Page 1/15 Excretion of Ergometrine Maleate Injection into Breast Milk and Safety Evaluation of Breastfeeding miaomiao Chen The First Aliated Hospital of Chongqing Medical University Tianmi Song The First Aliated Hospital of Chongqing Medical University Jiacheng Xu The First Aliated Hospital of Chongqing Medical University Bingdi Chao The First Aliated Hospital of Chongqing Medical University Jie Wang The First Aliated Hospital of Chongqing Medical University Xin Luo ( [email protected]) The First Aliated Hospital of Chongqing Medical University Hongbo Qi The First Aliated Hospital of Chongqing Medical University Research Article Keywords: ergometrine maleate injection, breastfeeding, prolactin Posted Date: September 22nd, 2022 DOI: https://doi.org/10.21203/rs.3.rs-2013085/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License
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Excretion of Ergometrine Maleate Injection intoBreast Milk and Safety Evaluation of Breastfeedingmiaomiao Chen
The First A�liated Hospital of Chongqing Medical UniversityTianmi Song
The First A�liated Hospital of Chongqing Medical UniversityJiacheng Xu
The First A�liated Hospital of Chongqing Medical UniversityBingdi Chao
The First A�liated Hospital of Chongqing Medical UniversityJie Wang
The First A�liated Hospital of Chongqing Medical UniversityXin Luo ( [email protected] )
The First A�liated Hospital of Chongqing Medical UniversityHongbo Qi
The First A�liated Hospital of Chongqing Medical University
BackgroundErgometrine maleate injection as a �rst-line drug to prevent postpartum hemorrhage. To investigate thesafety of ergometrine maleate injection and breastfeeding.
MethodsPregnant women were recruited into this study according to the inclusion and exclusion criteria and theirperipheral blood and breast milk were collected for the �rst time (some pregnant women have no milk atthis time). After the delivery of the fetus, some parturients were further excluded according to theexclusion criteria. The recruited women were randomly divided into the control group and the treat group.The peripheral blood was collected in the control group at 2h and 12h after delivery, respectively, and theperipheral blood and breast milk were collected in the treat group at 2h, 4h, 6h and 12h after delivery,respectively. The concentrations of ergometrine maleate in maternal plasma and breast milk at differentperiods were detected by ultra-high-performance liquid chromatography coupled with mass spectrometry(UHPLC-MS), and prolactin levels at different time gradients after delivery were detected withchemiluminescence.
ResultsSixty-four women were �nally recruited, with 32 in the treat group and 32 in the control group. The �nalconcentration of ergometrine maleate injection reached the peak at 2h after administration and basicallydecreased to the pre-administration level at 12h after administration in both serum and breast milk. TheRID was 4.5762% (2.5146%, 7.8638%) and 0.1842% (0.0000%, 1.1838%) at 6h and 12h afteradministration, respectively. Ergometrine maleate injection does not affect the PRL concentrations inperipheral blood at 2h and 12h.
ConclusionThe results suggest that breastfeeding at 12h after ergometrine maleate injection is relatively safe. In thisstudy, ergometrine maleate injection was not found to inhibit the concentration of PRL in the peripheralblood, and no serious adverse reactions were found.
