Metformin to Augment Low Milk Supply (MALMS) Study

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