Amitriptyline in Breastfeeding

Reference	Notes
Sabah Obstetrics Shared Care Guidelines (Sept 2018)	MENTAL DISORDERS IN PREGNANCY ·         Look for symptoms of postpartum psychosis / depression ·         Contraception for patient (refer to MEC) ·         Encourage breast feeding. Advise to take psychotropic medication just after breastfeeding. ·         Monitor the baby for adverse effects such as drowsiness, hypotonia, rigidity, tremor and withdrawal symptoms ·         Review family support
Uptodate: Amitriptyline	Amitriptyline and the metabolite nortriptyline are present in breast milk (Bader 1980). The relative infant dose (RID) of amitriptyline is 1.2 % when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 175 mg/day. In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). Using the highest milk concentration (197 ng/mL), the estimated daily infant dose via breast milk is 0.03 mg/kg/day. This milk concentration was obtained following maternal administration of oral amitriptyline 175 mg/day for ~28 days (Yoshida 1997). In a review article which included six mother/infant pairs, following maternal use of amitriptyline 75 to 175 mg/day, the estimated exposure to the breastfeeding infant was calculated as 0.2% to 1.9% of the weight-adjusted maternal dose (additional detail not provided) (Fortinguerra 2009). Very small amounts of amitriptyline can be detected in the plasma and urine of breastfeeding infants (Yoshida 1997). It should be noted that actual milk concentrations of tricyclic antidepressants are generally related to maternal serum concentration and vary by fat content of breast milk; the level of detection varies greatly by assay method (Yoshida 1997). Most sources have not reported adverse events in infants exposed to amitriptyline via breast milk (Fortinguerra 2009; Larsen 2015; Yoshida 1997). However, in a case report, severe sedation with associated poor feeding was observed in a breastfed infant (~15 days old) following the initiation of amitriptyline 10 mg/day in the mother. Symptoms in the infant decreased within 24 hours and resolved within 48 hours after the maternal dose was discontinued. Once amitriptyline was reinitiated in the mother, symptoms in the infant returned (Uguz 2017). Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (Bauer 2013) as well as infant growth and neurodevelopment (Sriraman 2015). Tricyclic antidepressants are not the preferred therapy for depression in breastfeeding women. However, if a TCA is needed, amitriptyline is one of the agents with information available (Larsen 2015). A woman already stabilized on a TCA during pregnancy may continue that medication while breastfeeding (Sriraman 2015). Migraine prophylaxis should be avoided in women who are breastfeeding; if needed, amitriptyline may be used if other agents are ineffective or contraindicated (Pringsheim 2012). The WHO considers amitriptyline to be compatible with breastfeeding in doses ≤150 mg/day (WHO 2002). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
https://www.drugs.com/breastfeeding/amitriptyline.html   (equivalent to LactMed)	Milk levels of amitriptyline and its metabolites are low. Immediate side effects have not been reported and a limited amount of follow-up has found no adverse effects on infant growth and development. Amitriptyline use during breastfeeding would usually not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. A safety scoring system finds amitriptyline use to be possible with caution during breastfeeding.[1] However, rare sedation has been reported in a neonate. Other agents with fewer active metabolites may be preferred when large doses are required or while nursing a newborn or preterm infant.
Maudsley 13th Edition 2018	Foetal exposure to tricyclic antidepressants (TCAs) via umbilicus and amniotic fluid is high.87,88. TCAs have been widely used throughout pregnancy without apparent detriment to the foetus.
Stahls’s Essential Psychopharmacology 2017	• Some drug is found in mother’s breast milk ✽ Recommended either to discontinue drug or bottle feed • Immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes, so drug may need to be reinstituted late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period • Must weigh benefi ts of breast feeding with risks and benefi ts of antidepressant treatment versus nontreatment to both the infant and the mother • For many patients this may mean continuing treatment during breast feeding
Briggs 2015	Amitriptyline and its active metabolites are excreted into breast milk (20–24). A recent study has measured the amount of a second active metabolite, E-10-hydroxynortriptyline, in milk (23). Serum and milk concentrations of amitriptyline in one patient were 0.14 and 0.15 mcg/mL, respectively, a milk:plasma ratio of 1.0 (20). No drug was detected in the infant’s serum. In another patient, it was estimated that the baby received about 1% of the mother’s dose (22). No clinical signs of drug activity were observed in the infant. In another study, the mother was treated with 175 mg/day of amitriptyline (23). Milk and maternal serum samples were analyzed for active drug and active metabolites on postpartum days 1–26. Amitriptyline serum levels ranged from 24 (day 1) to 71 ng/mL (days 3–26), whereas those in the milk ranged from 24 ng/mL (day 1) to only 54% of the serum levels on days 2–26. Nortriptyline serum levels ranged from 17 (day 1) to 87 ng/mL (day 26) with milk levels 74% of those in the serum. Mean concentration of the second metabolite, E-10-hydroxynortriptyline, was 127 ng/mL (days 1–26) in the serum and 70% of that in the milk. The total dose (parent drug plus metabolites) consumed by the male infant on day 26 was estimated to be 35 mcg/kg (80 times lower than the mother’s dose). The compounds were not detected in the nursing infant’s serum on day 26 and no adverse effects, including sedation, were observed in him (23). Ten nursing infants of mothers taking antidepressants (two with amitriptyline 100–175 mg/day) were compared with 15 bottle-fed infants of mothers with depression who did not breastfeed (24). Concentrations of clomipramine in fore- and hind-milk were 30 ng/mL (one patient) and 113 and 197 ng/mL (two patients), respectively. The milk:maternal plasma ratios were 0.2 and 0.9, respectively. One infant had a plasma level of 7.5 ng/mL when the mother was taking 100 mg/day. No toxic effects or delays in development were observed in the infants. The estimated daily dose consumed by the infants was about 1% of the mother’s weight-adjusted dose (24). A 1996 review of antidepressant treatment during breastfeeding found no information that amitriptyline exposure of the infant during nursing caused adverse effects (25).  Although amitriptyline and its metabolite have not been detected in infant serum, the effects of exposure to small amounts in the milk are unknown (26).