BackgroundThe American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for about the �rst 6months to be continued alongside the introduction of complementary foods for at least 1 year. Breastmilk is an ideal food for the healthy growth and development of infants. Studies have shown that the
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bene�ts of breastfeeding include but are not limited to: the reduction of childhood infections (upperrespiratory disease, otitis media, and gastroenteritis) and allergies, higher cognitive function andimproved neurocognitive[1–3] in newborns, of importance to the growth, active and passive immunity, theestablishment of circadian rhythms, as well as cognitive and psychosocial development amongnewborns.[4] However, some drugs can affect the infant through breast milk. Generally speaking, drugswith a short half-life period, strong protein binding capacity, low oral bioavailability to infants, highmolecular weight, and relative infant dose (RID) of less than 10% are safe for breastfed infants. [3, 5, 6] The�nal dose encountered by an infant must be determined with respect to both the milk secretion rate andthe disposition of the drug in the infant.[5, 6] Prolactin (PRL) is a polypeptide hormone synthesized andreleased from the anterior pituitary gland that regulates lactation, reproduction, metabolism, immuneresponses, and electrolyte balance.[7] When secreted into the circulation, pituitary PRL binds to theprolactin receptor (PRLr), required for lobuloalveolar development in the mammary gland duringpregnancy.[8, 9] Meanwhile, PRL is also the main factor in promoting lactation, and the PRL level affectson the onset time and lactation yield.[8]
Ergometrine maleate injection can directly act on uterine smooth muscle with a strong and long-lastingeffect, mainly used for the prevention and treatment of metrorrhagia due to inertia uterine or poor uterinecontractions after delivery or miscarriage, as well as for the postpartum subinvolution of uterine, etc.,which is the earliest and commonly used �rst-line uterotonic.[10, 11] The 2019 Queensland Guidelines forPostpartum Hemorrhage also pointed out that ergometrine maleate injection and oxytocin injection arethe �rst-line drugs to treat postpartum hemorrhage.[12] However, foreign literature has reported thatadministering methylergonovine as vitamin K1 to neonates can cause neonatal respiratory inhibition,which can be improved after treatment with naloxone.[13] There are also studies suggesting thatergometrine can inhibit lactation, but this conclusion has not been con�rmed.[14] The American BreastMilk Database reports that using a shorter course of methylergonovine during the colostrum period is notexpected to transfer a large number of drugs to or exert adverse effects on the breastfed infants, but it isrecommended to avoid breastfeeding within 12h after the last dose of methylergonovine.[15] This studyaims to explore the distribution of ergometrine maleate injection in maternal peripheral blood and breastmilk, thus providing the basis for guidance on breastfeeding.
1. Objects And Methods1.1 Research objects
1.1.1 Inclusion criteria: Age: 25-40 years old; Singleton pregnancy with vaginal delivery or cesareansection; Gestination weeks 37-41 weeks + 6 days; postpartum breastfeeding;
1.1.2 Exclusion Criteria
Subjects who meet one of the following criteria will not be enrolled:
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Maternity:
Had serious medical complications (heart disease, liver disease, kidney disease, etc.); abnormal liverand kidney function; severe endocrine diseases like diabetes and thyroid dysfunction (mild patients canbe included); Had pregnant hypertensive disorder and hypocalcemia; Hemoglobin <70g/L, or severecoagulation dysfunction or platelet count < 80×109/L; with occlusive peripheral vascular disease; Haduterine cavity and pelvic infection, severe systemic infection, septicemia, sepsis, etc. With epilepsy orhad a previous history of severe mental illness; Allergic to oxytocin or ergot preparations or havecontraindications; Had additional use of uterotonic or hemostatic drugs; 8. Inability to breastfeed due tovarious factors.
Newborn:
The neonate's birth weight < 2500g or ≥4000g; The 5-minute Apgar score of the neonate ≤7; Transferred to the NICU after delivered; Breastfeeding must be stopped for neonatal reasons.
1.2 Experimental Design
Screening phase:
The patients were screened before delivery (24-0 hours) and were enrolled according to theinclusion/exclusion criteria and signed the informed consent. The peripheral blood and pre-delivery milksamples were collected (some pregnant women have no milk at this time). Pregnant women in the controlgroup were given an intramuscular injection of 10U oxytocin, and an intravenous drip of 10U oxytocinadded to 500ml normal saline at a rate of 150ml/h after delivery. Those in the treat group were given anintramuscular injection of ergometrine maleate injection of 0.4 mg (2 pieces) plus 10U oxytocin, and anintravenous drip of 10U oxytocin added to 500ml normal saline at a rate of 150ml/h.
Treatment observation phase:
Studies have shown that PRL reached the peak at 2h postpartum and remained stable within 7-24 hourspostpartum.[16] Therefore, the peripheral blood was collected for PRL detection among 32 pregnantwomen(16 cesarean section and 16 vaginal delivery) in the control group at 2h and 12h after delivery toexclude the effect of the breastfeeding process on the concentration of PRL in serum.[17] For 32 pregnantwomen (16 cesarean section and 16 vaginal delivery) in the treat group, breast milk and maternalperipheral blood were collected at 2h, 4h, 6h, and 12h after delivery.
End phase:
The observation last to 24 hours after delivery, in which changes in the vital signs of pregnant womenwithin 24 hours after delivery were observed and recorded, and adverse drug reaction of the mother andnewborn within 24 hours was also recorded.
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A total of 64 pregnant women (respectively 32 in both groups, and 16 in each group were terminated bycesarean section, and 16 through vaginal delivery) were included in this study Figure 1 .
