Animal studies with the combination of amlodipine and valsartan have revealed evidence of fetotoxicity at doses that produced maternal toxicity. Animal studies with hydrochlorothiazide have failed to reveal evidence of teratogenicity. There are no controlled data in human pregnancy.

The use of drugs that act directly on the RAA system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should advise the patient to discontinue the use of valsartan-HCTZ as soon as possible.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, of whom 233 were exposed to thiazide or related diuretics during the first trimester. An increased risk of malformations was found for thiazide diuretics. Use of thiazides after the first trimester does not seem to carry this risk. Thiazide diuretics may, however pose metabolic risks to the mother and fetus (hyponatremia, hypokalemia, thrombocytopenia, hyperglycemia), and may have a direct effect on smooth muscle, resulting in inhibition of labor.

Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the RAA system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, valsartan-HCTZ should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury!

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Use should be avoided; use is contraindicated per some authorities.

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Risk Summary: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Comments: Adequate methods of contraception should be encouraged.

See references

Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Excreted into human milk: Yes (amlodipine, hydrochlorothiazide); Unknown (valsartan)
Excreted into animal milk: Yes (valsartan)

Comments:
-The effects in the nursing infant are unknown.

See references