Pharmaco-vigilance of oral MethylErgometrine prescriptions for delayed and secondary postpartum haemorrhage.

Objectives The objectives of this study were to quantify the prescription of oral methergin tablets in a busy Women's Hospital, assess the stated indications for such prescription and highlight the issues and safety profile of Methergin use especially in the postpartum patient. Methods Review of prescription data for oral Methergin and the corresponding annual figures on primary and secondary postpartum hemorrhage. Results Over a period of 5 years, oral Methergin prescriptions for delayed and secondary postpartum hemorrhage constituted less than 1% of the overall prescription in Obstetrics and Gynaecology, which ranged between 1214 and 2085 per year. The numbers were too few to ascertain any relationship with both types of postpartum hemorrhage. Although stated on the relevant Patient Information leaflet, no local or regional guideline on its use exist. Conclusions Specific and random trend monitoring of medications for continuing safety profile, risk benefit issues, or unapproved indication, may help in identifying, preventing and mitigating any medication safety matters. Clinical pharmacists in collaboration with physicians are well placed in conducting such pharmacovigilance activities to improve medication safety.

Exposure to methylergonovine maleate as a cause of sirenomelia.

BACKGROUND: Sirenomelia is a rare, but deadly condition characterized by fusion of the lower limbs, lower spinal column defects, severe malformations of the urogenital and lower gastrointestinal tract, and an aberrant abdominal umbilical artery. METHODS: The two main hypotheses, not mutually exclusive, that have been advanced to explain the pathogenesis of sirenomelia are the blastogenetic theory and the vascular disruption theory. RESULTS: We describe a case of sirenomelia, probably associated with the use of methylergonovine maleate, an ergot alkaloid, during the first weeks of pregnancy. CONCLUSION: On the basis of the mechanisms of vascular disruption and early administration of methylergonovine maleate at a critical stage of organogenesis, we conclude that exposure to methylergonovine maleate could be the cause of the development of sirenomelia. Birth Defects Research (Part A) 106:643-647, 2016. © 2016 Wiley Periodicals, Inc.

Inadvertent oral administration of methylergometrine maleate to children in the first months of life: from surveillance to prevention.

PURPOSE: Methylergometrine maleate is an ergot alkaloid frequently used in obstetrics for prevention and treatment of post partum haemorrhage. Accidental administration of this medicine to newborns can cause severe effects and should be carefully prevented. The present paper is aimed at describing the main characteristics of cases accidentally exposed to this medicine in Italy before and after Novartis, the manufacturer of Methergin®, a widely used methylergometrine maleate-containing gynecological medication, decided to withdraw the drop preparation from the European market. METHODS: The study design is a case-series study. The database of the National Poison Control Centre of Milan was searched retrospectively (from 1 January 2005 to 31 December 2011) and prospectively (from 1 January 2012 to 31 December 2013) in order to provide a descriptive analysis of the main characteristics of cases unintentionally exposed to methylergometrine maleate and to document the impact of Novartis' decision. RESULTS: In the first period under study (2005-2011), a total of 642 cases of exposure to methylergometrine maleate were identified. Most of them were children aged <1 year (No. 483, 75%). Patients aged 1-2 and 3-5 years accounted for 13% (No. 85) and 9% (No. 56) of cases, respectively. Among children aged <1 year, about 76% (No. 368) were exposed during the first month of life, including 44% (No. 211) of cases exposed in the first week of life. The main cause of exposure was medication error (No. 432, 89%), mainly due to oral administration of methyltergometrine maleate in place of a paediatric preparation (No. 469, 97%). About 14% of these cases suffered clinical effects as a consequence of the exposure. Severity of poisoning was minor in 45 cases, moderate in 12, and severe in one case. The main cause of exposure among children aged 1-2 and 3-5 years was uncontrolled access to the medicine, accounting for 78% (No. 66) and 77% (No. 43) of cases, respectively. Some 9% (No. 8) of cases aged 1-2 years and 7% (No. 4) of those aged 3-5 years developed signs/symptoms possibly related to the exposure. For all of them, severity of clinical effects was low, but one case suffered moderate effects. Exposure to the medicine in drops was reported for 87% (No. 74) and 84% (No. 47) of cases aged 1-2 and 3-5 years, respectively. In 2012-2013 a total of 25 cases were observed. Among them, two patients were aged <1 year (8%). Both cases occurred in 2012 and were inadvertently administered the medicine in drops still available (present) in the home. Fourteen (56%) and 8 (32%) cases were aged 1-2 and 3-5 years, respectively. All of them were exposed to the tablet formulation following uncontrolled access to the medicine. CONCLUSIONS: The observations here reported indicate that having different formulations for methylergometrine maleate-containing products intended for the mother and paediatric medicines can successfully prevent medication error due to medicine exchange in the first months of life.

