Vasodilator
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The use of nitroglycerin during pregnancy does not seem to present a risk to the fetus. However, the number of women treated during pregnancy is limited, especially during the 1st trimester. With the smaller doses reported, transient decreases in the mother’s blood pressure may occur, but these do not appear to be sufficient to jeopardize placental perfusion. Nitroglycerin appears to be a safe, effective, rapid-onset, short-acting tocolytic agent. The use of transdermal nitroglycerin patches may also prove to be effective when longer periods of tocolysis are required. With any route of administration, however, additional studies are required to determine the safest effective dose.
FETAL RISK SUMMARY
Nitroglycerin (glyceryl trinitrate) is primarily indicated for the treatment or prevention of angina pectoris. Because of the nature of this use, experience in pregnancy is limited. The drug, a rapid-onset, short-acting vasodilator, has been used to control severe hypertension during cesarean section (1,2). The use of nitroglycerin sublingually for angina during pregnancy without fetal harm has also been reported (3). Recent investigations, discussed below, have explored the use of nitroglycerin as both an emergency and a routine tocolytic agent.
Reproductive studies in rats and rabbits have been conducted with nitroglycerin (4–6). No adverse fetal effects or postnatal changes were observed in these experiments.
The Collaborative Perinatal Project recorded seven 1st trimester exposures to nitroglycerin and amyl nitrite plus eight other patients exposed to other vasodilators (7). From this small group of 15 patients, 4 malformed children were produced, a statistically significant incidence. The data did not indicate whether nitroglycerin was taken by any of the mothers of the affected infants. Because of the lack of specific information and the small number of patients, no conclusions as to the relative safety of nitroglycerin in the 1st trimester can be made from this study. Moreover, the authors of this study emphasized that statistical significance could not be used to infer causal relationships and that independent confirmation from other studies was required.
The use of nitroglycerin in gestational hypertension has been described (8–11). In three patients, IV infusions of nitroglycerin were effective in rapidly correcting the hemodynamic disturbances of gestational hypertension complicated by hydrostatic pulmonary edema, but a rapid improvement in arterial oxygenation did not occur (8). In another study by the same investigators, the effectiveness of IV nitroglycerin to decrease blood pressure in six women with gestational hypertension was dependent on the patient’s volume status (9). When volume expansion was combined with nitroglycerin therapy, a marked resistance to the hypotensive effect of the drug was observed. In two of the women treated with IV nitroglycerin alone, significant reductions in blood pressure occurred, resulting in fetal heart rate changes that included late decelerations and bradycardia. Recovery occurred after nitroglycerin therapy was terminated and then restarted at a lower dose. In three other fetuses, a loss of beat-to-beat variability (average variability <5 beats/minute) was noted. Therapy was continued and no abnormalities were observed in the umbilical blood gases or Apgar scores.
An abstract published in 1996 described the use of transdermal nitroglycerin patches (releasing 10 mg in 24 hours) in the treatment of gestational hypertension (10). The 24-hour mean systemic and diastolic blood pressures were significantly decreased (5% and 7%, respectively). In a 1995 study, 12 women with severe preeclampsia received an infusion of nitroglycerin starting at 0.25 mcg/kg/minute with stepwise dosage increases until a diastolic blood pressure of 100 mmHg was achieved (11). The mean systolic blood pressure decreased from 161 to 138 mmHg, whereas diastolic pressure decreased from a mean of 116 to 103 mmHg. The umbilical artery pulsatility index changed significantly but not the uterine pulsatility index, implying vasodilation in the umbilical circulation and avoidance of adverse impairment of fetoplacental perfusion (11).
Lowering of maternal blood pressure and a lessening of the hemodynamic responses to endotracheal intubation were beneficial effects obtained from IV nitroglycerin in six women with severe preeclampsia (12). A progressive flattening of fetal heart rate beat-to-beat variability was observed in all six patients. Prevention of an increase in mean arterial pressure of >20% was achieved in only two of the women, and all had nausea, retching, and vomiting that was apparently not dose-related.
Myocardial infarction, secondary to development of a thrombus on an artificial aortic valve, occurred in a 25-year-old woman at 26 weeks’ gestation (13). A portion of her initial treatment consisted of both oral and IV nitroglycerin, with the latter being continued for an unspecified interval. Maternal diastolic blood pressure was maintained above 50 mmHg while on nitroglycerin and, apparently, no fetal distress was observed. A viable 2608-g male infant was eventually delivered at 35 weeks’ gestation, but specific details were not provided on his condition.
A 1993 reference described two women, one with triplets, who suffered myocardial infarctions during pregnancy, at 16 and 28 weeks’ gestation, and who were treated with IV nitroglycerin and other agents (14). In addition, mild chest pain occurring during labor was successfully treated with sublingual nitroglycerin in one of the women. Both patients survived and eventually delivered infants apparently unaffected by the treatment. Another report described a woman at 26 weeks’ gestation who was treated with IV nitroglycerin and other agents for a myocardial infarction (15). She eventually delivered a healthy female infant by cesarean section at 39 weeks.
In gravid ewes, IV nitroglycerin was effective in counteracting norepinephrine-induced uterine vasoconstriction (16). The antihypertensive effect resulted in a significantly decreased mean aortic pressure but did not significantly change uterine blood flow or uterine vascular conductance. A 1994 abstract reported no adverse effects on fetal cardiorespiratory function in sheep from a 2-hour IV infusion of nitroglycerin at 3 times the minimum effective tocolytic dose (17).
