Efficacy of HIG treatment for prevention of maternal–fetal transmission of CMV
The role of HIG for prevention of maternal–fetal transmission during primary CMV infection in pregnancy is controversially discussed [16, 19]. A non-randomized study by Nigro et al. reported a significant reduction of cCMV to 16% in comparison to 40% in the control group with no obstetric adverse events [8]. The subsequent randomized-controlled study by Revello et al. showed no significant effect of HIG (30% HIG group vs. 44% control group; P = 0.13) but raised concerns regarding a higher rate of obstetrical adverse events (preterm birth, preeclampsia and fetal growth retardation) in the HIG group compared to the placebo group (13% vs. 2%) [7]. Furthermore the study by Revello et al. could have reached significance level in a greater study collective according to van Leeuwen et al. [25]. The study by Revello et al. was criticized for various reasons [9]. First of all, a monthly HIG administration was performed although the half-life of HIG seems to be only 11 days [20]. Second, women with primary infection in the second trimester were treated and a median time interval between the diagnosis of infection and first HIG administration was five weeks. Third, the HIG dose administered was 100 IU per kg body weight. In a recent study by Kagan et al., these controversial points were addressed and only women with primary infection during first trimester of their pregnancy were included. Treatment was initiated within 3 weeks, the gestational age at first HIG administration was ≤ 14 weeks and HIG was administered at 200 IU per kg body weight biweekly until 20 weeks gestation. Within this study protocol, the transmission rate was significantly lower compared to the rate in a historic cohort (7.5% intervention group vs. 35.2% in the control group; P < 0.0001) [9]. The transmission rate of 23.9% in our study was higher despite having the same HIG-dose as used by Kagan et al. In comparison to the Israeli control group with a transmission rate of 39.9% (112 transmission in 281 pregnancies with no HIG treatment), this reduction is significant (P = 0.026).
The risk for the neonate is highest if the infection occurs in the first trimester [26,27,28,29,30]. A recent study even suggests that only infections up to 23 weeks gestation lead to sequelae in the infant [15]. Hence, specifically the prevention of early transmission in pregnancy should be of high priority. When doing a subgroup analysis among the women who underwent AC within the first 23 weeks gestation, we also saw a lower rate of transmission (7.1%) than 35.2% in the historic German Belgian control group. The rate of 7.1% is nonetheless higher than 2.5% described by Kagan et al. First of all, our subgroup of only 14 ACs is very small. Second of all, this can possibly be due to less courses of treatment. Most of the women in our collective only received two courses of HIG, while Kagan et al. continued treatment until a median gestational age of 16.6 weeks and applied up to six courses of treatment [9]. Furthermore, treatment in our cohort was initiated delayed compared to Kagan et al. The median time lag between primary infection of the mother, approximated in this study by first suspicious lab result, and first HIG treatment course was 23 days. Only 57% of our patients received HIG within the first 3 weeks after CMV infection. This can be explained due to clinical reality and administrative barriers. Because serologic testing was performed in external outpatient clinics, referral of patients was delayed. Furthermore, sometimes in the cases of inconclusive blood results additional laboratory parameters were ordered from the laboratory until decision on HIG treatment was taken. After the decision for HIG due to administrative necessities such as the refunding of off-label treatment, a waiting period of at least three full working days had to be kept in order for the insurance company to check the indication.
Safety of HIG treatment in pregnancy
The second controversially discussed aspect about HIG treatment during pregnancy are its potential side effects. Revello et al. reported obstetrical complications (preterm delivery, preeclampsia, and fetal growth restriction) in 7 of 53 women (13%) in the HIG group compared to 1 of 51 women (2%) in the placebo group (P = 0.06) [7]. Other authors found no increased rate of adverse events [9, 31, 32]. In our cohort, no preeclampsia occurred, and median completed gestational week was 39 weeks. Neonate growth parameters were not different in the HIG group compared to the control group. A lower c-section rate in the study group is most likely due to the sampling method where the time of birth was not known in the study group the control group was selected as the deliveries before and after noon in our center of tertiary care. This is typically the time for planned c-sections. Furthermore, the center of tertiary care is a referral center for women and children with illnesses necessitating c-sections as a mode of delivery. In conclusion, according to our data, no increased rate of adverse obstetric outcomes was detected and thus HIG application during pregnancy can be regarded as safe.
Limitations of this study
The limitations in our study is the retrospective character and the lack of randomization. Furthermore, the cohort is very diverse. Time between infection and initiation of treatment is often later than advised by Kagan et al. Moreover, HIG was not only administered to first trimester infections. We suggest that a national or international prospective study with faster treatment initiation should follow.
Strength of this study
We report results from the largest German cohort of HIG treatment during pregnancy, published so far. The results have implications for clinical management of CMV infection.