Comparison the effects of oxytocin and methylergonovine in elective caesarean section under spinal anesthesia.

PURPOSE: In order to prevent postpartum hemorrhage in caesarean section under spinal anesthesia, patients routinely receive oxytocin. In this study we compared the efficacy of Methylergonovine and Oxytocin on hemodynamic stability and bleeding amount in caesarean section. MATERIALS AND METHODS: In this randomised controlled trial study, 80 patients candidate for elective caesarean section under spinal anesthesia divided to two groups: 40 patients in control group received oxytocin and 40 ones in case group received methylergonovine. RESULTS: There was no differences between groups in Mean age, baseline hemodynamic values, after spinal anesthesia and recovery (except diastolic blood pressure min 20), time of uterine atony, dizziness; nausea and vomiting. After drug administration (oxytocin and methylergonovine), systolic blood pressure in minutes 1, 10, 15 and diastolic blood pressure in minutes 1, 3, 20 increased in case group statistically more than control group. In control group, heart rate in minutes 1, 5 increased significantly more than the other group. Mean arterial blood pressure in minutes 1, 3, 5, 10, 15 reduced significantly more than in control group. Need to vasoconstrictor drug statistically was less in case group (p < 0.0001). CONCLUSION: Methylergonovine induced significantly more hemodynamic stability. Adverse effects were similar between two groups. We recommend the use of methylergonovine in patients with caesarean section under spinal anesthesia because of its hemodynamic stability and low need to vasoconstrictor drugs.

Prophylactic Methylergonovine and Oxytocin Compared With Oxytocin Alone in Patients Undergoing Intrapartum Cesarean Birth: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether the administration of prophylactic methylergonovine in addition to oxytocin in patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents. METHODS: This was a single-center, placebo-controlled, randomized trial of patients undergoing intrapartum cesarean birth. Patients were randomly allocated to receive intravenous oxytocin 300 mL/minute plus intramuscular methylergonovine 0.2 mg (1 mL) or intravenous oxytocin 300 mL/minute plus intramuscular normal saline (1 mL). The primary outcome was the receipt of additional uterotonic agents. Secondary outcomes included surgeon assessment of uterine tone, incidence of postpartum hemorrhage, quantitative blood loss, and blood transfusion. To detect a twofold decrease in the need for additional uterotonic agents (assuming a 42% baseline) with a two-sided type 1 error of 5% and power of 80%, a sample size of 76 patients per group was required. RESULTS: From June 2019 through February 2021, 80 patients were randomized to receive methylergonovine plus oxytocin and 80 were randomized to receive to oxytocin alone. Significantly fewer patients who were allocated to the methylergonovine group received additional uterotonic agents (20% vs 55%, relative risk [RR] 0.4, 95% CI 0.2-0.6). Participants receiving methylergonovine were more likely to have satisfactory uterine tone (80% vs 41%, RR 1.9, 95% CI 1.5-2.6), lower incidence of postpartum hemorrhage (35% vs 59%, RR 0.6, 95% CI 0.4-0.9), lower mean quantitative blood loss (967 mL vs 1,315 mL; mean difference 348, 95% CI 124-572), and a lower frequency of blood transfusion (5% vs 23%, RR 0.2, 95% CI 0.1-0.6). CONCLUSION: The administration of prophylactic methylergonovine in addition to oxytocin in patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03904446.

Eclampsia with RCVS: Postpartum seizure provoked by methergine.

BACKGROUND: Eclampsia is a pregnancy complicationcharacterized bygeneralized tonic-clonicconvulsions.Not all seizures in pregnancy are eclamptic, and othercauses include epilepsy, infection,stroke,tumor, and ruptured aneurysm. CASE: A 19-year-old G1P0 presentedinlabor at term. She had a generalized tonic-clonicseizure one hour aftervaginaldelivery for which she received methergine for uterine atony. Seizure activity resolved with lorazepam and magnesium sulfate for presumed eclampsia.Brain imaging revealedvasoconstriction of theleftposterior cerebral artery and blood in the subarachnoid space,andshewas diagnosed with eclampsia with reversible cerebral vasoconstrictive syndrome (RCVS). CONCLUSION: RCVS isapregnancy-related cause of seizure that should remain on the differential for any patient presenting with a seizure in the peripartum period, especially with use of vasoconstrictive agents. Management is controversial but involves calcium channel blockers and magnesium sulfate, as well as avoidance of vasoconstrictive agents.

