Metformin to Augment Low Milk Supply (MALMS) Study
Metformin to Augment Low Milk Supply (MALMS) Study
Most new mothers in the United States will start off breastfeeding. For some mothers, despite
 following best practices, they are not able to meet their breastfeeding goals due to
 unexplained low milk supply. At the same time, nearly 1 in 4 new mothers are pre-diabetic
 (elevated blood sugar, but not yet diabetic). My progression of research suggests that the
 same metabolic factors causing pre-diabetes may also be causing low milk supply. Metformin is
 a widely prescribed drug to treat high blood sugar. This study is a preliminary, small scale
 randomized trial designed to test for a trend in the hypothesis that metformin is safe and
 potentially effective in treating low milk supply in insulin resistant and pre-diabetic
 mothers.
Through a progression of research, the PI has developed the central hypothesis that waning
 insulin secretion in the context of insulin resistance is an important cause of low milk
 supply. The specific aim of the research described in this protocol is to enact a small-scale
 randomized placebo-controlled trial (RCT) that will inform a future larger double-masked RCT
 of adjuvant metformin treatment versus placebo for early postpartum low milk supply in women
 with evidence of insulin resistance based on the presence of at least one of the following:
 elevated fasting glucose (FPG, defined as >95 g/dL), history of polycystic ovary syndrome,
 history of gestational diabetes, or current abdominal obesity. The pilot study is designed to
 demonstrate feasibility, obtain variance estimates, and test for an trend in the following
 primary hypothesis: 1) Among eligible women with low milk supply, those randomly assigned to
 4 weeks of metformin treatment will experience a greater increase in milk output as compared
 to the placebo group. The RCT will be preceded by a"process testing phase" in which
 recruitment and data collection logistics will be confirmed by enacting the study protocol,
 except without any drug assignment. Upon completion of the process testing phase, the
 protocol will be amended according to insights gained. Once the revised protocol received IRB
 approval, the RCT phase will begin. During this phase, mothers meeting Stage 1 eligibility
 criteria will undergo baseline measurements of cardio-metabolic health and breast milk
 output. Among mothers meeting stage 2 eligibility criteria, including FPG >95 g/dL, N=30 will
 be randomly assigned to metformin or placebo using a 2:1 allocation, with replacement of
 non-completers. All low milk supply participants will receive the standard guidance for
 increasing milk supply with breast pumping. We will test the following secondary hypotheses:
 2) Mammary epithelial cell transcriptomes within the metformin group, but not placebo, will
 exhibit significantly greater modulation of insulin-stimulated genes between baseline and
 post treatment. Milk fat globules are a rich source of mammary epithelial cell mRNA. We will
 isolate milk fat RNA at baseline and post treatment and randomly select a subset for
 RNA-sequencing. 3) Fasting plasma glucose >95 g/dL will correctly identify low milk supply
 cases with >75% sensitivity; and <95 g/dL will correctly identify abundant milk supply
 (comparator group) with >90% specificity. Fasting plasma glucose (FPG) in women with abundant
 milk supply will be derived from 30 consecutively consenting breastfeeding medicine patients
 who meet all RCT eligibility criteria except low milk supply (i.e., diagnoses related to
 infant feeding at the breast such as poor latch, but with abundant milk output). We will
 combine all available baseline FPG data to determine the sensitivity and specificity of FPG
 >95 g/dL as biomarker of low milk supply caused by maternal metabolic impairment. 4)
 Metformin treatment will be safe and adequately tolerated by the lactating mother and her
 breastfeeding infant.
Inclusion Criteria among mother-infant dyads:

 Stage 1 Criteria (for participation in baseline measurement phase):

 -  identified with low milk supply by a Cincinnati-area IBCLC

 -  mother denies obvious cause of low milk supply such as pituitary disorder, breast
 surgery, severe lack of breast emptying (< 4 times per day), or failure to show any
 signs of lactogenesis

 -  mother at least 20 years of age

 -  infant is between 1 week and 2 calendar months old

 -  mother gave birth to a single, healthy, term (>37 weeks gestation) infant

 -  mother free of breast and nipple infections

 -  mother lives within study catchment area

 -  mother has not been diagnosed with Type 1 or Type 2 Diabetes Mellitus

 -  mother willing to sustain consistent use of herbal galactogogues (such as fenugreek)
 during follow up measurements (2-4 weeks) as was consumed during the baseline
 measurements

 -  mother not currently taking a prescription medication that may affect the hormones of
 lactation and not planning to initiate any such drug for at least the next 2-4 weeks.

 -  mother has established pediatric care for the infant

 Stage 2 maternal inclusion criteria (among those who meet Stage 1 criteria, to continue
 with enrollment into randomized controlled trial, goal, N=30 with replacement for
 non-completers to at least two weeks):

 -  successful completion of baseline measurements (involving 24-hour test weighing of
 milk output and undergoing baseline measurements at the clinical research center,
 including providing fasting blood samples)

 -  body mass index is >19.0 kg/m2 (i.e., not underweight)

 -  evidence of likely insulin resistance, based on at least one of the following: mean
 fasting plasma glucose between 95.0 - 125.0 g/dL, inclusive; abdominal obesity;
 history of polycystic ovary syndrome; or history of gestational diabetes

 -  estimated glomerular filtration rate > 60 mL/min

 -  liver function in normal range (AST <= 37 U/L, ALT < 87 U/L, and total bilirubin <=
 1.1 mg/dL

 -  willingness to continue trying to lactate for the next 2-4 weeks

 -  health history does not reveal illness/treatments for which metformin is
 contraindicated

 -  participant is not currently being treated with metformin

 Eligibility criteria for enrollment into abundant milk supply comparison group (goal, N=30,
 will be compared in baseline measurements).

 Inclusion criteria:

 -  exclusively feeding mother's own milk to infant, and presenting to Cincinnati area
 IBCLC with breastfeeding question or problem unrelated to milk supply

 -  mother at least 20 years of age

 -  infant is between 1 week and 2 calendar months old

 -  mother gave birth to a single, term infant

 -  mother free of breast and nipple infections

 -  mother lives within study catchment area

 -  mother has not been diagnosed with Type 1 or Type 2 Diabetes Mellitus

 -  mother willing to sustain consistent use of herbal galactogogues (such as fenugreek)
 during baseline measurements

 -  mother willing to avoid prescription medication that may affect the hormones of
 lactation