METHYLERGONOVINE MALEATE

Fetal Risk Summary

Methylergonovine maleate (methylergometrine maleate; methylergobasine maleate) is an ergot alkaloid derivative used in the treatment of postpartum and postabortion hemorrhage. It is contraindicated during pregnancy because it may cause sustained, tetanic uterine contractions and resulting fetal compromise.

Only one animal reproductive study has been located that has investigated the effect of methylergonovine on the fetus (1). Thirteen albino rats were administered 0.5 mg/kg intraperitoneally twice daily from the 12th day through the 21st day (second half of gestation) after sperm were found in the vaginal smears of the animals (1). Three other groups received different ergot alkaloids and another group acted as controls. Three (23%) of the methylergonovine group failed to conceive or resorbed their concepti compared with an average of 17% (10 of 58) in the other three treated groups and 17% (2 of 12) in the controls. The surviving pups were not examined for congenital malformations (drug-induced anomalies not expected), but their birth weights were similar to those of pups in the control group.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 32 of which were exposed to ergot derivatives other than ergotamine during the 1st trimester (2). Five of this group were exposed to methylergonovine maleate; 18, to ergonovine; 5, to ergot; 3, to dihydroergotamine; and 1, to methysergide. Three children with any malformation were observed in the total group, but only one had a malformation considered easily recognizable among the 12 medical centers participating in the study. The authors concluded that, although the numbers were small, there was no evidence that these agents were teratogenic (2).

A 1979 report described the effects of methylergonovine on a woman in the first stage of labor (i.e., from onset of labor to full dilation of the cervix) at 43 weeks' gestation (3). The woman was accidentally given 0.2 mg methylergonovine IM that had been ordered for a postpartum patient. Within 20 minutes, uterine hypertonus was evident, and the fetal heart rate (FHR) decreased to 80 to 90 beats/minute with increased variability. IV epinephrine (0.5 mL of 1:1000) was administered, with a rapid decline in excessive uterine activity, but the FHR fell to 40 to 50 beats/minute (most likely because of epinephrine-induced vasoconstriction) before slowly returning to baseline. When uterine tetany returned, a second dose of epinephrine (1/6 mL) was required, producing similar effects on uterine activity and the FHR, but of shorter duration. A 6-pound 0.25-ounce (about 2731-g) male infant was delivered 6 hours later with Apgar scores of 5 and 7 at 1 and 5 minutes, respectively. Examinations of the infant over the next 9 months were normal.

A similar case of accidental (i.e., a dose intended for another patient) methylergonovine administration resulting in uterine hypertonus was reported in 1988 (4). The 18-year-old woman at 37 weeks' gestation in the first stage of labor with uterine contractions every 2 to 3 minutes and a partially dilated and effaced cervix received 0.2 mg methylergonovine IM. Six minutes later, the FHR fell from 150 to 70 beats/minute and uterine hypertonus was detected on palpation. Terbutaline, 0.25 mg IV, reversed the fetal bradycardia but did not relax the uterus. Magnesium sulfate, 4-g IV loading dose followed by 2 g/hour, also failed to reverse the hypertonus. Adverse changes in the fetus, including loss of FHR beat-to-beat variability, late decelerations, development of tachycardia (170 beats/minute), and acidosis (scalp pH 7.12), impelled the authors to perform a cesarean section, under general anesthesia, to deliver the 7-pound 15-ounce (about 3604-g) male infant. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. At delivery, the umbilical artery blood had a pH of 7.13, confirming the diagnosis of metabolic acidosis (4). The infant did well after delivery and was discharged home at 4 days of age.

In summary, methylergonovine does not appear to be a major teratogen in either animals or humans, but the data are too limited for any conclusion. The drug is contraindicated during pregnancy because of its propensity to cause sustained, tetanic uterine contractions that result in fetal hypoxia. Because of this, it is used as an alternate drug to oxytocin for management of the third stage of labor (i.e., from delivery of the infant to delivery of the placenta) and for the treatment of postpartum or postabortion hemorrhage. Care must be taken before administering this agent to confirm that the intended recipient has delivered her fetus.