The study was approved by the ethics committee of the First A�liated Hospital of Chongqing MedicalUniversity (20200501).
1.3 Detection of the �nal concentration of ergometrine maleate and PRL in serum
The collected peripheral venous blood (2ml) was placed in an anticoagulant tube, centrifuged at1000rpm, extracted the supernatant, and then divided. PRL was measured by using thechemiluminescence immunoassay method.[18] The remaining supernatant was stored in a -80°C freezer(breast milk was stored directly in a -80°C freezer) and conveyed to the company on dry ice.[18] Detectionof ergometrine concentration in serum and breast milk was submitted to the Biotree (Shanghai, China) foranalysis and ergometrine levels in serum and breast milk were quanti�ed by the ultra-high-performanceliquid chromatography coupled with mass spectrometry detection (UHPLC-MS).
1.4 Observation indicators
Ergometrine drug concentration in breast milk or peripheral blood under different delivery modes anddifferent time gradients. Relevant indicators for evaluating drug exposure include M/P [19] (Milk/Plasma);TID[19] (Theoretical infant dose) [mg/(kg·d)]: drug concentration in breast milk × daily milk intake[mL/(kg·d)]; RID[19-21] (Relative infant dose) (%): TID [mg/(kg·d)]/maternal dose [mg/(kg·d)]). PRL level inserum was used to assess the effect of ergometrine maleate on lactation.
1.5 Statistical methods
If a continuous variable is found to conform to a normal distribution by the normality test, the variablewill be expressed as the mean ± standard deviation. If the variable does not conform to a normaldistribution, the variable will be expressed as the median P25, P75 . If the variable is categorical, it ispresented as a percentage and is further analyzed using the chi-square test. Two-way ANOVA was usedto analyze the effects of mode of delivery and different time gradients on the �nal concentration ofergometrine maleate and whether there was an interaction between the two factors. Sidak's method wasused for variables with equal variance. For variables with unequal variances, Dunnett's T3 test of thenonparametric test was used. P<0.05 was considered to be signi�cantly different between the twogroups. Data analysis was performed with SPSS 25.0. The �gures presented were plotted with PRISMversion 8.0 for Windows (GraphPad Software Inc, San Diego, CA).
2. Result2.1 The relationship between the �nal concentration of ergometrine in serum and breast milk at differenttime gradients and mode of delivery
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Two-way ANOVA analysis showed no interaction between mode of delivery and time gradient (Tables S1,S2). There was no correlation between the mode of delivery and the �nal concentration of ergometrine inperipheral blood and breast milk at different time gradients (Fig. 2). The results in Table 1 show that the�nal concentration of ergometrine in the peripheral serum was higher at 2–4 hours in both the cesareansection group and the vaginal delivery group. More importantly, the ergometrine concentration in theperipheral blood decreased almost to the 0-hour (pre-administration) level at 12h in both groups. The �nalconcentration of ergometrine in the breast milk of pregnant women with cesarean section reached thepeak of 4.9858 (2.9307, 7.7635) at 2h, then gradually decreased over time, and �nally decreased to0.3945 (0.0842, 1.0219), lower than the 0-hour concentration of 0.6879 (0.6335, 1.1760). The distributionof the �nal concentration of ergometrine in the breast milk of pregnant women with vaginal delivery atdifferent time gradients was the same as that of women delivered by cesarean section (Table 1).
Table 1The �nal concentration of ergometrine maleate in serum under different delivery modes and different
2.2 The relationship between the �nal concentration of ergometrine maleate in serum or breast milk andthe time gradient
Since the �nal concentration of ergometrine maleate in serum was not related to the mode of delivery, weregrouped the �nal concentration of ergometrine maleate in serum according to the time gradient andfurther analyzed the relationship between the �nal concentration of ergometrine maleate in serum andthe time gradient using Dunnett's T3 test of the nonparametric test. The results showed that the �nalconcentration of ergometrine maleate in serum reached the peak at 2h, and decreased to the pre-administration level at 12h after administration. And the �nal concentration of ergometrine in serum at 0hwas statistically different from those at 2h, 4h and 6h, with no statistical difference from those at 12h. Inaddition, the �nal concentration of ergometrine maleate in serum at 2h was not statistically differentfrom those at 4h and 6h, but the �nal concentration of ergometrine maleate in serum at 6h and 12h werestatistically different (Fig. 3A). The same method was used to analyze further the relationship betweenthe �nal concentration of ergometrine maleate in breast milk and the time gradient. The results in Fig. 3Bshowed that the �nal concentration of ergometrine maleate in breast milk reached the peak at 2h andbasically dropped to the pre-administration level at 12h. Although the distributions of the �nalconcentration of ergometrine maleate at 0h and 2h were statistically different, there was no statisticaldifference between the distributions at 0h and 4h, 6h or 12h. The �nal concentration of ergometrinemaleate in breast milk at 2h, 4h and 6h was statistically different from that at 12h.