Reversible cerebral vasoconstriction syndrome with limb myoclonus following intravenous administration of methylergometrine.

Neurological deficits associated with methylergometrine have been reported primarily as a result of reversible cerebral vasoconstriction syndromes (RCVS). RCVS are characterized by reversible multifocal vasoconstrictions of the cerebral arteries heralded by acute severe headache with or without neurological deficits. Here, we present the first case of suspected RCVS with transient limb myoclonus following the intravenous administration of methylergometrine during cesarean section. A 31-year-old woman who received slowly infused intravenous methylergometrine during a cesarean section suddenly reported severe occipital headache after 40 min, followed by apnea and unconsciousness for 8 min. A second administration of methylergometrine to treat the weakness of her uterine contractions resulted in a repeated loss of consciousness within minutes and the development of limb myoclonus. No abnormalities were detected by brain computerized tomography, magnetic resonance imaging, and electroencephalogram. She fully recovered spontaneously within 12 h. We consider that the transient limb myoclonus in our patient appeared as a result of RCVS caused by the intravenous administration of methylergometrine.

Efficacy of methylergometrine during the early puerperium: a randomized double-blind placebo-controlled clinical trial.

Objective: To determine if oral methylergometrine administration during the first 10 d following spontaneous vaginal delivery has any beneficial effect on the increase of hemoglobin levels.Methods: This was a parallel group double-blind placebo-controlled clinical trial conducted at single center university hospital in Italy. Participants were puerperal women, who delivered singleton gestation with spontaneous vaginal delivery at term. Participants were randomized into a 1:1 ratio to receive either 0.125 mg methylergometrine per os twice a day or placebo for 10 d. Hemoglobin levels were recorded on the day of delivery and after 10 d. The primary outcome was the variation in hemoglobin levels between the first and the 10th day of treatment.Results: From December 2012 to October 2015, 220 agreed to take part in the study, underwent randomization, and were enrolled and followed-up. Of the randomized women, 110 (50%) were randomized to the methylergometrine group and 110 (50%) to the placebo group. No women were excluded after randomization or lost to follow-up (100%). We found no significant difference in the median variation of hemoglobin levels between the intervention and the placebo groupConclusions: The use of 10 d oral methylergometrine in puerperal women was not associated with any benefit in the variation of hemoglobin levels from delivery to 10 d after delivery.Key MessageMethylergometrine in puerperal women was not associated with any benefit.

Effect of estradiol 17beta upon coronary artery vasoconstrictor response to methylergometrine maleate in female menopausal patients.

BACKGROUND: Estrogens produce several beneficial effects upon the cardiovascular system. Amongst these, an endothelium-independent effect has been convincingly demonstrated only in vitro, while there is no evidence for such an effect in vivo. The aim of the present study was to evaluate the effect of acute administration of estradiol 17beta upon coronary artery reactivity to methylergometrine in 16 menopausal patients with coronary artery disease. METHODS: Sixteen menopausal patients underwent coronary angiography at rest and after incremental doses of methylergometrine (intracoronary 2, 10, 30 microg) before and 20 min after either intracoronary estradiol 17beta (20 ng/mL at 1 mL/min for 20 min; 8 patients) or placebo (Dextrose 5%, 1 mL/min; 8 patients). RESULTS AND CONCLUSIONS: No significant differences were observed in baseline coronary artery diameter or area between the 2 groups. No significant differences in the degree of coronary artery constriction were observed after either estradiol 17beta or placebo at submaximal doses of methylergometrine. However, the degree of coronary artery constriction after maximal doses of methylergometrine was significantly attenuated by estradiol 17beta compared to placebo (change in diameter: -0.9+/-4.5% vs. -19+/-6%, p<0.001; change in area: -3.2+/-9% vs. -32.2+/-10%, p<0.001). Estradiol 17beta reduces coronary artery constriction following methylergometrine administration in menopausal patients with coronary artery disease. This effect may be related to the calcium-antagonist properties of the ovarian hormone.