 

Accessed by J. Ho @ 29.07.2021

Valproate in Breastfeeding

Reference	Description
Sabah Obstetrics Shared Care Guidelines 2018	·    Reinforce the importance of contraception and planned pregnancy (refer MEC) ·   AED dose adjustment (if required) need further discussion with physician/neurologist ·   Encourage breastfeeding ·   Monitor neonates for side effects of AEDs e.g.: drowsiness, jitteriness and hypotonia ·   Screen mothers for depression ·   Advise on safety issues and strategies to prevent accidental injury with involvement of family members
Drugs.com – Valproate [breastfeeding]	Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development; however, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study.[1] A safety scoring system finds valproic acid possible to use during breastfeeding.[2] If valproic acid is required by the mother, it is not a reason to discontinue breastfeeding. No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. A rare case of infant baldness might have been caused by valproate in milk. One author recommends monitoring infant serum valproate levels, platelets and liver enzymes during therapy.[3] Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions. Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. Blood hemoglobin and reticulocytes normalized between 12 and 19 days after discontinuing breastfeeding. The petechiae resolved 35 days after discontinuing breastfeeding and the infant's platelet count had almost reached the normal range by this time. By day 83, the infant's platelet count was well within the normal range. The authors believed the adverse effect to be caused by valproic acid in breastmilk.[16] However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.[19] Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.[17] Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.[19]
UptoDate: Valproate [Drug Information]	Valproate is present in breast milk.  A study presented information from 30 lactating women with epilepsy on monotherapy (51%), combination therapy with one additional agent (46%), or triple therapy (3%). In all cases, breast milk was collected between 6 and 32 days postpartum (median 7 days) and sampling occurred prior to the morning dose. Using information from all women in the study, values for maternal dose (3.6 to 20.6 mg/kg), maternal serum (5.4 to 69 mg/L), breast milk (<1 to 16.7 mg/L), and infant serum (<1 to 17.5 mg/L) were presented. Breast milk concentrations were highly variable and did not correlate with maternal dose. In this study, valproate concentrations were below the limit of quantification in 67% of breast milk and 33% of infant serum samples. This study did not monitor adverse events in the infants (Kacirova 2019).  The risk of valproate-related hepatotoxicity is increased following therapeutic use in pediatric patients <2 years of age; theoretically, this risk is also present in infants exposed to valproate via breast milk. Reported adverse effects in breastfed infants include a possible case of thrombocytopenia and anemia (Stahl 1997).  According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to valproate via breast milk should be monitored for signs of liver damage, including jaundice and unusual bruising or bleeding. Valproate is considered compatible with breastfeeding (Ito 2000; Larsen 2015; WHO 2002); monitoring of the infant for side effects (eg, jaundice) is recommended (WHO 2002).
