Antihypertensive
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports linking the use of hydralazine with congenital defects have been located. However, fetal toxicity has been associated with use of the drug in the 3rd trimester.
FETAL RISK SUMMARY
In England, hydralazine is the most commonly used antihypertensive agent in pregnant women (1). Neonatal thrombocytopenia and bleeding secondary to maternal ingestion of hydralazine have been reported in three infants (2). In each case, the mother had consumed the drug daily throughout the 3rd trimester. This complication has also been reported in series examining severe maternal hypertension and may be related to the disease rather than to the drug (3,4).
Hydralazine readily crosses the placenta to the fetus (5). Serum concentrations in the fetus are equal to or greater than those in the mother.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 8 of whom had 1st trimester exposure to hydralazine (6, p. 372). For use anytime during pregnancy, 136 cases were recorded (6, p. 441). No defects were observed with 1st trimester use. There were eight infants born with defects who were exposed in the 2nd or 3rd trimester. This incidence (5.9%) is greater than the expected frequency of occurrence, but the severe maternal disease necessitating the use of hydralazine is probably responsible. Patients with preeclampsia are at risk for a marked increase in fetal mortality (7–10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 40 newborns had been exposed to hydralazine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (2.5%) major birth defect was observed (two expected), a hypospadias (none expected).
A number of studies involving the use of hydralazine either alone or in combination with other antihypertensives have found the drug to be relatively safe for the fetus (4,7–17). Fatal maternal hypotension has been reported in one patient after combined therapy with hydralazine and diazoxide (18).
In a woman with chronic hypertension maintained on methyldopa, an increase in blood pressure at about 35 weeks’ gestation prompted the addition of hydralazine, 25 mg twice daily, to the treatment regimen (19). Fetal premature atrial contractions were diagnosed 1 week later, but tachyarrhythmias, which can be initiated by premature atrial contractions, were not observed (19). Hospitalization with bed rest allowed the patient’s blood pressure to decline enough to discontinue hydralazine therapy. Within 24 hours of stopping hydralazine, the fetal arrhythmia resolved. The infant was delivered at 38 weeks and cardiac evaluation after discharge at 3 days indicated a regular heart rate.
A syndrome resembling lupus erythematosus was diagnosed in a 29-year-old woman treated with IV hydralazine during the 28th week of pregnancy (20). The patient received 425 mg during a 6-day period for the treatment of hypertension. IV methyldopa was administered on the 6th day of therapy. Labor was induced for fetal distress and a 780-g growth-restricted male infant was delivered vaginally. The infant expired at 36 hours of age secondary to cardiac tamponade induced by 7 mL of clear sterile transudate in the pericardial space. Lupus-like symptoms consisting of macular rash, arthralgia, and bilateral pleural effusion developed in the mother on the 5th day of hydralazine therapy and gradually resolved after discontinuance of the drug and delivery. The findings of pericardial effusion and cardiac tamponade in the infant were also thought to represent clinical evidence of a lupus-like syndrome (20). The symptoms in both the mother and fetus were attributed to hydralazine sensitivity resulting in the induction of a lupus-like syndrome.
BREASTFEEDING SUMMARY
Hydralazine is excreted into breast milk (5). In one patient treated with 50 mg 3 times daily, the milk:plasma ratio 2 hours after a dose was 1.4. This value is in close agreement with the predicted ratio calculated from the pKa (21). The available dose of hydralazine in 75 mL of milk was estimated to be 13 mcg (5). No adverse effects were noted in the nursing infant from this small concentration. The American Academy of Pediatrics classifies hydralazine as compatible with breastfeeding (22).
References
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20.Yemini M, Shoham (Schwartz) Z, Dgani R, Lancet M, Mogilner BM, Nissim F, Bar-Khayim Y. Lupus-like syndrome in a mother and newborn following administration of hydralazine: a case report. Eur J Obstet Gynecol Reprod Biol 1989;30:193–7.
21.Daily JW. Anticoagulant and cardiovascular drugs. In: Wilson JT, ed. Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:61–4.
22.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.