design and implementation. A random-effects meta-analysis was implemented to quantitatively synthesize extracted estimates and assess likely influence of publication bias, residual confounding, heterogeneity of true effect size, and human papillomavirus prevalence and cervical cancer incidence in source populations. Women who used an IUD experienced less cervical cancer (summary odds ratio 0.64, 95% CI 0.53–0.77). Neither confounding by recognized risk factors nor publication bias seems a plausible explanation for the apparent protective effect, which may be stronger in populations with higher cervical cancer incidence.

CONCLUSION
Invasive cervical cancer may be approximately one third less frequent in women who have used an IUD. This possible noncontraceptive benefit could be most beneficial in populations with severely limited access to screening and concomitantly high cervical cancer incidence.

Pregnancy complications in patients with endometriosis

Prenatal exposure to estrogenic substances (such as DES) and environmental toxins (such as bisphenols) may increase the incidence of endometriosis in female offspring

Zullo et al. have done an extensive and thorough meta-analysis of the literature concerning endometriosis and pregnancy complications, one of the largest and most comprehensive studies to date.

Their systematic review and meta-analysis : endometriosis and obstetrics complications, provides further insight into endometriosis and pregnancy by combining the many heterogeneous studies on this topic, and it raises awareness of the many implications of endometriosis.

2017 Study Abstract

Objective
To evaluate the effect of endometriosis on pregnancy outcomes.

Design
Systematic review and meta-analysis.

Setting
Not applicable.

Patient(s)
Women with or without endometriosis.

Intervention(s)
Electronic databases searched from their inception until February 2017 with no limit for language and with all cohort studies reporting the incidence of obstetric complications in women with a diagnosis of endometriosis compared with a control group (women without a diagnosis of endometriosis) included.

Main Outcome Measure(s)
Primary outcome of incidence of preterm birth at <37 weeks with meta-analysis performed using the random effects model of DerSimonian and Laird to produce an odds ratio (OR) with 95% confidence interval (CI).

Result(s)
Twenty-four studies were analyzed comprising 1,924,114 women. In most of them, the diagnosis of endometriosis was made histologically after surgery. Women with endometriosis had a statistically significantly higher risk of preterm birth (OR 1.63; 95% CI, 1.32-2.01), miscarriage (OR 1.75; 95% CI, 1.29-2.37), placenta previa (OR 3.03; 95% CI, 1.50-6.13), small for gestational age (OR 1.27; 95% CI, 1.03-1.57), and cesarean delivery (OR 1.57; 95% CI, 1.39-1.78) compared with the healthy controls. No differences were found in the incidence of gestational hypertension and preeclampsia.

Conclusion(s)
Women with endometriosis have a statistically significantly higher risk of preterm birth, miscarriage, placenta previa, small for gestational age infants, and cesarean delivery.

Endometriosis, especially mild disease : a risk factor for miscarriages

Prenatal exposure to estrogenic substances (such as DES) and environmental toxins (such as bisphenols) may increase the incidence of endometriosis in female offspring

2017 Study Abstract

Objective
To investigate the prevalence of miscarriage in women with endometriosis (WwE) compared with disease-free control women (CW).

Design
Cross-sectional analysis nested in a retrospective observational study (n = 940).

Setting
Hospitals and associated private practices.

Patient(s)
Previously pregnant women (n = 268) within reproductive age in matched pairs.

Intervention(s)
Retrospective analysis of surgical reports and self-administered questionnaires.

Main Outcome Measure(s)
Rate of miscarriage, subanalysis for fertility status (≤12 vs. >12 months’ time to conception), endometriosis stages (revised American Society of Reproductive Medicine classification [rASRM] I/II vs. III/IV) and phenotypic localizations (superficial peritoneal, ovarian, and deep infiltrating endometriosis).

Result(s)
The miscarriage rate was higher in WwE (35.8% [95% confidence interval 29.6%–42.0%]) compared with CW (22.0% [16.7%–27.0%]); adjusted incidence risk ratio of 1.97 (95% CI 1.41–2.75). This remained significant in subfertile WwE (50.0% [40.7%–59.4%]) vs. CW (25.8% [8.5%–41.2%]) but not in fertile WwE (24.5% [16.3%–31.6%]) vs. CW (21.5% [15.9%–26.8%]). The miscarriage rate was higher in women with milder forms (rASRM I/II 42.1% [32.6%–51.4%] vs. rASRM III/IV 30.8% [22.6%–38.7%], compared with 22.0% [16.7%–27.0%] in CW), and in women with superficial peritoneal endometriosis (42.0% [32.0%–53.9%]) compared with ovarian endometriosis (28.6% [17.7%–38.7%]) and deep infiltrating endometriosis (33.9% [21.2%–46.0%]) compared with CW (22.0% [16.7%–27.0%]).

Conclusion(s)
Mild endometriosis, as in superficial lesions, is related to a great extent of inflammatory disorder, possibly leading to defective folliculogenesis, fertilization, and/or implantation, presenting as increased risk of miscarriage.

