Hexoprenaline in Pregnancy and Breastfeeding
Fetal Risk Summary
Hexoprenaline is a b2-sympathomimetic used as an IV tocolytic agent and as an oral or inhaled bronchodilator in the symptomatic treatment of bronchial asthma and chronic obstructive pulmonary disease. It is structurally similar to several other sympathomimetics including epinephrine, norepinephrine, and isoproterenol. Although available in other countries, it is not yet available in the United States.
Unpublished reproductive data involving hexoprenaline in rats and rabbits were cited in a 1977 review (1). No embryotoxic or teratogenic effects were noted in pregnant rats administered hexoprenaline 5 mg/kg/day between days 6 and 15. However, a slight decrease in the fertility index did occur. An increase in the number of stillborn and a decrease in fetal weight were observed in pregnant rabbits dosed with 0.5 mg/kg/day between days 16 and 18 of pregnancy (1). For comparison, the human oral dose for bronchodilation is approximately 0.04 mg/kg/day, based on 3 mg/day in a 70-kg human, whereas the usual tocolytic dose is approximately 0.1 g/minute (about 0.002 mg/kg/day for a 70-kg human).
In a study with pregnant rats at day 14 of gestation, a bolus injection of hexoprenaline 0.5 g/kg followed immediately by a 30-minute infusion of 0.1 g/kg/minute, increased blood flow to the placenta by 198% (2). This dose also increased the percentage of cardiac output distributed to the placenta by 229%. Renal blood flow was reduced by 24% (2).
Because of its relatively low molecular weight (about 519 for the sulfate salt), hexoprenaline should cross the placenta to the fetus. However, no measurable levels of radioactivity were found in fetal blood following administration of carbon-14-labeled hexoprenaline to pregnant sheep (3). Pregnant rabbits were given a 0.015-mg/kg dose of carbon-14-labeled hexoprenaline and the amounts of labeled drug were determined in the maternal and fetal compartments over a 60-minute interval (4). Very small amounts of radioactivity were measured in the fetal compartment, which the authors considered insignificant. In an in vitro perfused human placenta module, the transfer of 14C-labeled hexoprenaline to the fetal side was approximately 1.1%, significantly less than the transfer of three other b-sympathomimetics labeled with tritium (3H-fenoterol 2.3%, 3H-ritodrine 2.4%, and 3H-albuterol 2.8%) (5). The doses used for each drug were considered similar to those used in clinical practice and had equivalent tocolytic effects. The low placental transfer of these agents may have resulted from the use of only about 5% of the exchange area of the total placenta and a short measurement interval (5).
At least four studies have described the human use of hexoprenaline as a tocolytic (6,7,8 and 9). The uterine selectivity of four tocolytic agents (equivalent IV bolus doses are shown in parentheses), hexoprenaline (7.5 g), albuterol (200 g), fenoterol (50 g), and ritodrine (6 mg), were compared in a 1976 study (6). The study drugs were administered in a predetermined sequence to 10 women at term with oxytocin-induced labor. Hexoprenaline had the least effect on the maternal heart as measured by an increase in pulse rate. All of the drugs caused transient hypotension with the most pronounced effect on the diastolic blood pressure. Although the difference was not significant, hexoprenaline stopped uterine contractions for the longest average time (12.94 minutes) and ritodrine stopped uterine contractions for the shortest average time (8.63 minutes). The average time for the other two agents was about 10.3 minutes. All of the agents produced a transient rise in the fetal heart rate of about 10 beats/minute and an increase in beat-to-beat variation.
A second report by the same investigators compared the uterine and cardiovascular effects of a 20-minute IV infusion of the four tocolytics used in the study above (7). The dose infused per minute was 1/20th of the IV bolus dose. All of the drugs significantly reduced the activity of the uterus to less than 30% of the initial level, but the tocolytic effect of ritodrine lasted nearly twice as long as the effects of the other three agents. As in their first study, hexoprenaline produced the smallest rise in maternal pulse rate and the smallest increase in systolic blood pressure. The decrease in diastolic blood pressure was similar among the four drugs. No adverse fetal or neonatal effects were observed other than a slight rise in the fetal heart rate and an increase in beat-to-beat variability prior to birth. A 1981 study of 20 women in labor reported that 30 minutes of a hexoprenaline infusion, at doses up to 0.3 g/minute, decreased the uterine activity by nearly 74% while increasing the maternal pulse rate by 25% (8). No significant change was observed in the fetal heart rate.