Inadvertent Methylergonovine Administration to a Neonate.

BACKGROUND Methylergonovine is an ergot alkaloid used to treat post-partum hemorrhage secondary to uterine atony. Mistaking methylergonovine for vitamin K with accidental administration to the neonate is a rare iatrogenic illness occurring almost exclusively in the delivery room setting. Complications of ergot alkaloids in neonates include respiratory depression, seizures, and death. CASE REPORT A term infant was inadvertently given 0.1 mg of methylergonovine intramuscularly in the right thigh. The error was only noted when the vial of medication was scanned, after administration, identifying it as methylergonovine rather than vitamin K. The local poison center was notified, and the infant was transferred to the neonatal intensive care unit for observation. Two hours after transfer, the infant was noted to have oxygen desaturations and required oxygen via nasal cannula. Supplemental oxygen was continued for 4 hours until the neonate was able to maintain normal oxygen saturations in room air. Feeding was started by 10 hours of life, and the infant was discharged home in good condition after a 72-hour stay without further complications. CONCLUSIONS Because of the potential for serious adverse events, vigilance is required to prevent accidental administration of methylergonovine to the neonate as a result of possible confusion with vitamin K in the early post-partum period.

The Effect of the Combined Use of Methylergonovine and Oxytocin during Caesarean Section in the Prevention of Post-partum Haemorrhage.

We aimed to show to patients the benefit of post-partum haemorrhage prophylaxis treatment and the effectiveness as a uterotonic agent of the combined use of methylergonovine and oxytocin infusion in the prevention of haemorrhage during and after Caesarean section, by comparison with a control group which received oxytocin infusion only. Two groups of patients undergoing Caesarean section at the same clinic were included in the study. A combination of methylergonovine and oxytocin was administered to the first group during the intra-operative and post-operative periods. The second group did not receive methylergonovine and was administered only with oxytocin infusion in the intra-operative and post-operative periods. Pre-operative and post-operative haemogram readings were taken for all patients in each of the groups for comparison. No difference was found between the two groups with regard to mean ages and pre-operative haemogram values. The decrease in post-operative haemoglobin values for the group administered with methylergonovine maleate and oxytocin was found to be significantly greater than for the group administered with oxytocin only. Results indicated that prophylactic methylergonovine treatment was clearly successful for the patients and no adverse side effects were found. The routine use of methylergonovine and oxytocin infusion in combination during the intra-operative period of Caesarean section reduced the level of post-partum haemorrhage considerably. We believe that this procedure will also reduce the risk of uterine atony, but clearly, prospective studies will be necessary in future to confirm this assumption.

Effect of methylergonovine on puerperal prolactin secretion.

Serum prolactin concentration was measured by radioimmunoassay in 29 women, in the first 1 1/2 hours postpartum. Fourteen women received 0.2 mg methylergonovine maleate (Methergine) intramuscularly after the delivery of the placenta. Fifteen women who served as controls received only saline. The rise in serum prolactin concentration seen in the control women (266.4 ng/ml +/- 40.8 SE) was significantly greater than that seen in methylergonovine-treated patients (141.0 ng/ml +/- 29.0. SE).

Oral misoprostol for the third stage of labor: a randomized controlled trial.

OBJECTIVE: To compare oral misoprostol with conventional oxytocics in the management of the third stage of labor. In a controlled trial, 1574 women were randomized into four groups, as follows: Group 1 received intravenous infusion of oxytocin 10 IU plus oral misoprostol 400 micro g, followed by two doses of oral misoprostol 100 micro g 4 hours apart; group 2 received oral misoprostol 400 micro g, followed by two doses of oral misoprostol 100 micro g 4 hours apart; group 3 received intravenous infusion of oxytocin 10 IU; and group 4 received intravenous infusion of oxytocin 10 IU plus intramuscular administration of methylergonovine maleate (Methergine) 0.2 mg. The incidence of postpartum hemorrhage and decrease in hemoglobin concentration from before delivery to 24 hours postpartum were the main outcome measures. RESULTS: The primary outcome measures were similar in groups 2 and 3. The incidence of postpartum hemorrhage was 9% in group 2, compared with 3.2% in group 1 and 3.5% in group 4 (P <.01, and P =.01, respectively). There were no significant differences among the four groups regarding hemoglobin concentrations. Significantly more women needed additional oxytocin in group 2, when compared with group 4 (5.9% versus 2.2%; P =.01). The proportion of women requiring additional methylergonovine maleate was 4.8% in group 2, compared with 0.7% in group 1 and 1% in group 4 (P <.01 and P =.01, respectively). CONCLUSION: Oral misoprostol alone is as effective as oxytocin alone for the prevention of postpartum hemorrhage; it is less effective than oxytocin plus methylergonovine maleate and oral misoprostol plus oxytocin.