Breast Feeding Summary

Small amounts of methylergonovine are excreted into human breast milk. During the first 4 days postpartum, eight lactating women (not stated whether the women were nursing) were treated with the drug, 0.125 mg orally 3 times daily, because of incomplete uterine involution (5). On the 5th postpartum day, a 0.25-mg oral dose was administered, and milk and plasma samples were collected 1 and 8 hours later. Methylergonovine concentrations in the milk were determined by radioimmunoassay. Measurable (test sensitivity 0.5 ng/mL) amounts were found in four of the eight milk samples at 1 hour (average 0.8 ng/mL; range 0.6–1.3 ng/mL) and in one sample at 8 hours (1.2 ng/mL). Seven other milk samples had detectable amounts of the drug, but the concentrations were <0.5 ng/mL. In contrast, all eight of the plasma samples had measurable drug (average 2.5 ng/mL; range 0.6–4.4 ng/mL). At 8 hours after the dose, two plasma samples had measurable drug (0.5 and 0.6 ng/mL), and one had detectable drug (<0.5 ng/mL). In the four cases at 1 hour that had measurable drug in both the plasma and milk, the milk:plasma ratio was about 0.3. Based on the lack of accumulation of methylergonovine in the plasma or milk, the authors concluded that the use of the drug during breast feeding would not affect the infant (5).

Higher plasma, and presumably, milk drug levels may have occurred at 3 hours after a dose based on other research conducted by these investigators (6). In this study, conducted in the same manner as the study described above but with drug levels determined on the 3rd and 6th postpartum days, maternal plasma levels of methylergonovine at 1 and 3 hours after a 0.25-mg oral dose were about 1.7 ng/mL and 2 ng/mL, respectively (5,6). The authors, however, did not believe that measurement of the higher drug levels would have changed their conclusion (5).

The effect of methylergonovine, which is structurally related to bromocriptine, a known inhibitor of prolactin secretion and human lactation, on suckling-induced release of prolactin and subsequent milk production is controversial. In a study published in 1975, 14 women received a 0.2-mg IM dose of the drug after delivery of the placenta and 15 other women acted as controls (7). Serum prolactin levels before drug administration in the two groups were 90.1 and 93.6 ng/mL, respectively. At 80 to 90 minutes after delivery, the mean serum prolactin concentration in the treated group was 141 ng/mL (difference not significant from baseline). In contrast, the level in the controls was 266 ng/mL, significantly higher than baseline (p<0.002) and significantly higher than the methylergonovine group (p<0.02).

Similar effects of methylergonovine on prolactin release were published in a 1975 Reference (8). A 0.2-mg IM dose administered on the 3rd postpartum day produced a statistically significant decrease in serum prolactin between 45 and 60 minutes after injection. At 180 minutes after the dose, the prolactin levels began to rise, but they still had not returned to baseline by 240 minutes.

In another 1975 report, 10 breast-feeding mothers in the immediate postpartum period were treated with methylergonovine, 0.2 mg orally three times daily for 7 days (9). A similar group of 10 breast-feeding women received no medication. Plasma prolactin concentrations in both groups were measured each morning. No significant difference between the groups in prolactin concentrations was measured, with plasma levels of prolactin decreasing from a mean of 144 ng/mL (both groups) to 41 ng/mL (methylergonovine) and 37 ng/mL (controls) at 7 days. Milk let-down occurred between the 2nd and 4th postpartum day in both groups. Moreover, the mean milk volume production (estimated by infant weight gain and residual milk obtained by electric breast pump) on the 7th postpartum day was 386 mL in the treated group and 367 mL in the controls (n.s.).

Contrary to the above study, two reports, one in 1976 (10) and one in 1979 (11), described the inhibitory effects of ergot derivatives on prolactin secretion and lactation. In the 1976 paper, ergonovine, an agent closely related to methylergonovine, was given to 10 women in a dose of 0.2 mg orally three times daily from the 1st through the 7th postpartum day (10). None of the women nursed their infants. Six other women who were not breast feeding acted as controls. Blood samples for serum prolactin measurement were drawn each morning in both groups. Before-treatment mean serum prolactin concentrations in the ergonovine and control groups were 537 and 562 ng/mL (difference not significant), respectively, and on postpartum day 7 they were 89.7 and 218.0 ng/mL (p<0.01), respectively. Moreover, the serum prolactin concentrations were significantly lower each day than the levels in the ergonovine group. Three of the ergonovine-treated women showed progressive lactation inhibition, whereas the other seven women had painful breast engorgement and spontaneous milk let-down.