IV infusions of hexoprenaline (0.38 g/minute) and fenoterol (2.5 g/minute) as tocolytics in prostaglandin F2a-induced labor were compared in a 1984 study (9). Both drugs were alternatively infused for 20 minutes in each of 12 women at term. Uterine activity (pressure, intensity, and frequency) was reduced to less than 29% of the initial activity by both drugs. As in the above two studies, hexoprenaline produced the least effect on maternal pulse rate. The effects on systolic and diastolic pressure were similar. Other than the fetal heart rate changes noted above, no adverse effects on the fetuses or newborns were observed.
Like other b-sympathomimetic tocolytic agents, hexoprenaline has been used in the emergency treatment of fetal distress resulting from various causes during labor (10,11 and 12). A 1977 study described the successful treatment of six women in labor with a single, 10-g IV bolus dose of hexoprenaline for acute, severe fetal bradycardia (10). Fetal acidosis was documented in three of the cases. The Apgar scores were 79 in five infants (4 in one infant) at 1 minute and 710 in six infants at 5 minutes. In a 1986 study, 12 women with severe fetal distress from various causes in labor were treated with a 7.510-g IV bolus of hexoprenaline followed by an IV infusion of the drug titrated to inhibit uterine contractions (11). According to protocol, all were delivered by cesarean section approximately 40 minutes after the IV bolus dose. Nine of the newborns had Apgar scores of 7 or greater at 1 minute (2 in one infant, 6 in two), and twelve had Apgar scores of 8 or greater at 5 minutes. The mean fetal scalp pH before treatment was 7.17, and the mean cord blood pH was 7.31. A randomized, controlled study published in 1997 studied the benefits and disadvantages of therapy with a b-sympathomimetic in 37 women in labor at 35 weeks' gestation or more who were scheduled for cesarean section because of fetal distress (12). Comparisons were made between the maternal, fetal, and newborn outcomes for the study group (hexoprenaline; N=17) and the controls (no therapy; N=20). The mean time to cesarean section was 60 minutes in the study group and 54 minutes for the controls. The study group received a 10-g IV bolus of hexoprenaline (N=17) administered over 5 minutes. There were no statistical differences between the groups in the main outcomes measured: cord blood gas values, Apgar scores at 1 and 5 minutes, need for resuscitation, and admission to the neonatal intensive care unit (12). Significantly more fetuses, however, had an improvement in their heart rate patterns after hexoprenaline. Two infants in the control group were stillborn; one had hydrocephalus, and the other was delivered vaginally 55 minutes after the onset of fetal distress.
Fetal and maternal cardiac toxicities have been reported with the use of hexoprenaline tocolysis (13,14,15 and 16). A 1991 case report described severe fetal tachycardia in a woman at 32 weeks' gestation given a 10-g IV bolus dose of hexoprenaline for fetal distress (13). The patient had been treated 3 days earlier with glucocorticoids for fetal lung maturity and with indomethacin and hexoprenaline (for 4 hours) followed by oral fenoterol for tocolysis. Because of the suspected occurrence of intrauterine infection 3 days later, fenoterol was stopped and oxytocin was initiated for labor induction. Shortly thereafter, with the fetal heart rate at 160175 beats/minute, a sudden deceleration to 80 beats/minute occurred without evidence of a hypertonic uterine contraction. Oxytocin was discontinued, and an IV bolus of hexoprenaline was administered. The fetal heart rate increased to at least 210 beats/minute. A 1440-g, male infant was delivered by emergency cesarean section with Apgar scores of 2, 3, and 5 at 1, 5, and 10 minutes, respectively. The infant survived after ventilation for 24 hours. No evidence of infection or cardiac defect was found.
A healthy, 20-year-old woman at 33 weeks' gestation was treated with an IV infusion of hexoprenaline 0.15 g/minute, increased to 0.3 g/minute over 20 minutes, for preterm labor (14). Her pulse rate increased from 80 beats/minute to 112124 beats/minute. After 1.5 hours, her pulse suddenly increased to 160 beats/minute and became irregular. Her blood pressure remained unchanged at 90/60 mm Hg. An electrocardiogram (ECG) revealed atrial fibrillation that reverted spontaneously to a normal sinus rhythm 8 hours later. She had no further symptoms of cardiac dysfunction or preterm labor and eventually delivered, at term, a 3220-g female infant with Apgar scores of 6 and 9 at 1 and 5 minutes, respectively. In the absence of other known causes, the atrial fibrillation was attributed to hexoprenaline.