Valproate : le formulaire d’accord de soins utilisé seulement une fois sur deux

Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant

Plusieurs mesures ont été mises en place par l’ANSM depuis 2015 afin de réduire les risques liés à l’utilisation pendant la grossesse des médicaments contenant du valproate ou un dérivé (Depakine, Depakine Chrono 500, Micropakine, et génériques, Depakote, Depamide) et en particulier une démarche sécurisée de prescription et de délivrance. Cette démarche repose sur la présentation en pharmacie pour les patientes d’un formulaire d’accord de soin co-signé avec le médecin spécialiste associé à une ordonnance de ce spécialiste datant de moins d’un an. L’ANSM, en collaboration avec l’Ordre des pharmaciens, a demandé à Sanofi de réaliser une étude pour s’assurer de la bonne application de ces conditions de prescription et de délivrance (CPD).

” … le respect des conditions de prescription et délivrance était de l’ordre de 31% en 2016. Il n’atteint que 47% en 2017. … Le formulaire d’accord de soins n’était présenté que pour 50% des dispensations en 2017 (33% en 2016)… ”

Les résultats de l’étude montrent que les CPD ne sont pas suffisamment respectées.

“Actuellement, tout n’est pas fait pour éviter le valproate chez la femme enceinte. Il faut que l’information soit la plus répandue possible”

Dominique Martin, directeur général de l’ANSM.

L’utilisation des médicaments contenant du valproate ou un dérivé nécessite une attention particulière de l’ensemble des professionnels de santé et une information complète des patientes. En effet, ces médicaments présentent des risques importants de malformation et de troubles neuro-développementaux pour les enfants s’ils sont utilisés pendant la grossesse.

Communiqués ANSM
  • Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant – Communiqué, ansm, 20/10/2017.
  • Dossier Valproate et dérivés de l’ANSM.
Articles de Presse:

Cytotec misoprostol dans le déclenchement de l’accouchement : arrêt de commercialisation proche

Le Cytotec, médicament détourné de son usage, va être retiré du marché

Malgré les différentes mises en garde de l’ANSM, le Cytotec reste majoritairement utilisé hors AMM dans des indications en obstétrique, soit pour déclencher l’accouchement à partir de 37 semaines d’aménorrhée soit dans l’interruption volontaire de grossesse médicamenteuse (IVG).

L’ANSM rappelle que cette utilisation hors AMM peut entraîner des effets indésirables graves pour la mère et l’enfant, comme la survenue d’une rupture utérine (déchirure du muscle utérin), d’hémorragies ou d’anomalies du rythme cardiaque fœtal.

Aussi, le laboratoire Pfizer a décidé d’arrêter la commercialisation de Cytotec. En accord avec l’ANSM, cet arrêt sera effectif le 1er mars 2018

Communiqué ANSM
  • Cytotec (misoprostol) : arrêt de commercialisation à compter du 1er mars 2018 – Communiqué, ANSM, 20/10/2017.
  • Mise en garde sur les risques potentiels liés à l’utilisation hors AMM du Cytotec (misoprostol) dans le déclenchement de l’accouchement et toute autre utilisation gynécologique (25/02/2013) – Point d’information, ANSM, 25/02/2013.
Articles de Presse:
  • Le Cytotec, médicament détourné de son usage, va être retiré du marché, lemonde, 19/10/2017
  • Le Cytotec® sera retiré du marché en 2018, Allodocteurs, 19/10/2017.
  • Cytotec : “On a considéré mon bébé comme un produit à rentabiliser”, francetvinfo, 19/10/2017

Epilepsy drug warnings DO NOT reach enough women, 2017 survey finds

Almost 70% of women surveyed about a powerful epilepsy drug have not received new safety warnings about the dangers of taking it during pregnancy

Two thirds of women who take the antiepileptic drug sodium valproate said they had not received new safety warnings about the dangers of taking it during pregnancy, a survey carried out by epilepsy charities has found. A similar survey last year found that half of women taking the drug were unaware it could harm their fetus.

The new results are to be presented at a public hearing on the safety of valproate drugs organised by the European Medicines Agency on 26 September in London. …

… continue reading Women still not being told about pregnancy risks of valproate on The BMJ doi.org/10.1136/bmj.j4426, published 22 September 2017.
Featured image credit @bmj_latest.

USPSTF Draft Recommendation Statement Cervical Cancer : Screening

The US Preventive Services Task Force has New Draft Guidance for Cervical Cancer Screening

These recommendations do NOT apply to women with in utero exposure to diethylstilbestrol or women who have a compromised immune system (e.g., women living with HIV).

The major change from the US Preventive Services Task Force (USPSTF) 2012 recommendation is that testing for high-risk strains of human papillomavirus (hrHPV) alone is now recommended as an alternative to cytology or Papanicolaou (Pap) screening alone beginning at age 30 years; cotesting is no longer recommended.

As in the 2012 recommendation, the USPSTF continues to recommend that women aged 21 to 29 years undergo Pap screening every 3 years.

The USPSTF recommend against screening in women younger than age 21 years because there is adequate evidence that regardless of sexual history, screening younger women does not reduce cervical cancer incidence or mortality.

The USPSTF also continues to give a thumbs down to screening in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, as well as in women who have had a hysterectomy and their cervix removed and do not have a history of a high-grade precancerous lesions or cervical cancer.

More Information

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.)