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