Intraoperative blood loss in midtrimester dilatation and extraction.

Intraoperative blood loss was evaluated in 215 patients undergoing a midtrimester dilatation and extraction procedure using a paracervical-intracervical block. Patients were assigned to four randomized drug regimens using a combination of 0.5% bupivacaine, dilute epinephrine, and methylergonovine maleate. From these four regimens, a select group of patients were given fentanyl. No significant difference in blood loss was observed in any group at less than 17 weeks' gestation. Only in gestations of 17 weeks or more was there a significant increase in blood loss, and this increase was associated specifically with the use of fentanyl in the nonrandomized selected group.

Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women.

OBJECTIVE: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women. DESIGN: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender). RESULTS: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%. CONCLUSION: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Oral administration of methylergometrine shows a late and unpredictable effect on the non-pregnant human menstruating uterus.

OBJECTIVE: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation. STUDY-DESIGN: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design. RESULTS: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (Cmax), the time at which Cmax is reached (tmax) and the half-life of absorption (t1/2abs) also demonstrated large individual variations after oral administration. CONCLUSIONS: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.

The role of oral (methyl)ergometrine in the prevention of postpartum haemorrhage.

Postpartum haemorrhage (PPH) is one of the most important causes of maternal mortality in developing countries. A consensus was reached on active management of the third stage of labour for all parturients especially for those for whom the access to hospital services is difficult or time-consuming. Oral (methyl)ergometrine was considered to be a possible alternative prophylactic oxytocic, that was easy to administer and suitable to be used in developing countries. A research project was set up to investigate its suitability to be used for active management of the third stage of labour. It was examined on its stability under tropical conditions; on its pharmacokinetic and pharmacodynamic properties and on its clinical effect on the amount of bloodloss after childbirth. Oral (methyl)ergometrine is unstable even when stored after refrigerated conditions. Its pharmacokinetic and dynamic properties are unpredictable and no clinical effect on reduction of bloodloss after childbirth has been shown. To ameliorate a product's stability seems unlogical, if the same product shows unfavourable pharmacokinetics. All the more so, since the tablets do not show the wanted clinical effects. Oral (methyl)ergometrine is not an alternative to parenteral prophylactic oxytocic drugs in the active management of the third stage of labour.

Instability of (methyl)ergometrine in tropical climates: an overview.

Parenteral ergometrine is widely used for the prevention and treatment of excessive uterine bleeding following birth. Unfortunately, in tropical climates it is often found to contain very little active ingredient: only 32 of 100 field samples from Bangladesh, Gambia, Malawi, Yemen and Zimbabwe contained 90-110% of the amount of active ingredient stated on the label, and 34 contained less than 60%. In this paper the results of nine studies, of which eight were initiated and coordinated by WHO, are reviewed to formulate answers to the following questions: (1) what is the extent of the problem of low potency of ergometrine in tropical climates; (2) is the problem due to instability or low initial quality, or both; (3) which practical measures can assure the quality of injectable ergometrine; and (4) are there any alternative drugs which are more stable? Injectable ergometrine is very unstable under tropical conditions and particularly if stored unrefrigerated and exposed to light, when it may loose up to 20% of its potency per month. However, there are differences between brands. Practical measures to assure the quality of injectable ergometrine therefore include a careful supplier selection and refrigerated storage. Ergometrine injection should always be protected from light until given to the patient. Loss of active ingredient can easily be detected by regular visual checks of the colour of the solution. Any discoloration implies that the solution contains less than 90% of the stated amount of active ingredient, and should not be used. Methylergometrine is no more stable than ergometrine. Parenteral oxytocin is more stable than both ergometrine and methylergometrine injection. Oral and buccal dosage forms are less stable than injections. In view of the better stability in tropical climates, similar cost, fewer side effects and comparative efficacy, parenteral oxytocin, rather than parenteral ergometrine, is the drug of choice in the prevention and treatment of postpartum haemorrhage.