Hexoprenaline 9 g/hour was used for tocolysis in a healthy 29-year-old patient with preterm labor at 32 weeks' gestation (15). Her baseline pulse rate was 95 beats/minute. An IV infusion of verapamil was added to prevent maternal tachycardia, but after 24 hours the patient developed retrosternal pain, dyspnea, palpitations, and nausea. An ECG revealed supraventricular tachycardia with a rate of 180 beats/minute. Her blood pressure fell from 95/60 mm Hg to 70/45 mm Hg. The hexoprenaline dose was reduced to 6 g/hour and then discontinued 5 hours later. Other measures, including digoxin, continuous verapamil, carotid sinus massage, and Valsalva maneuvers, failed to stop the arrhythmia. Metoprolol (5 mg IV), a cardioselective b-adrenergic blocking agent, was administered 52 hours after the onset of the tachycardia, and 4 hours later the heart rate fell to 100 beats/minute. The fetal heart rate remained in the 130140-beats/minute range throughout and did not appear to be affected by any of the above events. In the absence of labor, the patient was treated with oral metoprolol (100 mg/day) until the recurrence of tachycardia (130 beats/minute) with signs of cardiac decompensation at 39 weeks' gestation. A cesarean section was performed to deliver a 3850-g female infant with Apgar scores of 9, 10, and 10 at 1, 5, and 10 minutes, respectively. In the absence of cardiac disease, the authors thought the tachycardia was most likely induced by hexoprenaline (15).
Two studies have reported follow-up examinations of 72 children exposed in utero to hexoprenaline during the 3rd trimester (16,17). Examinations were conducted during the first week of life in 28 (16), at a mean age of 15 months (range 240 months) in 23 (17), and at 3 years of age in 21 (16). The mean maternal hexoprenaline dose in one group was 51.103 mg over an average period of 13.8 days (17). The examinations included general health, neurological development, ECG, blood analyses, and ultrasonography (not all of the examinations were conducted in each group). Except for an incidental systolic murmur in two children and borderline cardiomegaly in a third, all of the children appeared to be developing within normal limits.
Like all b-sympathomimetics, hexoprenaline may cause transient maternal hyperglycemia with an increase in serum insulin levels (18). Sustained neonatal hypoglycemia may be observed if maternal hyperglycemia occurs close to delivery.
In summary, no reports describing the use of hexoprenaline during early human pregnancy have been located. Although several studies have investigated the use of the drug as a tocolytic agent, the amount of published research is less than that available for other similar agents (e.g., see Terbutaline and Ritodrine). Hexoprenaline does not appear to offer any advantage over these tocolytic agents. As with any b-sympathomimetic, including hexoprenaline, avoiding continuous IV infusions will lessen the chance of serious maternal cardiac toxicity. The administration of the drug as a bronchodilator during pregnancy has not been reported.
Breast Feeding Summary
No reports describing the use of hexoprenaline during lactation have been located. The molecular weight of the sulfate salt of hexoprenaline (about 519) is low enough, however, that passage into milk should be expected. The effects of this exposure on a nursing infant are unknown, but other b-sympathomimetics (e.g., see Terbutaline) are considered compatible with breast feeding.
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- Lipshitz J, Ahokas RA, Broyles K, Anderson GD. Effect of hexoprenaline on uteroplacental blood flow in the pregnant rat. Am J Obstet Gynecol 1986;154:3104.
- Lipshitz J, Yau MK, Meyer MC, Ahokas RA, Maduska AL, Whybrew WD, Anderson GD, Morrison JC, Schneider J. Hexoprenaline pharmacokinetics in pregnant and nonpregnant sheep. Res Commun Chem Pathol Pharmacol 1981;34:316.
- Lipshitz J, Broyles K, Whybrew WD, Ahokas RA, Anderson GD. Placental transfer of 14C-hexoprenaline. Am J Obstet Gynecol 1982;142:3135.
- Sodha RJ, Schneider H. Transplacental transfer of beta-adrenergic drugs studied by an in vitro perfusion method of an isolated human placental lobule. Am J Obstet Gynecol 1983;147:30310.
- Lipshitz J, Baillie P, Davey DA. A comparison of the uterine beta2 -adrenoreceptor selectivity of fenoterol, hexoprenaline, ritodrine and salbutamol. S Afr Med J 1976;50:196972.
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- Lipshitz J, Lipshitz EM. Uterine and cardiovascular effects of fenoterol and hexoprenaline in prostaglandin F2a-induced labor in humans. Obstet Gynecol 1984;63:396400.
- Lipshitz J. Use of a b2-sympathomimetic drug as a temporizing measure in the treatment of acute fetal distress. Am J Obstet Gynecol 1977;129:316.
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