Outcome Following Tranexamic Acid Exposure During Breastfeeding

Introduction

The postpartum period is associated with an increased risk of vaginal bleeding, especially for women who suffer from a bleeding tendency. The use of antifibrinolytic drugs by the breastfeeding mother may be required; however, information on safety of these medications during lactation is scarce.

Tranexamic acid can be administered orally and is inexpensive; thus this drug may be preferable to alternative therapies. Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that is indicated for conditions with abnormal bleeding in which local or systemic hyperfibrinolysis is considered to be involved. ¹ Tranexamic acid acts by binding to plasminogen and competitively blocking the interaction of plasminogen with fibrin, thereby preventing dissolution of the fibrin clot.^1–3 At much higher concentrations it is a noncompetitive inhibitor of plasmin.^2,3 Tranexamic acid has been shown to be effective for various postpartum conditions that may occur during lactation, including menorrhagia,^4–8 postpartum hemorrhage,^9–14 and uterine bleeding disturbances secondary to depot implant contraceptives. ¹⁵

It is recommended by the drug manufacturer that caution be used when administering tranexamic acid while breastfeeding.^2,3,16,17 This is mainly due to the lack of information on safety of use of this drug in the lactating woman. The recommended drug dose greatly varies, depending on the indication for treatment. For the most common indication, menorrhagia, a dose of 1,300 mg, three times daily for up to 5 days during monthly menstruation, is used.^1,4 A recent international consensus panel recommended against use of tranexamic acid during breastfeeding. ¹⁸ As many women would like to breastfeed at almost any cost, the alternatives are often either not to use a needed drug or to use the drug despite inadequate information. Thus it is clear that information regarding the safety of tranexamic acid for the breastfeeding mother and her infant is needed. The aims of the present study were to obtain information on the safety of use of tranexamic acid during lactation.

Subjects and Methods

A prospective, controlled observational study design was used to assess the safety of tranexamic acid use during lactation.^19,20 Data were obtained from the Beilinson Teratology Information Service (BELTIS), which is a free service accessible to the public for all questions related to drug effects during pregnancy and lactation. During the initial query information was obtained using a standard questionnaire. Items covered included maternal age, parity, number of gestations, smoking habits, alcohol or drug use, use of other medications, gestational age, infant sex, birth weight, examination at birth, and data regarding breastfeeding.

During the initial call the mothers were told that information regarding tranexamic acid during breastfeeding was limited. Because pharmacokinetic drug properties suggested minimal infant exposure (relative infant dose, 1%),^16,17 lactation was permitted under medical supervision of the mother and her infant. The mothers were specifically instructed to check for changes in the infant's appetite and for the presence of somnolence or agitation or other unusual symptoms.

All queries were regularly followed up after maternal consent was obtained during the initial phone call. Mothers who sought information regarding use of tranexamic acid during the period 2010–2013 were contacted 1–3 years after their initial query for a follow-up telephone interview using a structured questionnaire focusing on possible adverse effects to the mothers and their infants. Data regarding duration of breastfeeding, drug dose, and infant growth and development were recorded.

The study group (n=21), which was composed of breastfeeding mothers taking tranexamic acid and their infants, was compared with a control group (n=42) composed of breastfeeding mothers who contacted BELTIS regarding use of a drug known to be safe during lactation (amoxicillin) and their infants. The control group was matched with the study group for year of birth (±1 year), gestational age (±2 weeks), and birth weight (±500 g). The control group was followed similarly to the study group. The study was approved by the Rabin Medical Center Research Ethics Board.

Results

During the study period 32 women contacted BELTIS regarding use of tranexamic acid during lactation. Follow-up was obtained for 28 of the 32 women (87.5%). Of the 28 women for whom follow-up was obtained, six did not take tranexemic acid, and one refused to participate, leaving 21 women included in the study group. The indications for use of tranexamic acid were thrombocytopenia/-pathy, intrauterine device insertion, presurgical procedure, or menorrhagia. The dose and duration of therapy varied depending on the indication for treatment (the dose ranged between 1,500 and 4,000 mg/day).

Maternal and infant characteristics of the study and control groups are described in Table 1. Mean maternal age was 32.1 (±5.2) years versus 31.9 (±4.6) years in the study and control groups, respectively (p=0.8). There were no differences in the mean parity or maternal habits. Cesarean delivery was more common in the study versus the control group (38% versus 9.5%, p=0.01). The control and study groups were similar regarding mean birth weight (3,228±495 g versus 3,190±397 g, p=0.77) and mean gestational age (38.7±1.5 weeks versus 38.3±1.8 weeks, p=0.29).

