Microcephaly: An epidemiologic analysis

doi:10.1067/mob.2003.452

American Journal of Obstetrics and Gynecology

Volume 188, Issue 6, June 2003, Pages 1484-1490

Presented at the Sixty-Ninth Annual Meeting of the Central Association of Obstetricians and Gynecologists, October 27-30, 2002, Las Vegas, Nev.

https://doi.org/10.1067/mob.2003.452 Get rights and content

Abstract

Objective: This study was conducted to identify all risk factors that are associated with microcephaly and to quantify the magnitude of risk that is associated with these factors. Study Design: This population-based case-control study used the Missouri Birth Defects Registry to identify 360 microcephaly cases and 3600 control cases during 1993 through 1999. Logistic regression was used to calculate adjusted odds ratios and 95% CIs. Results: Significant risk factors for isolated microcephaly include alcohol use, inadequate weight gain during pregnancy, inadequate prenatal care, black race, and low education. Mothers with one previous live birth were protected against isolated microcephaly compared with nulliparous women. Conclusion: Our results suggest that microcephaly may arise from some preventable factors. These findings may be useful in aiding clinicians, patients, and policymakers in reducing the risk of microcephaly, a source of high perinatal mortality and morbidity rates. (Am J Obstet Gynecol 2003;188:1484-90.)

Section snippets

Material and methods

The Missouri Birth Defects Registry is a passive data collection system that identifies live-born infants <1 year of age who are diagnosed with birth defects, such as microcephaly. This registry receives information from multiple sources, including birth certificates, death certificates, abstracts from medical records of newborn patients, pediatric inpatients and outpatients, and other state-assisted children programs. The prevalence of microcephaly in Missouri was 7.0 cases per 10,000 infants

Crude odds ratios

The crude odds ratios and 95% CI for potential risk factors are presented in Table I.Tobacco and alcohol use during pregnancy significantly increased the risk of microcephaly. Mothers who drank alcohol during their pregnancy were 3.8 times (95% CI, 2.2-6.5) more likely to have an infant with microcephaly than mothers who abstained.

Data on maternal infection (cytomegalovirus, herpes, HIV, rubella, and toxoplasmosis) were insufficient to determine whether specific maternal infections were

Comment

Fetal exposure to maternal alcohol and tobacco use increased the risk of microcephaly. Maternal alcohol use had a more pronounced effect on isolated microcephaly (2.6-fold increase) than all microcephaly cases that included other major anomalies (1.9-fold increase). The magnitude of the risk estimates for both was noteworthy but may be underestimated because frequency and quantity of alcohol and tobacco use are often under reported on birth certificates.21, 22 Previous epidemiologic and animal

Acknowledgements

We thank Garland Land, Joseph Stockbauer, and Janice Bakewell from the Missouri Department of Health and Senior Services for their helpful comments and support while conducting this study.

