In a small-scale study of women with previously
diagnosed mood disorders, Johns Hopkins researchers
report that lower levels of the hormone
allopregnanolone in the second trimester of
pregnancy were associated with an increased chance
of developing postpartum depression in women already
known to be at risk for the disorder.
In a report on the study the researchers say the
findings could lead to diagnostic markers and
preventive strategies for the condition, which
strikes an estimated 15 to 20 percent of American
women who give birth.
The researchers caution that theirs was an
observational study in women already diagnosed with
a mood disorder and/or taking antidepressants or
mood stabilizers, and does not establish cause and
effect between the progesterone metabolite and
postpartum depression. But it does, they say, add to
evidence that hormonal disruptions during pregnancy
point to opportunities for intervention.
Infants of women with the disorder may be neglected
and have trouble eating, sleeping and developing
normally, and an estimated 20 percent of postpartum
maternal deaths are thought to be due to suicide,
according to the National Institute of Mental
“Many earlier studies haven’t shown postpartum
depression to be tied to actual levels of pregnancy
hormones, but rather to an individual’s
vulnerability to fluctuations in these hormones, and
they didn’t identify any concrete way to tell
whether a woman would develop postpartum
depression,” says Lauren M. Osborne, M.D., assistant
director of the Johns Hopkins Women’s Mood Disorders
Center and assistant professor of psychiatry and
behavioral sciences at the Johns Hopkins University
School of Medicine.
“For our study, we looked at a high-risk population
of women already diagnosed with mood disorders and
asked what might be making them more susceptible.”
For the study, 60 pregnant women between the ages of
18 and 45 were recruited by investigators at study
sites at The Johns Hopkins University and the
University of North Carolina at Chapel Hill.
About 70 percent were white and 21.5 percent were
All women had been previously diagnosed with a mood
disorder, such as major depression or bipolar
Almost a third had been previously hospitalized due
to complications from their mood disorder, and 73
percent had more than one mental illness.
During the study, 76 percent of the participants
used psychiatric medications, including
antidepressants or mood stabilizers, and about 75
percent of the participants were depressed at some
point during the investigation, either during the
pregnancy or shortly thereafter.
During the second trimester (about 20 weeks
pregnant) and the third trimester (about 34 weeks
pregnant), each participant took a mood test and
gave 40 milliliters of blood.
Forty participants participated in the
second-trimester data collection, and 19 of these
women, or 47.5 percent, developed postpartum
depression at one or three months postpartum.
The participants were assessed and diagnosed by a
clinician using criteria from the Diagnostic and
Statistical Manual of Mental Disorders, version IV
for a major depressive episode.
Of the 58 women who participated in the
third-trimester data collection, 25 of those women,
or 43.1 percent, developed postpartum depression.
Thirty-eight women participated in both trimester
Using the blood samples, the researchers measured
the blood levels of progesterone and
allopregnanolone, a byproduct made from the
breakdown of progesterone and known for its calming,
The researchers found no relationship between
progesterone levels in the second or third
trimesters and the likelihood of developing
They also found no link between the third-trimester
levels of allopregnanolone and postpartum
However, they did notice a link between postpartum
depression and diminished levels of allopregnanolone
levels in the second trimester.
For example, according to the study data, a woman
with an allopregnanolone level of 7.5 nanograms per
milliliter had a 1.5 percent chance of developing
At half that level of hormone (about 3.75 nanograms
per milliliter), a mother had a 33 percent
likelihood of developing the disorder. For every
additional nanogram per milliliter increase in
allopregnanolone, the risk of developing postpartum
depression dropped by 63 percent.
“Every woman has high levels of certain hormones,
including allopregnanolone, at the end of pregnancy,
so we decided to look earlier in the pregnancy to
see if we could tease apart small differences in
hormone levels that might more accurately predict
postpartum depression later,” says Osborne.
She says that many earlier studies on postpartum
depression focused on a less ill population, often
excluding women whose symptoms were serious enough
to warrant psychiatric medication — making it
difficult to detect trends in those women most at
Because the study data suggest that higher levels of
allopregnanolone in the second trimester seem to
protect against postpartum depression, Osborne says
in the future, her group hopes to study whether
allopregnanolone can be used in women at risk to
prevent postpartum depression.
She says Johns Hopkins is one of several
institutions currently participating in a clinical
trial led by Sage Therapeutics that is looking at
allopregnanolone as a treatment for postpartum
She also cautions that additional and larger studies
are needed to determine whether women without mood
disorders show the same patterns of allopregnanolone
levels linked to postpartum depression risk.
If those future studies confirm a similar impact,
Osborne says, then tests for low levels of
allopregnanolone in the second trimester could be
used as a biomarker to predict those mothers who are
at risk of developing postpartum depression.
Osborne and her colleagues previously showed and
replicated in Neuropsychopharmacology in 2016 that
epigenetic modifications to two genes could be used
as biomarkers to predict postpartum depression;
these modifications target genes that work with
estrogen receptors and are sensitive to hormones.
These biomarkers were already about 80 percent
effective at predicting postpartum depression, and
Osborne hopes to examine whether combining
allopregnanolone levels with the epigenetic
biomarkers may improve the effectiveness of the
tests to predict postpartum depression.
Of note and seemingly contradictory, she says, many
of the participants in the study developed
postpartum depression while on antidepressants or
The researchers say that the medication dosages
weren’t prescribed by the study group and were
monitored by the participant’s primary care
physician, psychiatrist or obstetrician instead.
“We believe that many, if not most, women who become
pregnant are undertreated for their depression
because many physicians believe that smaller doses
of antidepressants are safer for the baby, but we
don’t have any evidence that this is true,” says
“If the medication dose is too low and the mother
relapses into depression during pregnancy or the
postpartum period, then the baby will be exposed to
both the drugs and the mother’s illness.”
Osborne and her team are currently analyzing the
medication doses used by women in this study to
determine whether those given adequate doses of
antidepressants were less likely to develop symptoms
in pregnancy or in postpartum.
Additional authors on the study include Fiona Gispen,
Abanti Sanyal, Gayane Yenokyan, Samantha Meilman and
Jennifer L. Payne of The Johns Hopkins University.
For more information
Lower allopregnanolone during pregnancy predicts
postpartum depression: An exploratory study