LACTOLOGY FOUNDATION

Proton pump inhibitors (PPIs, ATC A02BC) are substituted benzimidazoles that irreversibly inhibit the gastric H++/K++-ATPase, providing potent and long‑lasting suppression of gastric acid secretion and are widely used for acid‑related disorders in adults and children. Overall human data suggest low teratogenic risk in pregnancy and very low exposure during breastfeeding, with omeprazole and esomeprazole being the best studied molecules.

ATC A02BC and members

The ATC group A02BC includes proton pump inhibitors such as omeprazole (A02BC01), pantoprazole (A02BC02), lansoprazole (A02BC03), rabeprazole (A02BC04), esomeprazole (A02BC05), dexlansoprazole (A02BC06) and newer agents like vonoprazan (A02BC08), as well as their fixed‑dose combinations (A02BC5x). These agents share a common basic structure (substituted benzimidazoles) and class mechanism but differ in pharmacokinetic properties and formulation options.

Mechanism of action and indications

PPIs are pro‑drugs that accumulate in the acidic canaliculi of gastric parietal cells, where they are converted to active sulfenamide intermediates that covalently bind and inactivate H++/K++-ATPase, the final step in acid secretion. This results in profound and long‑lasting suppression of basal and stimulated gastric acid output, which makes PPIs first‑line therapy for GERD, peptic ulcer disease, erosive esophagitis, Zollinger–Ellison syndrome and prophylaxis of NSAID‑associated ulcers.

General toxicological profile

In the general population PPIs are considered safe and well tolerated, and are included in the WHO Model List of Essential Medicines (omeprazole) because of their favourable benefit–risk balance. However, prolonged or inappropriate use has been associated with increased risk of Clostridioides difficile infection, community‑acquired pneumonia, micronutrient deficiencies (vitamin B12, magnesium), bone fractures and possibly kidney disease, particularly in elderly or polymorbid patients.

Maternal adverse effects and drug interactions

Common adverse effects include headache, abdominal pain, diarrhea, constipation and nausea, usually mild and reversible. Less frequent but clinically relevant effects include cutaneous reactions, liver enzyme elevations, rare interstitial nephritis, gynecomastia (reported for omeprazole) and potential rebound acid hypersecretion after abrupt discontinuation.

PPIs are substrates and, to varying degrees, inhibitors of cytochrome P450 isoenzymes such as CYP2C19 and CYP3A4, leading to potential interactions with drugs like clopidogrel, diazepam, warfarin, phenytoin and certain antiretrovirals. Concomitant use with antiplatelet agents and NSAIDs is common in clinical practice and in fixed combinations, and requires balancing GI protection against possible modification of antiplatelet effect.

Reproductive toxicity and pregnancy

Human observational data and systematic reviews indicate that omeprazole exposure in early pregnancy is not associated with an increased risk of major congenital malformations compared with disease‑matched or non‑teratogenic controls. Pooled data on the whole PPI class (hundreds of exposed pregnancies) show relative risks for major malformations close to 1 with confidence intervals including unity, suggesting absence of a clinically relevant teratogenic effect.

Available studies also do not suggest an increased risk of miscarriage, preterm birth or low birth weight with omeprazole or esomeprazole exposure, although data for newer agents remain limited. Current evidence‑based reviews conclude that PPIs can be used during pregnancy when clinically indicated, after individual risk–benefit assessment and preferably at the lowest effective dose.

Lactation pharmacokinetics

Omeprazole and esomeprazole are weak bases with short plasma half‑lives but long pharmacodynamic effects due to irreversible enzyme binding; their high protein binding and instability at neutral pH limit transfer and persistence in breast milk. Pharmacokinetic studies show that maternal omeprazole 20 mg daily results in low breast milk concentrations with calculated infant doses around 0.003 mg/kg/day, far below therapeutic infant doses, and no detectable drug in infant serum for esomeprazole.

Clinical lactation safety

Lactation databases and teratology information services report that maternal omeprazole doses of 20 mg/day produce low milk levels and are not expected to cause adverse effects in breastfed infants. Case reports of infants exposed to omeprazole or esomeprazole through breast milk describe normal growth and development without drug‑related adverse events.

Expert reviews therefore consider omeprazole compatible with breastfeeding, and state that women should not be discouraged from continuing breastfeeding while receiving omeprazole given the minimal milk transfer and substantial benefits of breastfeeding. No special timing of breastfeeding relative to dosing appears necessary, although feeding just before dosing can theoretically further minimize exposure.

Class considerations in lactation

Although omeprazole and esomeprazole have the most robust lactation data, PPIs as a class are expected to have similarly low milk transfer due to shared physicochemical and pharmacokinetic properties. In the absence of specific data for newer agents (e.g. dexlansoprazole, vonoprazan), it is prudent to prefer well‑studied molecules, particularly omeprazole, in breastfeeding women who require PPI therapy.

When possible, PPIs should be prescribed at the lowest effective dose and for the shortest necessary duration, with regular reassessment of the indication to avoid unnecessary long‑term exposure in both mother and infant. Additional caution is warranted in premature infants or neonates with significant comorbidities, where theoretical risks of altered gastric pH, infection, or sensitization must be balanced against maternal benefit, and clinical monitoring is advisable.

Practical prescribing notes for perinatal care

In pregnancy and lactation, non‑pharmacological measures and antacids or H2‑receptor antagonists may be considered before initiating PPIs in mild cases of reflux, but PPIs are appropriate when symptoms are severe, persistent or complicated (e.g. erosive esophagitis, ulcer, GI bleeding risk). For breastfeeding women already stable on a particular PPI, switching solely because of lactation is usually unnecessary if the drug is omeprazole or esomeprazole; if using less‑studied agents, a switch to omeprazole can be considered if clinically feasible.

When PPIs are co‑prescribed with antithrombotic agents or chronic NSAIDs in perinatal patients, providers should reassess ongoing need, dose and duration of both gastroprotective and primary therapies, documenting individual risk–benefit considerations. Counseling should include discussion of potential long‑term maternal risks of PPIs, expected minimal infant exposure during breastfeeding, and reassurance based on current human data, while acknowledging that experience is most extensive with omeprazole.