The association of cytomegalovirus hyperimmune globulin with adverse pregnancy outcomes.

OBJECTIVE

: Because a prior randomized trial suggested that cytomegalovirus (CMV) hyperimmune globulin (HIG) might increase the frequency of adverse pregnancy outcomes, we assessed whether there was such an association in our more recent and larger trial.

STUDY DESIGN

: This was a secondary analysis of a multi-center randomized placebo-controlled trial of CMV HIG to prevent congenital CMV infection. Individuals were eligible for the trial if they had primary CMV infection and were carrying a singleton fetus without ultrasound abnormalities suspicious for congenital CMV infection. Participants received a monthly infusion of CMV HIG (100 mg/kg) or matching placebo until delivery. Trained research staff abstracted all outcomes according to the standard criteria. Our primary outcome for this secondary analysis was a composite of any of the following as defined in the original trial: gestational hypertension (GHTN), any form of preeclampsia, small for gestational age (SGA) (birthweight<10%ile), placental abruption, preterm delivery (PTD) before 37 weeks, or perinatal death. We also evaluated the association of treatment with a more severe composite outcome defined as any of the following: GHTN or preeclampsia in association with delivery before 37 weeks, birthweight<5%ile, PTD<34 weeks, or perinatal death. These composite outcomes were chosen to encompass a full range of important adverse pregnancy outcomes including those which have been previously reported in association with the use of CMV HIG, and to provide an aggregate perspective of outcomes that were reported only individually in the primary trial report. <.05 was used to denote statistical significance. Statistical analysis included chi-square analysis or Fisher exact test, as appropriate, for categorical variables. All analyses were carried out using SAS software (SAS Institute Inc, Cary, NC).

RESULTS

: From 2012 to 2018, 399 participants were enrolled in the trial, and 390 had complete data for this analysis. Baseline characteristics were generally balanced between the treatment groups and not suggestive that those in the CMV group were at higher risk for adverse pregnancy outcome (Table). The primary adverse composite outcome was significantly more common in the CMV HIG group: 30% vs 20%; relative risk, 1.49; 95% confidence interval, 1.04 to 2.13 (Table). Though each of the individual components of the composite outcome, as well as the more severe composite outcome and its components, occurred more often in the CMV HIG group, the differences were not statistically significant (Table).

CONCLUSION

: We found that maternal receipt of CMV HIG was significantly associated with the frequency of a composite of GHTN, any form of preeclampsia, SGA, placental abruption, PTD, or perinatal death. Similarly, in the randomized trial of Revello et al, 7/53 (13%) of participants randomized to CMV HIG had a preterm birth, developed preeclampsia, or had a fetus diagnosed with growth restriction compared to 1/51 (2%) randomized to placebo, .06. Importantly, in neither trial did CMV HIG reduce the rate of congenital CMV infection. Why our primary outcome rate was higher is not clear. We acknowledge that both we and Revello et al have created composite outcomes that include components which are somewhat heterogenous and which may derive from differing underlying mechanisms. Nonetheless, both comprise components that are unarguably important.