Two other women in the above study received ergonovine 0.2 mg IV before nursing on the 5th postpartum day (10). One of these women also received ergonovine, 0.2 mg orally three times daily, before and after the IV dose. In the woman who received both IV and oral doses, the normal rise in serum prolactin induced by suckling was abolished.

The 1979 report described the effects of methylergonovine, 0.2 mg orally 3 times daily, in 30 breast-feeding women compared with 30 nonmedicated, breast-feeding control women (11). Plasma prolactin concentrations were determined in both groups on postpartum days 1, 3, and 7. Milk yields, estimated by weighing the nursing baby before and after suckling, were determined on postpartum days 3 and 7. In the control group, mean plasma prolactin levels on days 1, 3, and 7 were 374.1, 226.2, and 166.3 ng/mL, respectively. Mean plasma prolactin levels in the treated group on these days were 352.9, 219.6, and 88.7 ng/mL, respectively. Only the levels on day 7 were statistically different (p<0.01) (11). Milk production (in g/day) was significantly less in the treated group compared with the controls on days 3 (p<0.05) and 7 (p<0.01) (specific weights of milk in the two groups not stated).

In summary, methylergonovine is excreted into breast milk in very small quantities. No accumulation of the drug in breast milk has been measured. This ergot derivative appears to inhibit release of prolactin, including that induced by suckling, resulting in a decreased milk production, but not to the same degree as the structurally related drug bromocriptine. The clinical significance of the lactation suppression and the exposure of the nursing infant to the drug, however, is most likely nil. This may be a result of its usual short-term use after delivery and its lower potency (on a mg-to-mg basis) as a prolactin-release inhibitor. No adverse effects attributable to methylergonovine in a nursing infant have been reported. Moreover, methylergonovine is one of the most commonly prescribed drugs during the first postpartum week.

References

1. Sommer AF, Buchanan AR. Effects of ergot alkaloids on pregnancy and lactation in the albino rat. Am J Physiol 1955;180:296–300.
2. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:357–65.
3. Wong R, Paul RH. Methergine-induced uterine tetany treated with epinephrine: case report. Am J Obstet Gynecol 1979;134:602–3.
4. Moise KJ Jr, Carpenter RJ Jr. Methylergonovine-induced hypertonus in term pregnancy. A case report. J Reprod Med 1988;33:771–3.
5. Erkkola R, Kanto J, Allonen H, Kleimola T, Mantyla R. Excretion of methylergometrine (methylergonovine) into the human breast milk. Int J Clin Pharmacol Biopharm 1978;16:579–80.
6. Allonen H, Juvakoski R, Kanto J, Laitinen S, Mantyla R, Kleimola T. Methylergometrine: comparison of plasma concentrations and clinical response of two brands. Int J Clin Pharmacol Biopharm 1978;16:340–2.
7. Weiss G, Klein S, Shenkman L, Kataoka K, Hollander CS. Effect of methylergonovine on puerperal prolactin secretion. Obstet Gynecol 1975;46:209–10.
8. Perez-Lopez FR, Delvoye P, Denayer P, L'Hermite M, Roncero MC, Robyn C. Effect of methylergobasine maleate on serum gonadotrophin and prolactin in humans. Acta Endocrinol 1975;79:644–57.
9. Del Pozo E, Brun Del Re R, Hinselmann M. Lack of effect of methyl-ergonovine on postpartum lactation. Am J Obstet Gynecol 1975;123:845–6.
10. Canales ES, Garrido JT, Zarate A, Mason M, Soria J. Effect of ergonovine on prolactin secretion and milk let-down. Obstet Gynecol 1976;48:228–9.
11. Peters F, Lummerich M, Breckwoldt M. Inhibition of prolactin and lactation by methylergometrine hydrogen maleate. Acta Endocrinol 1979;91:213–6.