The use of nitroglycerin during cesarean section to allow delivery of babies entrapped by a contracted uterus has been described in two case reports (18,19). In the first case, the head of a baby presenting as a double footling breech was trapped in the hypertonic upper segment (18). Uterine relaxation was achieved with a 1000-mcg IV bolus of nitroglycerin. The mother’s blood pressure fell to 70/30 mmHg but responded to ephedrine. The Apgar scores of the 3090-g, term infant were 5 and 9 at 1 and 5 minutes, respectively. In the second case, a woman received a 100-mcg bolus of nitroglycerin to quickly relax a contracted uterus and to allow the successful delivery of her twins (19). Other than a systolic blood pressure decrease (preoperative pressure 120 mmHg; after nitroglycerin 85 mmHg) that responded rapidly to ephedrine, no other adverse effects from nitroglycerin were encountered in the mother or her newborns.
Two references have discussed the use of IV nitroglycerin as a short-acting tocolytic agent during intrapartum external cephalic version (20,21) and one involving internal podalic version (22). A woman in premature labor (uterine contractions every 2 minutes with the cervix dilated to 9 cm) at 30 weeks 5 days was given a 50-mcg IV bolus of nitroglycerin (20). The uterus relaxed palpably within 20 seconds and the fetus was repositioned to allow for vaginal delivery. A decrease in the maternal blood pressure was noted (145/100 to 130/75 mmHg, then stabilizing at 130/85 mmHg within 2 minutes), but the heart rate and oxygen saturation remained unchanged. The premature infant was delivered vaginally shortly after rupture of the membranes and start of an oxytocin infusion. A second mother at 39 weeks 4 days of gestation received a 100-mcg IV bolus dose before external cephalic version (blood pressure decreased from 120/60 to 112/60 mmHg within 1 minute) and subsequently underwent a vaginal delivery of a healthy infant.
In the second report, a woman delivered one twin vaginally and then received a 50-mcg IV nitroglycerin bolus to allow external version of the second transverse-lie twin (21). No significant maternal adverse effects (e.g., headache or dizziness) or changes in blood pressure or heart rate were observed. The healthy twin was delivered vaginally 45 minutes after the version.
Internal podalic version and total breech extraction of the second twin was accomplished in a third case with sublingual nitroglycerin by aerosol after the uterus had contracted down on the operator’s forearm (22). Two 400-mcg boluses were given, resulting in uterine relaxation within 30 seconds. No adverse effects on the newborn were observed.
Three cases of total breech extraction, with internal podalic version in two, of the second twin were aided by the use of nitroglycerin spray (0.4 mg) administered sublingually after either contraction of the uterine corpus and lower segment or uterine or cervical contractions with failure of the fetal head to engage (23). Minimal changes were observed in the maternal blood pressures and pulses. All three newborns were doing well.
A 1996 report described nine cases of internal podalic version of a second nonvertex twin with the assistance of an IV bolus of nitroglycerin (1 mg in eight and 1.5 mg in one) (24). One of the women had a panic attack that required general anesthesia for sedation, although the version was successful. In another case, nitroglycerin failed to induce uterine relaxation and an emergency cesarean section was required for fetal distress. Postpartum hemorrhage (2000 mL) occurred in a third woman. A significant fall in maternal blood pressure was observed in all cases, but no adverse effects from the decrease occurred in the mothers or newborns (24).
Transdermal patches of nitroglycerin have been tested as tocolytics in 13 women in preterm labor (23–33 weeks’ gestation) (25). Most of the women received a single patch that delivered 10 mg of nitroglycerin for 24 hours, but some patients were given a second patch if uterine contractions had not subsided within 1 hour. Patches were changed every 24 hours. The mean prolongation of pregnancy, as of the date of a subsequent report (one woman was still pregnant), was 59 days (26). The babies who had been delivered were all doing well.
Small IV bolus doses of nitroglycerin (60 or 90 mcg for one or two doses) were used in 24 laboring women for severe fetal distress, related to uterine hyperactivity that was unresponsive to standard measures (27). Six of the patients developed hypotension with a mean nadir of 93.2 mmHg (minimum 85 mmHg) that was reversed with a single dose of ephedrine (4.5–6 mg). Four newborns had low 1-minute Apgar scores (3, 4, 5, and 6, respectively), but all newborns had Apgar scores of 9 or 10 and were vigorous at 5 minutes.
Nitroglycerin has also been used to relax the uterus in postpartum cases with retained placenta (28–31), two of which occurred in patients with an inverted uterus (30,31). The IV bolus dose was 500 mcg in 15 women (28), 50 mcg (some patients required two doses) in 23 cases (29,30), and 100 mcg in 1 woman (31). No significant changes in blood pressure or heart rate were recorded, and no adverse effects, such as headache, palpitations, or prolonged uterine relaxation, were observed.
BREASTFEEDING SUMMARY
No reports describing the use of nitroglycerin during human lactation have been located. The molecular weight (about 227) suggests that the drug will be excreted into breast milk.
References
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2.Hood DD, Dewan DM, James FM III, Bogard TD, Floyd HM. The use of nitroglycerin in preventing the hypertensive response to tracheal intubation in severe preeclamptics. Anesthesiology 1983;59:A423.
3.Diro M, Beydown SN, Jaramillo B, O’Sullivan MJ, Kieval J. Successful pregnancy in a woman with a left ventricular cardiac aneurysm: a case report. J Reprod Med 1983;28:559–63.
4.Oketani Y, Mitsuzono T, Ichikawa K, Itono Y, Gojo T, Gofuku M, Konoha N. Toxicological studies on nitroglycerin (NK-843). 6. Teratological studies in rabbits. Oyo Yakuri 1981;22:633–38. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:91.
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17.Bootstaylor B, Roman C, Heymann MA, Parer JT. Fetal cardiorespiratory effects of nitroglycerin in the near-term pregnant sheep (abstract). Am J Obstet Gynecol 1994;170:281.
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