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The cohort included 11,404 participants (6000 males and 5404 females). The curve for male head circumference was significantly higher than the female curve for all gestational weeks (P<.0001). Applying gender customized curves resulted in fewer cases of male fetuses defined as 2 standard deviations above the normal range and female fetuses defined as 2 standard deviations below of the normal range. Cases reclassified as normal head circumference after the application of gender-customized curves were not related to increased adverse postnatal outcomes. The rate of neurocognitive phenotypes was not higher than the expected rate in both male and female cohorts. Polyhydramnios and gestational diabetes mellitus were more common in the normalized male cohort, whereas oligohydramnios, fetal growth restriction, and cesarean delivery were more common in the normalized female cohort.
Prenatal gender-customized curves for head circumference can reduce the overdiagnosis of microcephaly in females and macrocephaly in males. According to our results, gender-customized curves did not affect the clinical yield of prenatal measurements. Therefore, we suggest that gender-specific curves be used to avoid unnecessary workup and parental anxiety.
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Citation Excerpt :
Congenital microcephaly (CM) is defined by an occipital frontal circumference (OFC) that is >2 SD below the mean at birth, although some suggest 3 SD as the cutoff value.1-3
Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.
Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.
We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.
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Zika virus (ZIKV) was an emergent flavivirus transmitted by Aedes genus mosquitoes and made an explosive outbreak in Latin America in 2015. A few months later, an obvious increase in the number of microcephaly neonates has been observed, which might be related to ZIKV infection during the mothers’ pregnancy. Since then, researchers in many countries and territories have been working on the causal link between ZIKV and microcephaly and have made a number of achievements. To summarize the most recent evidence and the contribution of Chinese researchers on this issue, and to provide perspectives and challenges for future studies, we reviewed the literature of both microcephaly and ZIKV. Based on previous research results, ZIKV has been preliminarily proved to be the direct cause of microcephaly in newborns and Chinese researchers have made many important discoveries in the pathogenesis of microcephaly. Even so, future researches should also further investigate the mechanism of ZIKV-related microcephaly to advance the development of therapeutic and preventive strategies.
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The awesome complexity of the human brain begins its evolution after the essential external form is established by the events described in Chapters 1 and 2. The events that follow are proliferation of the brain's total complement of neurons, estimated at 86 billion, the migration of these neurons to specific sites throughout the central nervous system, the series of organizational events that result in the brain's characteristically intricate circuitry, and finally the ensheathment of this circuitry with myelin, its neuron-specific membrane. These events span a period from the second month of gestation to adult life, including the perinatal period. Aberrations of brain development may be an important consequence of genetic perturbations as well as a variety of prenatal and perinatal insults at critical times during development. This chapter reviews the normal aspects of neuronal proliferation and discusses disorders encountered when normal development goes awry.
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Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015–16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities.
How to deal with a fetal head circumference lower than the third percentile?
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La découverte d’un périmètre céphalique (PC) inférieur au 3^epercentile (p), au même titre que le fémur court ou l’hyperclarté de nuque à caryotype normal, demeure l’une des situations les plus difficiles pour le praticien en diagnostic prénatal. La microcéphalie constitue une porte d’entrée d’éventuelles pathologies cérébrales diverses; cependant l’objectif principal est d’identifier les situations graves accessibles en période prénatale. Une mesure standardisée du PC, l’utilisation d’outils et de courbes de références adaptés, un suivi longitudinal des biométries céphaliques dans les situations à risques, et une analyse systématisée du système nerveux central peuvent permettre d’augmenter les performances diagnostiques de l’échographie souvent décevantes pour la microcéphalie. La distinction précoce entre microcéphalie associée ou isolée permet d’orienter rapidement la conduite à tenir et le conseil prénatal. L’IRM fœtale et la consultation de génétique sont fondamentaux dans ce contexte, ils permettent de préciser, au mieux, le diagnostic étiologique et d’apporter une aide au neuropédiatre dans l’établissement d’un pronostic souvent incertain. La récente augmentation des cas de microcéphalie concomitante à l’épidémie du virus ZIKA est un argument supplémentaire pour améliorer nos pratiques et l’appréhension au quotidien des PC < 3^e p.
The prenatal finding of a head circumference (HC) below the 3rd percentile (p) remains, in the same way as short femur or increased nuchal translucency with normal karyotype, one the most difficult situations for the praticionner in the setting of prenatal diagnosis. Microcephaly is a gateway to possible cerebral pathologies, but the main objective is to identify serious prenatal situations. A standardized HC measurement, the use of adapted reference tools and charts, longitudinal following of cephalic biometrics in high-risk situations, and systematic central nervous system analysis can increase the diagnostic performance of ultrasound which is often disappointing for microcephaly. The early distinction between associated or isolated microcephaly makes it possible to quickly orient the prenatal management and counseling. Fetal MRI and genetic counseling are fundamental in this context, making it possible to specify at best the etiological diagnosis and to provide assistance to the neuropediatrician in the establishment of an often uncertain prognosis. The recent increase in cases of microcephaly concomitant with the epidemic of the ZIKA virus is an additional argument to improve our practices and the daily apprehension of HC < 3rd p.

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Transactions of the Sixty-Ninth Annual Meeting of the Central Association of Obstetricians and GynecologistsMicrocephaly: An epidemiologic analysis☆

Abstract

Section snippets

Material and methods

Crude odds ratios

Comment

Acknowledgements

J Pediatr

J Pediatr

Neurol Clin

Ann Epidemiol

Microcephaly

Pediatr Rev

Births: final data for 1999

Natl Vital Stat Rep

The clinical significance of “measurement microcephaly.”

Arch Pediatr Adolesc Med

A case-control study of maternal smoking and congenital malformations

Paediatr Perinat Epidemiol

Adverse effects on offspring of maternal alcohol abuse during pregnancy

N Engl J Med

Ethanol-induced microcephaly in neonatal rats: relation to dose

Alcohol Clin Exp Res

Congenital malformations in babies of diabetic mothers

Diabet Med

Maternal viral infection with adverse results: cytomegalovirus and herpes virus

Semin Perinatol

Neurological findings in HIV-infected children: a review of 49 cases

J Can Sci Neurol

The incidence of cytomegalovirus, herpes simplex, rubella, and toxoplasma antibodies in microcephalic, mentally retarded, and normocephalic children

Pediatrics

Toxoplasmosis: maternal and pediatric findings in 23,000 pregnancies

Pediatrics

Microcephaly: a review of genetic implications in its causation

J Ment Defic Res

Missouri birth defects 1995-1999

Transactions of the Sixty-Ninth Annual Meeting of the Central Association of Obstetricians and Gynecologists
Microcephaly: An epidemiologic analysis☆