89Effect of Anti-TNFα Medications on Newborn Outcomes
Intrauterine anti-TNF exposure, particularly later in pregnancy, has raised con-
cerns about an increased risk for infections in the infant as well as concerns about
altering neonatal immune development. One case series of four newborns with
intrauterine exposure to IFX, including in the third trimester (T3), reported severe
neutropenia at birth in all of the infants, which returned to normal by 14 weeks of
age [ 58 ]. This finding has not been replicated in other studies. Using the PIANO
registry, Mahadevan et al. assessed outcomes related to anti-TNF exposure during
T3, including 422 pregnant women exposed to biologics in the third trimester of
pregnancy compared with 597 pregnant women unexposed to biologics in the
third trimester (70 with exposure to an anti-TNF in the first and/or second trimes-
ter but discontinued prior to T3), and found no difference in the risk of preterm
birth, risk of worsening disease activity in T3 or in the first 4 months postpartum,
or an increased risk of infant infections in up to 12 months of follow-up [ 59 ].
Specifically looking at immune response following vaccination in infants with
gestational exposure to anti-TNF agents, a recent prospective study of a subset of
subjects from the PIANO registry, including ten infants exposed to IFX and two
exposed to ADA, measured immunoglobulin levels and antibodies to tetanus and
Haemophilus influenzae after vaccination and found five infants with low IgM
levels, with unclear clinical significance, but an adequate vaccine response in
92% of the infants [ 60 ]. Other similar studies have confirmed an adequate immune
response to vaccinations in infants with intrauterine anti-TNF exposure [ 22 , 28 ].
Following a case report [ 61 ] and systematic review [ 62 ] that suggested intrauter-
ine anti-TNF exposure leads to a VACTERL (includes vertebral defects, anal atresia
or imperforate anus, cardiac abnormalities, tracheoesophageal fistula or tracheal
atresia/stenosis, esophageal atresia, renal and/or radial abnormalities, preaxial limb
abnormalities) congenital anomaly, a subsequent population database study evalu-
ated this association and could not confirm an increased risk for congenital anoma-
lies within the VACTERL spectrum [ 63 ]. Despite these few studies and the
previously mentioned studies which found an increased risk of infection within the
first year of life following intrauterine exposure to combined anti-TNF and immu-
nomodulatory medications [ 26 , 48 ], most studies of neonatal outcomes in preg-
nancy following intrauterine anti-TNF medication exposure have not found an
increased risk of adverse fetal outcomes, particularly congenital malformations,
compared to disease-matched cohorts or cohorts on immunomodulators [ 43 – 47 , 50 ,
51 , 64 ].
Several studies have investigated long-term outcomes following intrauterine
anti-TNF exposure. A study of 25 children ages ≥12 months who were exposed to
anti-TNF agents during gestation were all found to have normal growth and devel-
opment except 1 child (a dizygotic twin, diagnosed with a mild delay at 6 months of
age) [ 65 ]. Twenty (80%) of the children had at least one infection with 60% receiv-
ing antibiotics. Vaccinations were given according to the recommended protocol,
including BCG within 1 week of birth in 15 of the children with intrauterine
exposure to IFX, which resulted in large skin reactions in three of the children, but
6 Biologics in Pregnancy and Breastfeeding