Inclusion and exclusion criteria for malformations in newborn infants exposed to potential teratogens

Holmes, Lewis B.; Westgate, Marie-Noel

doi:10.1002/bdra.20842

Cited by 40 publications

(35 citation statements)

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“…However, discrepancies between reported and actual congenital malformations are not unique to resource-limited settings. Holmes and Westgate [10] reviewed physical findings documented by Pediatricians performing newborn exams from 1,000 consecutive deliveries involving live born infants, stillborn infants, and elective terminations of fetal malformations at a Boston-based hospital, and found 240 of the infants had documentation of an abnormal physical finding. Yet only 18 (1.8%) of the reported abnormalities actually represented major congenital malformations, using identical criteria to that used in this sub-study.…”

Section: Discussionmentioning

confidence: 99%

Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana

et al. 2017

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IntroductionA large and increasing number of HIV-infected women are conceiving on antiretroviral treatment (ART). While most antiretrovirals are considered safe in pregnancy, monitoring for rare pregnancy and infant adverse outcomes is warranted.MethodsWe conducted a retrospective secondary analysis nested within a clinical trial of infant cotrimoxazole vs. placebo prophylaxis in Botswana (the Mpepu Study). Infants were examined at birth, and at least every 3 months through 18 months of age. Abnormal physical findings and diagnostic testing revealing malformations were documented. Post hoc, a geneticist classified all reported malformations based on available documentation. Structural malformations with surgical, medical or cosmetic importance were classified as major malformations. We present a descriptive analysis of identified malformations.ResultsBetween 2011 and 2014, 2,933 HIV-infected women who enrolled in the Mpepu study delivered 2,971 live-born infants. Study staff conducted 2,944 (99%) newborn exams. One thousand eighty-eight (38%) women were taking ART at conception; 1,147 (40%) started ART during pregnancy; 442 (15%) received zidovudine monotherapy; and 223 (7%) received no antiretroviral during pregnancy. Of 33 reported anomalies, 25 (76%) met congenital malformations criteria, 10 (30%) were classified as major malformations, 4 (40%) of which were identified after the birth exam.DiscussionOur results highlight the importance of staff training on identification of congenital malformations, programmatic monitoring beyond the birth examination and the value of geneticist involvement in the malformations classification process in resource-limited settings. These elements will be important to fully define antiretroviral drug safety in pregnancy.SignificanceSurveillance systems for monitoring the safety of antiretroviral use during pregnancy among HIV-infected women in resource-limited setting are lacking. The World Health Organization’s published programmatic recommendations for such surveillance systems represents the gold standard. We employed data from a clinical trial in Botswana, a country with a generalized HIV epidemic and high antiretroviral uptake by HIV-infected women, to highlight practical opportunities to strengthen congenital malformation surveillance systems in these settings where over 1 million HIV infected pregnant women reside.Trial registrationClinical Trials.gov NCT01229761

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Section: Discussionmentioning

confidence: 99%

Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana

et al. 2017

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“…An expert birth defect panel established by the WHO Pregnancy Registry pilot project [31], the WHO Birth Defect Panel, independently and blinded to exposure status, reviewed and classified all the congenital anomalies from three sites under a multicenter study protocol, the Assessment of the Safety of Antimalarial Drug Use during Early Pregnancy (ASAP) study. For the other studies, criteria to differentiate between major and minor anomalies and to determine anomalies for exclusion, such as genetic and chromosomal disorders, were applied based on the WHO Birth Defect Panel recommendations and published criteria [32]. Data from Rwanda were not included in the analysis of congenital anomalies as only major anomalies were reported, and two out of the six anomalies were detected in participants enrolled after delivery.…”

Section: Methodsmentioning

confidence: 99%

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies

et al. 2017

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BackgroundAnimal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment.Methods and findingsElectronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model.There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08–1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36–1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6–12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54–2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26–2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52–2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%–3.5%]) and quinine exposures (1.2% [95% CI 0.6%–2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns.ConclusionsCompared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which ...

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“…Epidemiologic studies typically include only birth defects considered major (e.g., open spina bifida, but not spina bifida occulta [18]). Some minor defects may represent the milder end of a spectrum and thus have the same risk factors as corresponding major defects; however, there is evidence that minor defects are inconsistently ascertained [19], so exclusion criteria for minor defects should be established as part of the case definition [20]. Defects may also be excluded based on known pathogenesis of the defect.…”

Section: Ascertainment Definition and Classification Of Birth Defecmentioning

confidence: 99%

Challenges in Studying Modifiable Risk Factors for Birth Defects

et al. 2014

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Conducting research to identify modifiable risk factors for birth defects is difficult for a variety of reasons. While some challenges are familiar to researchers across many disciplines, the confluence of issues affecting birth defects research may not be well understood by those outside of the field. This article describes several methodological challenges to the study of birth defects and ways these challenges might be addressed: (1) ascertainment, definition and classification of birth defects; (2) exposure assessment on modifiable risk factors; (3) analytical challenges related to small numbers and multiple statistical tests; (4) the role of genetics, including the collection of specimens and analysis of genetic data; and (5) challenges in translating research and demonstrating public health impact. Understanding these issues is important for researchers planning studies, reviewers evaluating the scientific merit of results from these studies, and consumers of the research, including fellow researchers, policy makers, health care providers, and families.

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Inclusion and exclusion criteria for malformations in newborn infants exposed to potential teratogens

Cited by 40 publications

References 33 publications

Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana

Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies

Challenges in Studying Modifiable Risk Factors for Birth Defects

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