Uptodate: Management of epilepsy during preconception, pregnancy, and the postpartum period	Given the benefits to breastfeeding with regard to both short- and long-term neonatal health, taking AEDs does not contraindicate breastfeeding In agreement with a 2019 report from International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy [2], we encourage women to consider breastfeeding, but with adaptation according to how sensitive their seizures are to sleep deprivation, based upon their history and their epilepsy syndrome. Many women choose to breastfeed but will introduce the bottle in the hospital. This allows another adult to give at least one feeding via bottled formula or pumped breastmilk, permitting the mother to obtain at least one four-hour stretch of uninterrupted sleep per 24 hours. We recommend this and another two hours of sleep through naps to achieve a minimum of six hours of sleep per 24 hours to reduce the risk of seizures.   There is little evidence to support that this form of AED exposure has clinical effects on the newborn [26]. Anecdotal reports suggest that problems tend to occur only with the highly sedating drugs, such as phenobarbital, primidone, or benzodiazepines. Nursing newborns may become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this occurs, breastfeeding may need to be discontinued. However, for the vast majority of AEDs, especially those used first line in contemporary neurology practice, adverse effects on nursing infants are lacking.  Moreover, neurodevelopmental studies in children of women with epilepsy on AEDs demonstrate benefits to nursing. Neurodevelopmental outcomes were examined in 181 children exposed to ither carbamazepine, lamotrigine, phenytoin, or valproate in utero; 42.9 percent of these children were breastfed a mean of 7.2 months. Intelligence quotients (IQs) for breastfed children were four points higher than the non-breastfed group after adjusting for potential confounding through propensity score matching, and in specific cognitive domains, verbal abilities were higher [88]. No adverse effects of AED exposure via breastmilk were observed. Another study that included 223 children exposed to AEDs in utero found that prenatal exposure was associated with adverse developmental outcomes regardless of breastfeeding status during the first year of life, but that infants who were breastfed continuously for more than six months had slightly better outcomes than those who were not breastfed
Briggs: Pregnancy and Lactation 2015	Valproic acid and its salt, sodium valproate, are excreted into human milk in low concentrations (1,2,4,5,8,10,12,91,92). Milk concentrations up to 15% of the corresponding level in the mother’s serum have been measured. In two infants, serum levels of valproate were 1.5% and 6.0% of maternal values – less than 10% (92).  Only one report of adverse effects in a nursing infant attributable to valproate in breast milk has been located. Thrombocytopenia purpura, anemia, and reticulocytosis were observed in a 3-month-old male breastfed infant whose mother was taking sodium valproate (monotherapy; 1200 mg/day) for epilepsy (93). The infant had a 2-week history of increasing petechiae and minor hematoma on the lower part of the legs. The infant’s serum valproate level was 6.6 mcg/mL. Breastfeeding was discontinued for 5 days but had no effect on the infant’s low platelet count. The mother continued to nurse for another 2 weeks and again stopped. Twelve days later, valproate was undetectable in the infant’s serum and 7 days later (19 days after nursing was stopped), the platelet count began to rise, reaching normal values sometime after 35 days. At about this same time, the petechiae had resolved. The blood hemoglobin and the reticulocytes normalized between 12 and 19 days after breastfeeding was stopped (93). In a 2010 study, 199 children who had been breastfed while their mothers were taking a single antiepileptic drug (carbamazepine, lamotrigine, phenytoin, or valproate) were evaluated at 3 years of age cognitive outcome (94). Mean adjusted IQ scores for exposed children were 99 (95% CI 96–103), whereas the mean adjusted IQ scores of nonbreastfed infants were 98 (95% CI 95–101).  The American Academy of Pediatrics classifies valproic acid as compatible with breastfeeding (95).