2.3 Area Under The Concentration-time Curve OfErgometrine Maleate In Serum And Breast Milk-auc CurveThe results in Fig. 4 show that the concentration of ergometrine in breast milk is higher than that inmaternal serum (M/P > 1) within 3h after administration, but lower between 3h and 10h. In addition, bycalculating the RID values at different times, we found that the RID was 0.0000% (0.000, 0.4121%) at 0h,9.2555% (1.0836%, 16.0682%) at 2h, 8.5650% (5.0154%, 18.0585%) at 4h, 4.5762% (2.5146%, 7.8638%)at 6h, and 0.1842% (0.0000%, 1.1838%) at 12h.
2.4 The Effect Of Ergometrine Injection On Prl At DifferentTime GradientsPRL concentrations in peripheral blood of 32 pregnant women at different time gradients weredetected(Table 2). In the control group (intramuscular injection of 10U oxytocin and intravenous drip of10U oxytocin added into 500ml of normal saline at a rate of 150ml/h), the proportion of pregnant womenwith PRL concentrations > 200ng/mL increased gradually as time went on, but the distribution of the �nalconcentration of ergometrine in peripheral blood at different time gradients in the two groups was notstatistically signi�cant (p > 0.05).
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Table 2Relationship between ergometrine injection and PRL
Time (hour) Final Concentration of PRL in serum (ng/mL) Total
(Number)
χ 2 P-value
Control Group Treat Group
≥ 200
N(%)
<200
N(%)
≥ 200
N(%)
<200
N(%)
0 6(37.5) 10(62.5) 8(50.0) 8(50.0) 16 2.0 0.572
2 8(50.0) 8(50.0) 7(43.75) 9(56.25) 16
12 13(81.25) 3(18.75) 8(50.0) 8(50.0) 16
3. DiscussionMilk production and nursing constitute the bio-logical norm for mammals. Breast milk provides necessarynutrients to the infant for the �rst 6 months of life. Failure to breastfeed increases morbidity and mortalityin both mothers and children in developed and developing countries.[27] Drugs are routinely administeredin labor for a number of indications and fall into several pharmacological categories. The indications are,broadly: uterotonics for induction and augmentation of labor (prostaglandins and oxytocin) or preventionof postpartum hemorrhage (PPH), etc. Ergometrine maleate injection is a commonly used drug for theprevention and treatment of postpartum hemorrhage, which is widely used in clinical practice. Based onthe clinical practice, this study used UHPLC-MS to detect the concentration of ergometrine maleate inmaternal plasma and breast milk at various time periods and used the chemiluminescence method todetect the prolactin level of subjects at different time periods after delivery, to explore the safety ofergometrine maleate injection and breastfeeding and understand the effects of ergometrine maleateinjection on lactation.
