What is the safety of Tumor Necrosis Factor-alpha (TNF-alpha) inhibitors during pregnancy?

TNF-α Inhibitors Are Safe During Pregnancy and Lactation

TNF-α inhibitors can be safely continued throughout pregnancy, particularly in women with active disease or high risk of relapse, as the benefits of disease control outweigh theoretical risks to the fetus. 1

Key Safety Principles

Overall Safety Profile

• TNF-α inhibitors are safe in pregnancy and during lactation according to the Joint AAD-NPF Guidelines 1
• Meta-analysis of six studies confirmed no increased risk of adverse pregnancy outcomes, congenital abnormality, preterm birth, or low birth weight 1
• The largest retrospective cohort study (1457 pregnancies) found no increased infection rates in children born to mothers exposed to anti-TNF therapy (adjusted OR 0.89,95% CI 0.76-1.05) 1, 2

Maternal Outcomes

• Active, uncontrolled disease poses greater risks than medication exposure 1
• Disease activity during pregnancy is associated with low birth weight (OR 2.05) and preterm birth (OR 2.64, increasing to OR 3.6 in moderate-to-severe disease) 1
• Discontinuing therapy increases relapse risk (adjusted OR 1.98,95% CI 1.25-3.15) 1, 2
• Treatment continuation was associated with higher overall maternal complications (adjusted OR 1.49) and infections (adjusted OR 1.31), but these risks must be weighed against disease flare consequences 1, 2

Timing Considerations During Pregnancy

First and Second Trimesters

• Continue TNF-α inhibitors through the first and second trimesters for women with active disease or high relapse risk 1
• Placental transfer is minimal during early pregnancy, as these IgG-based antibodies do not cross in significant concentrations until the second trimester 3, 4

Third Trimester Decision-Making

• For women with well-controlled disease: Consider discontinuation at the start of the third trimester (week 24-30) 1
• For women with active disease or high relapse risk: Continue through delivery, as ongoing use beyond 24 weeks does not increase maternal complications 1, 2
• There is greater theoretical risk with third-trimester use due to transplacental transfer, but clinical data do not support increased adverse outcomes 1

Certolizumab Pegol Exception

• Certolizumab pegol has shown minimal to no placental transfer and may be preferred if third-trimester exposure is a concern 1

Neonatal Considerations

Immunosuppression Risk

• Neonates and infants should be considered immunosuppressed for at least 1-3 months postpartum (depending on the specific TNF inhibitor) in mothers who received these medications during pregnancy 1
• Cord blood levels of etanercept at delivery varied from undetectable to 32% of maternal serum levels in published reports 4

Vaccination Timing

• Delay live or live-attenuated vaccines in exposed infants if third-trimester exposure occurred 5
• The theoretical risks of live vaccine administration should be weighed against vaccination benefits 4
• Consider avoiding live vaccines for the first 12 months after birth if TNF-α inhibitors were continued during pregnancy 5

Long-Term Infant Outcomes

• A Dutch multicentre study of 1000 children (20% exposed to anti-TNF in utero) found no influence on long-term adverse health outcomes, adverse reactions to vaccination, or infection rates up to 5 years 1
• The TEDDY study showed similar incidence rates of severe infections between exposed and non-exposed groups (HR 1.2,95% CI 0.8-1.8) 1

Congenital Anomalies: Addressing Conflicting Evidence

Reassuring Data

• The OTIS Registry (319 exposed pregnancies) showed 9.4% major birth defects versus 3.5% in diseased unexposed controls, but the lack of pattern of birth defects is reassuring and differences in disease severity between groups may have impacted outcomes 4
• A Scandinavian study (344 etanercept-exposed pregnancies) showed 7.0% major birth defects versus 4.7% in diseased unexposed controls 4
• Available studies do not reliably support an association between etanercept and major birth defects 4

Historical Concerns

• An older FDA database review (1999-2005) reported 61 congenital anomalies in 41 children, with 59% having VACTERL-associated anomalies 1
• However, this data is from voluntary postmarketing surveillance with significant limitations and has not been replicated in subsequent larger, better-controlled studies 1

Clinical Interpretation

• The weight of recent, higher-quality evidence supports safety, particularly when disease severity differences between exposed and unexposed groups are considered 4
• Uncommon adverse pregnancy outcomes with TNF inhibitor therapy appear to approximate those in women not receiving such therapy 6

Lactation Safety

• TNF-α inhibitors are safe during lactation 1
• Etanercept is present in low levels in human milk (ranging from <2 to 7% of maternal levels) but is not detected in plasma of breastfed infants 4
• Large monoclonal antibodies have minimal transfer into breast milk and poor oral bioavailability 5
• There have been no consistent reports of adverse events in breastfed infants over decades of use 4

Male Fertility

• TNF-α inhibitors are safe in men attempting conception with their partners 1

Common Pitfalls to Avoid

Do Not Automatically Discontinue Upon Pregnancy Confirmation

• The greatest risk comes from uncontrolled disease, not medication exposure 1
• Approximately 70% of pregnant patients can discontinue TNF inhibitors early in pregnancy without augmenting maternal or fetal risks, but this applies primarily to women with well-controlled disease 6

Do Not Ignore Disease Activity

• Disease activity is correlated with adverse pregnancy outcomes including fetal loss, preterm delivery, and low birth weight 3, 4
• Interrupting treatment increases relapse risk significantly 1, 2

Do Not Forget Neonatal Follow-Up

• Plan for appropriate neonatal monitoring and vaccination timing based on third-trimester exposure 5
• Document exposure timing and coordinate with pediatrics regarding live vaccine administration 5