 

All info accessed on 12.08.2021 (J Ho)

Carbimazole and Breastfeeding

Carbimazole and Breastfeeding

Reference	Description
New Zealand Data Sheet. Carbimazole 5 mg Tablet. Available at: https://www.medsafe.govt.nz/Profs/Datasheet/n/Neo-Mercazoletab.pdf   Chapter 4 - Feline Hyperthyroidism, Editor(s): Edward C. Feldman, Richard W. Nelson, Claudia E. Reusch, J. Catharine R. Scott-Moncrieff, Canine and Feline Endocrinology (Fourth Edition),W.B. Saunders, 2015, Pages 136-195, Available at: https://doi.org/10.1016/B978-1-4557-4456-5.00004-3	Carbimazole is a prodrug which is converted to it’s active metabolite methimazole in the blood by hydrolysis and enzymatic decarboxylation.  10 mg of carbimazole is equivalent to 6 mg of methimazole. Carbimazole:Methimazole = 5:3
Sabah Obstetrics Shared Care Guidelines (2018)	ü  Carbimazole in doses up to 20-30mg/d is safe for lactating mothers and infants. ü  2nd line: PTU at 300mg/d (concerns of hepatotoxicity.) ü  To administer ATDs (antithyroid) following a feeding, in divided doses. ü  Refer all babies born to mothers with hyperthyroidism to Paediatric team. ü  Type 1 DM, Grave’s disease in remission and chronic viral hepatitis: ➢   at risk of developing post-partum thyroiditis ➢   To measure TSH level at 6-12 weeks gestation and 6 months postpartum ü  Women known to be thyroid antibody positive:        ➢    To measure TSH level at 6-12 weeks gestation and 6 months                 postpartum, or as clinically indicated.
https://www.drugs.com/breastfeeding/carbimazole.html	Doses of carbimazole of 30 mg daily or 50 mg weekly have not adversely affected the few breastfed infants studied. Carbimazole is a prodrug for methimazole which has been studied extensively during breastfeeding; maternal methimazole therapy does not affect thyroid function or intellectual development in breastfed infants with doses up to 20 mg daily. Some experts now recommend that methimazole should be considered the antithyroid drug of choice in nursing mothers.[1-3]   The American Thyroid Association recommends only monitoring infants for appropriate growth and development during routine pediatric health and wellness evaluations and routine assessment of serum thyroid function in the child is not recommended.[4] Rare idiosyncratic reactions (e.g., agranulocytosis) might occur, and the infant should be watched for signs of infection. Monitoring of the infant's complete blood count and differential is advisable if there is a suspicion of a drug-induced blood dyscrasia.
UptoDate: Methimazole (Drug Information)	·   Methimazole is present in breast milk. ·   Information related to the presence of methimazole in breast milk is available from 6 lactating women with Graves disease following a single dose of methimazole 15 mg. Peak methimazole concentrations were 0.32 ± 0.10 mcg/mL (breast milk) and 0.31 ± 0.09 mcg/mL (maternal plasma) 2 hours after administration. The half-life of methimazole was calculated to be 4.2 ± 0.8 hours in breast milk. Twelve hours after the dose, breast milk concentrations of methimazole had decreased to 0.03 ± 0.01 mcg/mL (Abe 1995). ·   Based on available data, thyroid function is normal in infants exposed to lower doses of methimazole via breast milk. In addition, IQ and physical development up to 74 months of age were not impaired in a long-term study of breastfed infants whose mothers were receiving treatment with methimazole. ·   The treatment of hyperthyroidism in breastfeeding patients is the same as non-breastfeeding females. ·   The lowest effective dose should be used; maternal doses of methimazole ≤20 mg/day are advised in breastfeeding patients. ·   Infants exposed to antithyroid medications via breast milk should be monitored for adequate growth and development; routine tests of thyroid function are not recommended (ATA [Alexander 2017]). ·   Taking the dose of methimazole after breastfeeding may help decrease potential infant exposure by providing a 3- to 4-hour interval before the next feed (Amino 2020).
Uptodate Hyperthyroidism during pregnancy: Treatment	o   Given the concerns about potential propylthiouracil (PTU)-associated hepatotoxicity, we suggest methimazole rather than PTU for nursing mothers. o   Methimazole should be administered following a feeding in divided doses. When the maternal dose of methimazole is >20 mg daily, infants should have thyroid function tests assessed after one and three months. o   PTU is less soluble than methimazole and is more bound to plasma proteins, whereas methimazole is free in serum, so that relatively more methimazole reaches the infant via breast milk [54]. Nonetheless, there is little difference in serum thyroid hormone concentrations or thyroid function in infants of mothers given moderate doses of either drug. As an example, in a study of 139 mothers taking up to 20 mg methimazole daily, thyroid function, growth, and development of their breastfed infants were normal [55]. Similar results were seen in a study of mothers taking PTU [56]. o   There has yet to be a report of agranulocytosis or liver disease in an infant who was nursed by a woman taking PTU or methimazole.
