CFTR Modulators in Pregnancy: Reassuring Early Signals, Persistent Long-Term Uncertainty

Zihanjiao Wang, Rasa Ruseckaite, Aleksandar Dobric et al.

Summary: This scoping review systematically examined published literature from 2003–2025 on CFTR modulator use during pregnancy and the postpartum period in women with cystic fibrosis. The authors assessed maternal outcomes (lung function, nutritional status, complications) and fetal/neonatal outcomes (birth weight, congenital anomalies, neonatal complications) across all approved modulator regimens. The central finding is that elexacaftor/tezacaftor/ivacaftor (ETI) appears to confer maternal benefit, and inadvertent fetal exposure has not been clearly linked to serious adverse outcomes — but long-term data on exposed children and safety during lactation remain genuinely insufficient.

Why it matters: CFTR modulators, particularly ETI, have transformed the health trajectory of people with CF, enabling more women to survive into reproductive age and pursue pregnancy in substantially better health than prior generations. This creates an urgent and practical clinical question: should CFTR modulators be continued, modified, or discontinued during pregnancy and lactation? The answer carries real stakes — discontinuation risks maternal pulmonary decline, while continuation exposes a developing fetus and potentially a nursing infant to drugs whose long-term developmental effects are unknown. Clinicians and patients currently make these decisions with limited evidence, and this review maps the current state of that evidence base honestly.

Expert perspective: Scoping reviews are designed to characterize the landscape of available literature rather than to synthesize effect estimates, and this one performs that function appropriately. The review's value lies in what it reveals about the shape of the evidence gap rather than in generating new conclusions about safety or efficacy.

Most available data come from case series, registry cohorts, and pharmacovigilance reports — not randomized trials, which are neither feasible nor ethical in this context. Confounding by indication is pervasive and largely uncontrollable: women who continue ETI during pregnancy may differ systematically from those who discontinue, both in disease severity and in access to specialist care. Sample sizes across nearly all reviewed studies are small; ETI has only been widely available since 2019, and the reassuring neonatal outcomes reported to date reflect short follow-up windows and modest numbers. Rare teratogenic signals, neurodevelopmental effects, or metabolic consequences in exposed children cannot be excluded by the current evidence. Lactation safety remains particularly data-sparse, with drug concentrations in breast milk and their pharmacokinetic implications for nursing infants poorly characterized for most modulators.

The conclusion that ETI "may improve maternal health" is reasonable and consistent with the broader clinical literature, but extrapolating this benefit to pregnancy remains observational. The absence of a clear harm signal from fetal exposure is genuinely reassuring as a starting point, but absence of detected harm in small, short-term datasets is not equivalent to established safety — a distinction the authors draw responsibly.

The call for registry integration is well-founded. National and international CF registries — including the US Cystic Fibrosis Foundation Patient Registry and the European CF Society Patient Registry — are among the few instruments with the longitudinal reach and sample aggregation needed to study pregnancy outcomes at meaningful scale. Linkage of CF registry data to obstetric, neonatal, and pediatric developmental databases would substantially improve the evidence base, and harmonized data definitions and cross-registry collaboration could deliver insights that no single-centre study can achieve. The main unanswered questions — long-term neurodevelopmental and metabolic outcomes in ETI-exposed children, optimal dosing strategies during pregnancy, and lactation pharmacokinetics — will require coordinated registry infrastructure and prospective follow-up extending well beyond current data collection norms in CF research.

Relevance: Cystic Fibrosis | CF Registry and Real-World Evidence

Source: https://pubmed.ncbi.nlm.nih.gov/42778208/

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