The results of the relationship between the �nal concentration of ergometrine maleate in serum and thetime gradient suggest that serum remains at a high level of ergometrine concentration 2h afterergometrine injection and lasts until 6h after administration. Since the dose of 0.4 mg ergometrine (one0.2 mg, 2 intramuscular injections each time) was used in this study, it is recommended that ergometrinemaleate can be administered 6h after the �rst use of 0.4mg ergometrine maleate, but the total dose isrecommended not exceed 1.0 mg according to the ergometrine instructions. The results of therelationship between the �nal concentration of ergometrine in breast milk and the time gradient suggestthat the �nal concentration of ergometrine in breast milk reached the peak at 2h after administration, withM/P > 1 and RID of 9.2555% ( 1.0836%, 16.0682%). According to the principle of safe medication forpregnant women, breastfeeding is not recommended. [18, 20] There was no statistical difference betweenthe �nal concentration of ergometrine in breast milk before administration and at 4h, 6h and 12h afteradministration. It shows that the concentration of ergometrine in breast milk is at a relatively safe level at4h after administration with M/P < 1, but the RID was 8.5650% (5.0154%, 18.0585%) at 4h and 4.5762%
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(2.5146%, 7.8638%) at 6h. Theoretically speaking, breastfeeding is relatively safe at 6h afteradministration.[18, 20] On the other hand, the �nal concentrations of ergometrine in breast milk at 2h, 4hand 6h were statistically different from that at 12h. More importantly, the �nal concentration ofergometrine in breast milk was restored to the pre-administration level at 12h, with the RID of 0.1842%(0.0000%, 1.1838%). Therefore, strictly speaking, breastfeeding should be recommended at 12h afteradministration.[19 ]
Lactation is a complex process, and many studies rely on the concentration of PRL to re�ect the amountof lactation. There are limited data on ergometrine maleate injection, but studies on methylergonovineindicate that whether the use of methylergonovine inhibits PRL concentrations in peripheral bloodremains controversial.[22–25] Studies have shown that methylergonovine does not affect theconcentration of PRL in the peripheral blood within 48h, but does affect the duration of lactation.[25]
Studies have shown that routine prevention of PPH with oxytocin, either alone or in combination withergometrine, was associated with a reduction in breastfeeding rates of 6–8% at 48 hours.[26] Data in thisstudy show that the administration of ergometrine maleate injection does not affect the concentrationsof PRL in peripheral blood at 2h and 12h. But whether ergometrine maleate injection affects lactationduration remains unknown.
In this study, 3 cases of adverse reactions were reported in the treat group, including 1 case of nausea, 1case of dizziness and 1 case of hypertension, and 2 cases of dizziness were reported in the control group.As for neonates, 2 neonates occurred with jaundice in the treat group and the control group, respectively,but none of them needed to be transferred to the neonatal department for hospitalization. No obviousserious adverse reactions were found within 24 hours. However, this study only observed for 24 hoursafter administration, while Oded Gilad et al. followed up the mothers who used methylergonovine for 1–3years, which showed that compared with the control group, the use of methylergonovine did not affectthe neonatal growth and development (evaluation indicators: length, weight, head circumference), noraffect the incidence of neonatal complications.[26]
4. Advantages And Disadvantages1. UHPLC-MS was used to detect the concentration of ergometrine in maternal plasma and breast milk
at various periods, and the concentration changes of ergometrine maleate injection in maternalplasma and breast milk were described;
2. A relatively comprehensive analysis of ergometrine maleate injection and the safety of breastfeedingwas conducted;
3. Since this study is a single-center study, a multi-center RCT study should be conducted further toverify the safety of ergometrine maleate injection and breastfeeding;
4. Long-term follow-up should be performed for lactation production, PRL concentration in peripheralblood, and possible adverse reactions.
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5. ConclusionThe results of this study suggest that breastfeeding at 12 hours after ergometrine maleate injection isrelatively safe. In this study, ergometrine maleate injection was not found to inhibit the concentration ofPRL in the peripheral blood, and no serious adverse reactions were found.
List Of AbbreviationsUHPLC-MSultra-high-performance liquid chromatography coupled with mass spectrometryRIDrelative infant doseAAPAmerican Academy of PediatricsPRLProlactinPRLrprolactin receptorM/PMilk/PlasmaTIDTheoretical infant dose
DeclarationsEthics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki. It was approved by the ethicscommittee of the First A�liated Hospital of Chongqing Medical University (20200501). Oral informedconsent was given by all participants. And all methods were performed in accordance with the relevantguidelines and regulations.
Consent for publication
Not applicable.
Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author onreasonable request.
Competing interests
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The authors declare that they have no competing interests.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82171668, No.81771614, No. 82171662).
Authors' contributions
HBQ, XL and TMS contributed to the protocol design. TMS Jointly complete the data collection . MMCdrafted the manuscript. JCX, WJ, and BDC contributed to the interpretation of results. HBQ and XL revisedthe �nal version and are guarantors of this manuscript. All authors made substantial contributions to thepaper and read and approved the �nal manuscript.
Acknowledgements
Not applicable.
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Figures
Figure 1
The �ow chart of the study
Note: CS, cesarean section; VD, vaginal delivery.
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Figure 2
Relationship between the �nal concentration of ergometrine with delivery modes and time gradient. A: inserum, B: in breast milk.
Figure 3
The relationship between the �nal concentration of ergometrine and the time gradient. A: in serum, B: inbreast milk.
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Figure 4
Area under the concentration-time curve of ergometrine maleate in serum and breast milk-AUC curve.
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