To the Editor:
The article by Francis and colleagues1 of maternal–fetal transmission of herpesviruses as a cause of gastroschisis was prompted by our study, which showed that early pregnancy seropositivity to selected herpesvirus antibodies was associated with gastroschisis.2 However, the two studies addressed different research questions, which invite an opportunity to consider the complexities of studying the role of infections on risks of birth outcomes.
It has been well established that maternal–fetal transmission of viruses can cause congenital anomalies, though associations between maternal and fetal infection can be difficult to measure in population-based studies. In a clinical setting, diagnosis of maternal–fetal transmission typically includes evidence of maternal infection by symptoms paired with monoclonal antibody, polymerase chain reaction (PCR) of viral DNA/RNA, or cell culture evidence, followed by phenotypic evidence of infection in offspring paired with positive PCR or cell culture. However, this diagnostic workup is driven by identification of maternal symptoms, and it is known that a majority of cases are asymptomatic. Thus, population-based studies are needed to quantify risks of maternal–fetal transmission, but are hampered by the complexity of measuring maternal infection. The virus may only be present in blood, urine, or other obtainable tissue for a limited duration after infection, reducing sensitivity of detection for samples collected outside this window, such as newborn bloodspots. Likewise, antibody testing may be uninformative due a short-duration increase in immunoglobulin M. To more accurately measure risk of maternal–fetal transmission, serial sampling from the mother throughout gestation and sampling from the offspring are necessary, which is prohibitive in most large-scale epidemiology studies.
Although gastroschisis has never been described as part of a congenital herpesvirus phenotype, study by Francis et al.1 sought to identify maternal–fetal transmission for six viruses in the herpes family using newborn blood spots. Indeed, it would have been surprising if herpesvirus DNA had been detected, given the low probability of in utero transmission (e.g., <0.0001 for herpes simplex virus and <0.02 for recurrent cytomegalovirus).3,4 Francis et al.1 state that their study was prompted by our report of increased associations between gastroschisis and maternal antibody levels to selected herpesviruses. However, in our study, we did not seek to identify maternal–fetal transmission; rather, we explored whether infection exposure might be a risk factor for gastroschisis, along the same lines that we might study environmental exposures. The possibility that maternal infection might play a role in organogenesis is generally accepted, but it is often then assumed to only manifest in congenital infection.
Martha M. Werler
Samantha E. Parker
Department of Epidemiology
Boston University School of Public Health
1. Francis SS, Wiemels JL, Yang W, Shaw GM. Herpesvirus infection in infants with gastroschisis. Epidemiology. 2018;29:571–573.
2. Werler MM, Parker SE, Hedman K, Gissler M, Ritvanen A, Surcel HM. Maternal antibodies to herpes virus antigens and risk of gastroschisis in offspring. Am J Epidemiol. 2016;184:902–912.
3. James SH, Sheffield JS, Kimberlin DW. Mother-to-child transmission of herpes simplex virus. J Pediatric Infect Dis Soc. 2014;3(1 suppl):S19–S23.
4. Davis NL, King CC, Kourtis AP. Cytomegalovirus infection in pregnancy. Birth Defects Res. 2017;109:336–346.