SCIENTIFIC
Microcephaly After Multiple Fetal Exposures
AUTHORS : Lesley Cottrell , PhD 1
Alicia Moise , MD 1 Carrie A . Moore , MD 2 Mark J . Polak , MD 1
1
West Virginia University School of Medicine Department of Pediatrics
2
University of Louisville School of Medicine , Department of Pediatrics , Division of Neonatal Medicine
INTRODUCTION
The Centers for Disease Control and Prevention ( CDC ) defines microcephaly as a head circumference ( HC ) less than the third percentile for the child ’ s gestational age and sex . 1 A report from the American Academy of Neurology estimates the proportion of infants with a HC less than two standard deviations below the mean at birth to be 0.54 % to 0.56 % of live births . 2 State birth defect tracking systems have estimated that microcephaly ranges from two to 12 babies per 10,000 live births in the United States ( 0.02 % to 0.12 %). 3 Between 2014 and 2018 at West Virginia University ’ s ( WVU ) Medicine Children ’ s Hospital , 1.0 % of the newborns were found to have congenital microcephaly , which would be two to 50 times the national average . 2 , 3
Appalachia , and West Virginia ( WV ) in particular , are experiencing an opioid use crisis in the general population and equally in women of childbearing age . When umbilical cord tissue was examined for drug use , 14 % of women who gave birth during a onemonth period in eight birth hospitals in WV were found to be positive for opioid use . 4 Furthermore , tobacco use among pregnant women in this region is significant . A report from American Health Rankings in 2020 noted that 23.9 % of pregnant women in WV were exposed to tobacco , three times the national average . 5 The ramifications of multiple substance exposures in the fetus are not fully known . 6 Multiple exposures likely put the fetus at significant risk of neurodevelopmental harm .
A report from by Visconti , et . al ., from the Tennessee ( TN ) region found that infants exposed to opioids in amounts enough to cause Neonatal Abstinence Syndrome ( NAS ) were associated with smaller head circumferences , defined as a head circumference less than the 10th percentile . 7 Somewhat surprisingly , although their population of mothers had a high rate of tobacco use , the authors concluded that tobacco exposure did not contribute to the additional risk of developing microcephaly . In this retrospective study from 2015 , the incidence of smoking in the group with small HC was not higher than those with HC greater than 10 %. However , in a subsequent prospective study published in 2019 , 8 the authors did not compare the prevalence of microcephaly among the infants used as controls ( infants not exposed to chronic opioid use ) who were exposed to tobacco with infants not exposed to tobacco . The percentage of fetuses exposed to tobacco in both NAS infants ( 75 %) and those not exposed to opioids ( 51 %) were extremely high in this study population . In this study , they compared HC in infants treated for NAS with control infants without antenatal opioid exposure . They noted 8.2 % of infants with NAS had a HC of less or equal to the third percentile . Multivariate analysis was used and determined that the only significant risk factor for a smaller HC was chronic opioid use during gestation resulting in a neonate who was treated for NAS . However , the investigators did not account for other fetal exposures .
Cannabis exposure was added to standard urine drug screening in 2019 and has shown that its use is not rare . Several papers have shown that cannabis exposure may not be benign . In a recent systematic review and meta-analysis by Marchand et . al . published in 2022 , quoting from this paper , a significant difference was found in neonatal outcomes of pregnant women with exposure to marijuana compared to pregnant women without exposure . These differences included increased risk of low birth weight (< 2500 g ), small for gestational age diagnosis , preterm delivery (< 37 weeks ), NICU admission , decreased mean birth weight ( in grams ), Apgar score at one minute , and infant HC ( in centimeters ). There was no significant difference in the outcomes of mean gestational age ( in weeks ), risk of five-minute Apgar scores less than seven , mean Apgar scores at five minutes , or mean infant length ( in centimeters ). 9 A meta-analysis from 2016 from Conner et . al . reported marijuana use during pregnancy was associated with an increased risk of low birth weight and preterm delivery , but when controlling for tobacco use and other confounding factors , these associations were no longer present . 10 A 2017 cross-sectional study by Haight et . al . found that the frequency of cannabis use was associated with low-birth-weight delivery , apart from cigarette use . 11
Given the increased prevalence of both microcephaly ( 1.02 %) and opioid use ( 6 %) along with a significant percentage of tobacco use ( 11 %) and cannabis use ( 5 %) among pregnant women from our delivery service , we reviewed newborns with a diagnosis of microcephaly born in the given period ( 2014-2018 ). Unlike the previous studies that focused only on opioids and microcephaly , 7 , 8 our primary hypothesis was that tobacco use during pregnancy is associated with microcephaly . Our secondary hypothesis was that tobacco use plus opioids and / or cannabis will increase the probability of a diagnosis of microcephaly .
METHODS
We performed a chart review of all infants coded for microcephaly from January 1 , 2014 , through July 31 , 2018 . We noted opioid exposure ( primarily women on treatment with buprenorphine , buprenorphine / naloxone ), as well as tobacco and cannabis exposure in pregnancy to assess whether microcephaly was more frequent with opioid exposure , tobacco , cannabis exposure , or a combination of these in pregnancy . This study was approved by the WVU School of Medicine Institutional Review Board .
As a standard practice , HC is measured for all infants and charted on the Fenton
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