Four of 21 study group women versus nine of 42 control group women suffered from chronic medical conditions requiring pharmaceutical treatment: in the study group, migraine (n=1), treated with amitriptyline, gastroesophageal reflux (n=1), treated with proton pump inhibitors, hypothyroidism (n=1), treated with eltroxin, and type 1 diabetes mellitus (n=1), treated with insulin; in the control group, peptic ulcer disease/gastroesophageal reflux (n=4), treated with proton pump inhibitors, chronic allergy (n=1), treated with loratadine, hypothyroidism (n=3), treated with eltroxin, and depression (n=1), treated with selective serotonin reuptake inhibitors) (p=1). As expected, more women in the study group had a medical history indicative of coagulopathy, which led them to take tranexamic acid during lactation (Table 1). Additional medications were used during breastfeeding in eight of 21 study group women versus eight of 42 control group women: in the study group, methylergonovine (n=2), desmopressin (n=2), oral contraceptives (n=2), and acetaminophen (n=2); in the control group, acetaminophen (n=2), nonsteroidal anti-inflammatory drugs (n=3), dipyrone (n=1), and metronidazole (n=3).

The rate of exclusive breastfeeding was similar in the study versus the control group (80.9% versus 78.6%, p=0.87). Difficulties during breastfeeding were reported by two of 21 study group women (headache [n=1], decrease in amount of milk [n=1]) versus four of 42 control group women (discontinued breastfeeding [n=2], decrease in amount of milk [n=2]) (p=1.0). Two women in the control group were concerned about infant exposure and as a result discontinued breastfeeding.

Neonatal outcomes are described in Table 2. The mean infant age at drug exposure was similar in both groups; however, the mean infant age at follow-up was older in the study versus the control group (35.7±20 months versus 23.9±11 months, p=0.0036). Growth parameters were similar for both study groups. Possible adverse drug effects were reported for one of 21 (4.8%) study group infants (restlessness) and for one of 42 (2.4%) control group infants (gastroesophageal reflux) (Table 2).

At the time of follow-up two children of the study group were reported as suffering from abnormal medical conditions (one had failure to thrive, and one had gastroesophageal reflux disease) compared with eight of the control group children (p=0.38) (four had failure to thrive/abnormal weight gain, five had gastroesophageal reflux disease, two had hyperreactive airway disease, and one had atopic dermatitis). No neurological abnormal development was reported in the study group, compared with two control group children (one had hydrocephalus, and the other had slow motor development); however, in both cases the symptoms presented prior to the amoxicillin exposure.

Discussion

This is the first study that relates directly to tranexamic acid use during breastfeeding in mothers and their infants. The present study showed that the rate of adverse outcomes in tranexamic acid–exposed breastfed infants did not differ from control group infants, supporting the relative safety of maternal tranexamic acid therapy during breastfeeding.

Breastfeeding while taking tranexamic acid drugs is controversial because of lack of established safety on the breastfeeding infant. Breastfeeding has well-known proven benefits contributing to normal infant development. Both the World Health Organization^21,22 and the American Academy of Pediatrics ²³ recommend exclusive breastfeeding during the first 6 months of life. The benefits of breastfeeding should be weighed against the potential risks to the baby from drug exposure through breastmilk, including adverse drug effects and undetermined long-term effects on neurobehavioral development.

Tranexamic acid is recommended to be used with caution in the nursing mother only if clearly indicated.^2,3,17 Breastmilk concentrations were reported to be approximately 1% of peak serum levels 1 hour after the last dose of a 2-day treatment course.^2,3,16,17 To minimize exposure, we suggest that the drug should be taken immediately after breastfeeding.

In our study we compared a group of breastfeeding women using tranexamic acid and their infants with a control group composed of breastfeeding mothers using a drug known to be safe during lactation and their infants. The groups were similar in most respects. The women in the study group suffered from bleeding and coagulation disorders that influenced their preference toward elective cesarean surgery (38% versus 9.5%) to decrease the risk of bleeding during vaginal delivery.

More women from the control group reported having lactation difficulties during or immediately after drug use (9.5% versus 4.7%, difference not significant). Immediate neonatal side effects described were similar and negligible in both groups. There were no differences between the groups regarding long-term growth and development.

Despite the lack of identifiable drug-related adverse outcomes, some study limitations should be acknowledged. The sample size is relatively small. Our data are based on maternal reporting, and the duration of follow-up may lead to a possible recall bias. The follow-up period is insufficient to identify minor developmental difficulties. Because of the study design, maternal plasma/milk and neonatal plasma drug levels were not obtained and could not be correlated with possible adverse drug effects.

In conclusion, long-term follow-up of infants exposed to tranexamic acid during breastfeeding was not associated with an increased rate of adverse outcomes compared with control infants. Our data in conjunction with previous estimates of low drug exposure through breastmilk support continuation of breastfeeding in women requiring treatment with tranexamic acid; however, until additional information becomes available, medical supervision and follow-up of the infant are prudent.