Drugs in Pregnancy and Lactation (Briggs & Freeman 2015)	Methimazole is excreted into breast milk (54–57). In a patient given 10 mg of radiolabeled carbimazole (converted in vivo to methimazole), the milk:plasma ratio was a fairly constant 1.05 over 24 hours (54). This represented about 0.47% of the given radioactive dose. In a second study, a patient was administered 2.5 mg of methimazole every 12 hours (55). The mean milk:plasma ratio was 1.16, representing 16–39 mcg of methimazole in the daily milk supply. Extrapolation of these results to a daily dose of 20 mg indicated that approximately 3 mg/day would be excreted into the milk.  Five lactating women were given 40 mg of carbimazole, producing a mean milk:plasma ratio at 1 hour of 0.72 (56). For the 8-hour period after dosing, the milk:plasma ratio was 0.98. A new radioimmunoassay was used to measure methimazole milk levels after a single 40-mg oral dose in four lactating women. The mean milk:plasma ratio during the first 8 hours was 0.97, with 70 mcg excreted in the milk (56).  A 1987 publication described the results of carbimazole therapy in a woman breastfeeding twins (57). Two months after delivery, the mother was started on carbimazole, 30 mg/day. The dose was decreased as she became euthyroid. Three paired milk:plasma levels revealed ratios of 0.30–0.70. The mean free methimazole concentration in milk, determined between 2 and 16 weeks of therapy, was 43 ng/mL (range 0–92 ng/mL). Peak milk levels occurred 2–4 hours after a dose. Mean plasma levels in the twins were 45 ng/mL (range 0–105 ng/mL) and 52 ng/mL (range 0–156 ng/mL), with the highest concentrations occurring while the mother was taking 30 mg/day. No evidence of thyroid suppression was found clinically or after thyroid function tests in the nursing twins (57).  Two other studies also found no effect on clinical status or thyroid function in nursing infants of mothers taking carbimazole or methimazole (58,59). In one report, no adverse effects were observed during a 3-week study of 11 infants whose mothers were taking carbimazole 5–15 mg/day (58). In the other study, normal thyroid function in 35 nursing infants, whose mothers were taking methimazole, was documented over periods ranging from 1 to 6 months (59). Most mothers were taking 5–10 mg/day, but six received 20 mg/day for 1 month and then tapered to 5 mg/day.  Because the amounts found in some studies may cause thyroid dysfunction in the nursing infant, methimazole and carbimazole have, in the past, been considered contraindicated during lactation. If antithyroid drug therapy was required, PTU was considered the treatment of choice, partially because PTU is ionized at physiologic pH and because 80% of the drug is protein bound (60). Methimazole is neither ionized nor protein bound, but small doses of methimazole (e.g., 10–20 mg/day or less) do not appear to pose a major risk to the nursing infant if thyroid function is monitored at frequent (e.g., weekly or biweekly) intervals (58–60). In 2000, a long-term study confirmed the lack of toxicity in infants of mothers being treated with methimazole (61). A total of 139 thyrotoxic lactating mothers and their nursing infants were studied, 51 of the mothers were treated with methimazole during pregnancy and continued their treatment during lactation. The other 88 women started methimazole therapy during lactation with 10–20 mg/day for 1 month, 10 mg/day during the second month, then 5–10 mg/day thereafter. Methimazole serum levels in six infants whose mothers were taking 20 mg/day were <0.03 mcg/mL, 2 hours after breastfeeding. No effects on infant thyroid function were detected at various times up to 12 months. In a blinded assessment, the total IQ scores, including verbal and performance IQ, of 14 children (age 48–74 months) exposed to methimazole in milk did not differ from 17 nonexposed controls (61). The American Academy of Pediatrics classifies methimazole and carbimazole as compatible with breastfeeding (62).

 All info accessed on 24/08/2021 (J Ho)