Is (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate Safe in Breastfeeding

I am a breastfeeding mother and i want to know if it is safe to use (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate? Is (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate safe for nursing mother and child? Does (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate extracts into breast milk? Does (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate has any long term or short term side effects on infants? Can (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate influence milk supply or can (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate decrease milk supply in lactating mothers?

(Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate, together with its active metabolites, aldophosphamide, acrolein and nitrogenated mustard, is an antineoplastic from the group of nitrogen mustards with very marked immunosuppressive properties. (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate is excreted in breast milk (Wiernik 1971). In two studies, breastfed infants developed neutropenia, thrombocytopenia, and anemia. (Durodola 1979, Amato 1977). Given the variability in interindividual pharmacokinetics, potential pharmacokinetic changes with co-administration with other medication and its serious side effects, it is prudent not to breastfeed during treatment (Anderson 2016, Götestam 2016, Grunewald 2015, Pistilli 2013, Østensen 2006, WHO 2002, Pediatrics 2001). When possible, detection in breast milk of each patient to determine the total elimination of the drug would be the best indicator for resuming breastfeeding between two rounds of chemotherapy. It is known via Pharmacokinetics that after 3 elimination half-lives (T½) 87.5% of the drug is eliminated from the body; after 4 T½ 94%, after 5 T½ 96.9%, after 6 T½ 98.4% and after 7 T½ 99%. Plasma drug concentrations in the body are negligible after 7 T½. In general, a period of five half-lives may be considered a safe waiting period before returning to breastfeeding (Anderson 2016). Based on this, expert authors recommend waiting 72 hours after the last dose (practically 10 T½) to restart breastfeeding. Meanwhile, express and discard breast milk regularly (Hale 2017 p.239).

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially alkylating agents such as (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate.[1] Neutropenia has been reported in 2 infants whose mothers breastfed them while receiving (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[2] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.

In one 23-day-old infant, neutropenia, thrombocytopenia and a low hemoglobin were possibly caused by (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate after 3 days of maternal treatment with (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate 6 mg/kg IV daily (total dose 300 mg).[4] In a 4-month-old, neutropenia was probably caused by (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate in a mother 9 days after the last of 6 weekly doses of 800 mg (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate intravenously, 2 mg vincristine intravenously and daily doses of 30 mg of prednisolone orally. Neutropenia persisted at least 12 days and was accompanied by a brief episode of diarrhea.[5]

Telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 56 women who received a (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 monohydrate-containing regimen, 34 had breastfeeding difficulties.[7]