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Original Investigation
September 14, 2020

Association Between Congenital Cytomegalovirus and the Prevalence at Birth of Microcephaly in the United States

Author Affiliations
  • 1Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 2Harvard Medical School, Boston, Massachusetts
  • 3Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
JAMA Pediatr. Published online September 14, 2020. doi:10.1001/jamapediatrics.2020.3009
Key Points

Question  What is the association of congenital cytomegalovirus with the prevalence at birth of microcephaly in the United States?

Findings  In this population-based cohort study of 2.3 million pregnancies identified in health care data from 2000 to 2015 in the United States, the prevalence of microcephaly was 2.1 to 7.7 per 10 000 live births, depending on case definition. Congenital cytomegalovirus diagnosis was the strongest measured risk factor for microcephaly, increasing the risk by at least 7-fold.

Meaning  Congenital cytomegalovirus is an important cause of microcephaly and other newborn neurologic outcomes in the United States and warrants greater attention from public health and medical fields.


Importance  Congenital cytomegalovirus (cCMV) has received far less clinical and public health attention as a teratogenic infection than the Zika virus epidemic. However, cCMV may be responsible for a large fraction of microcephaly cases in the United States.

Objective  To evaluate the association between cCMV and the prevalence at birth of microcephaly in the United States.

Design, Setting, and Participants  This population-based cohort study included pregnant women and their newborns identified in 2 insurance claims databases from the United States: Medicaid Analytic eXtract (January 1, 2000, to December 31, 2013) and IBM Research MarketScan, a database for employer-sponsored private health insurance (January 1, 2011, to September 30, 2015). All pregnancies that resulted in live births in women with full health benefits were included. Analysis began June 2016 and ended May 2020.

Exposures  Congenital cytomegalovirus infection documented in inpatient or outpatient newborn claims records.

Main Outcomes and Measures  The primary outcome was microcephaly at birth documented in inpatient or outpatient newborn and/or maternal claims records. Cases with chromosomal abnormalities or neural tube defects were excluded. The association between cCMV and microcephaly was estimated in the pooled cohort using prevalence ratios (PRs) and 95% CIs.

Results  In the pooled cohort of 2 338 580 pregnancies (2 075 410 pregnancies [88.7%] were among women younger than 35 years), 336 infants (0.014%) had a cCMV diagnosis. The prevalence of microcephaly among newborns with and without a cCMV diagnosis was 655 and 2.8 per 10 000 live births, respectively (PR, 232; 95% CI, 154-350). After restricting to CMV-tested newborns (572 [0.024%]) to correct for preferential testing of infants with microcephaly, the PR was 15 (95% CI, 5.2-41). However, this PR is biased if other cCMV-related outcomes (eg, hearing loss) trigger testing because cCMV prevalence in tested infants, with ([46%]) or without microcephaly (22 of 559 [3.9%]), would overestimate that in the source population. Therefore, the prevalence of cCMV in overall infants with microcephaly (22 of 669 [3.2%]) was compared with that from an external unbiased sample of US infants screened at birth (449 of 100 332 [0.45%]) to estimate a PR of 7.4 (95% CI, 4.8-11.5) as a conservative lower bound.

Conclusions and Relevance  Congenital cytomegalovirus infection increases the prevalence of microcephaly at birth by at least 7-fold. Prevention of CMV infection during pregnancy might substantially reduce the number of newborns with microcephaly and other cCMV-related outcomes in the United States.

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