Interpretation
We found no evidence to suggest biologics, with the strongest evidence for the TNFα inhibitor class, increase the risk of congenital anomalies. This further expands on the evidence provided from previous meta-analyses that found no difference in congenital anomalies such as reported by Tsao et al (OR 1.18, 95% CI 0.88 to 1.5)11, Komaki et al12 and Neilsen21.This is the largest preterm birth meta-analysis to date, with twenty-six studies included in the preterm birth meta-analysis with 7728 pregnancies exposed to biologics. As expected, a higher rate of PTB was observed in the treated group (12% compared with 6% in the disease-free group (p=0.008), with no difference in the rates observed between the treated and disease matched groups. The disease free group rates of 6% compare with WHO PTB rates for Europe and North America of 9% and 11% respectively.22 The lower rate of PTB in our disease free population likely reflects the inclusion of a large study by Broms et al4 which encompasses population registry data from Denmark, Finland and Sweden.
One of the primary factors which may impact PTB rates is disease activity. Geldhof concluded that women with active or flaring disease during pregnancy were at a much higher risk of complications irrespective of exposure to biologics with their exposure group having a PTB rate of 9.2% (n=143) and their corticosteroid group a PTB rate of 14.7% (n=36).23 Of concern, maternal disease may flare when biologic agents are discontinued and this itself may impact on PTB rates; this was reported with discontinuation of biologics prior to 24 weeks and a higher incidence of preterm delivery in a number of studies included in this analysis. 4,23,24
Our meta-analysis revealed no statistical difference in severe neonatal infection between groups. This was similar to the findings of two studies which were eligible but could not be included in the metanalysis, Tsao et al 2019 (due to a data sharing agreement) and Luu et al . Tsao et al 2019 found no increased risk of serious infections in the first year postpartum for either the mothers or the neonates3. Similarly, Luu et al found no difference in community or hospital acquired infections in the biologic treated group compared to a disease matched population.24 Interestingly studies specifically examining biologic use during the third trimester found no alteration in the neonatal infection rate during the first 12 months of life for the neonate.19,20,25–27 The only variable associated with an increased incidence of neonatal infection in multiple studies was PTB.19,20,24
Our meta-analysis found no statistical difference in birth weight with biologic use. Literature around this topic has been controversial with previous studies highlighting the greater prevalence of growth restriction/low birth weight babies in women with chronic inflammatory conditions4,17. Of the eligible studies included in this meta-analysis, Moens had the largest treated group and found no difference between their treated and untreated groups.28 Tsao et al found an OR for the association between biologic exposure and SGA was 0.91 (95% CI 0.46 to 1.78).29 The PIANO trial found no difference in LBW in those exposed to biologics after controlling for PTB and disease activity20.
Our analysis included only two studies examining severe maternal infection. The recent large Canadian 10 year retrospective cohort study by Tsao et al data could not be obtained.3However in published work they reported the occurrence of serious maternal infections to be rare with an incidence of 0-5% which is similar to the proportions found in our meta-analysis. Luu et alfound no difference in infection rates (community or hospital treated) in women treated with biologic agents in their third trimester but echoing findings above, those who discontinued were more likely to have a flare of their inflammatory disease.24 There was no greater likelihood of miscarriage for biologic treated patients compared to the comparator populations. This mirrors previous data reported18,30–32 which did not find an increased risk of miscarriage with biologics. Assimilating the data on pre-eclampsia, which is a less studied outcome of interest, we found no data to suggest that TNF inhibitors increase the risk. This data reflects information obtained from a small number of studies. Notably, no pre-eclampsia cases were reported with CZP use in Clowse et al.18 Chaparroet al found pre-eclampsia equally distributed across both the biologics exposed group and the disease matched cohort.19 Julsgaard et al specifically found no difference in the pre-eclampsia rates between women who ceased their medication prior to 30 weeks’ gestation or continued.33