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Nutrition During Pregnancy and Lactation: Exploring New

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GET THIS BOOK Meghan Harrison, Rapporteur; Food and Nutrition Board; Health and Medicine
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Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop

Maternal Nutrient Intake and

Early-Life Programming

A mother’s intake from the prenatal through postnatal periods influ-

ences programming of the growth and development of her child. The
mechanisms by which this takes place involves a complex interplay of
systems, including the microbiome, metabolome, placenta, and epigenetic
changes. The seventh session of the workshop, moderated by Emily Oken of
the Harvard Medical School and the Harvard Pilgrim Health Care Institute,
explored the evidence on these systems and the implications of maternal
nutrition on early-life programming. Highlights from the session presenta-
tion and panel discussion are presented in Box 8-1.

THE ROLE OF THE PLACENTA IN DELIVERING NUTRIENTS

AND IN DEVELOPMENTAL PROGRAMMING
“I firmly believe the placenta is the director of pregnancy. It’s in
charge,” said Leslie Myatt, professor of obstetrics and gynecology, direc-
tor of perinatal research, and Endowed Professor in the Bob and Charlee
Moore Institute of Nutrition and Wellness at the Oregon Health & Science
University, Portland, to set the stage for his remarks. The placenta not only
transfers nutrients to the infant and removes waste products, it also com-
municates with the mother and fetus, explained Myatt. Over the course of
his presentation, Myatt reviewed advances in evidence on developmental
programming, roles of the placenta, sexual dimorphism in fetal outcomes,
placental growth and development, and factors that affect the placenta and
developmental programming.

107
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108 NUTRITION DURING PREGNANCY AND LACTATION

BOX 8-1
Highlights from the Session 7 Presentation
and Panel Discussion

• The placenta directs maternal metabolism and promotes fetal growth and
development (Myatt).
• The placenta responds to changes in nutrient supply, which may develop­
mentally program the fetus through epigenetic mechanisms (Myatt).
• There are sexually dimorphic placental adaptations (Myatt).
• A common set of data across different populations could facilitate much more
rapid comparisons to make strides toward personalized nutrition (Myatt).
• Current dietary patterns are not sustainable, and efforts are needed to deter-
mine locally sourced diets specific to each region of the world across seasons,
in an effort to reduce the need for supplementation (Aagaard).
• Diet quality is of critical importance, as improvements in diet quality shift
­intakes away from sugar, environmental toxins, and contaminants (Goran).

NOTE: These points were made by the individual workshop speakers identified
above. They are not intended to reflect a consensus among workshop par-
ticipants. The statements have not been endorsed or verified by the National
­Academies of Sciences, Engineering, and Medicine.

Advances in Evidence on Developmental Programming

The rise in obesity and diabetes in the population over the past 30 years
affects pregnancy outcomes. The bulk of human existence has faced nutri-
tional deficits. Accordingly, the placenta and fetus adapted to develop
mechanisms to handle these deficits. In modern times, however, there is an
excess of nutrients, explained Myatt.
Originally called the Barker Hypothesis, the Developmental Origins
of Health and Disease (DOHaD) suggests that risk for chronic diseases—
particularly cardiovascular disease, diabetes, metabolic syndrome, and
neurobehavioral outcomes—are determined in utero. Myatt remarked
that there can be differential effects to the same insult, and that male
fetuses tend to be more severely affected than female fetuses. Differences
in the type and level of nutrition, physical factors, environmental con-
taminants, and other factors affect fetal growth, development, and pro-
gramming. These factors tend to operate through epigenetic mechanisms.
The resulting DNA methylation and histone modification affects gene
expression and transcription.

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MATERNAL NUTRIENT INTAKE AND EARLY-LIFE PROGRAMMING 109

Roles of the Placenta

Myatt described a variety of roles the placenta plays, in addition to
nutrient, oxygen, and waste exchange. The placenta serves as an immune
barrier between mother and fetus and helps prevent the mother from reject-
ing the semiallogenic fetus. Notably, the placenta makes hormones and
other metabolites that enter maternal circulation. These chemical signals
can alter the amount of nutrients in maternal circulation thus changing
the availability of glucose, fatty acids, and amino acids for transport to
the fetus. The placenta metabolizes a substantial portion of the substrates
to generate adenosine triphosphate (ATP) for its own processes. A current
line of investigation is exploring the role of placental metabolites (e.g.,
serotonin) in fetal development.
Characterizing the placenta as “selfish,” Myatt explained that the
­placenta regulates the supply and composition of nutrients coming from
the mother, and provides the fetus what it does not consume itself. The
placenta is four to six times more metabolically active per unit weight than
the fetus. At term, the placenta is about one-sixth the size of the fetus and
yet consumes approximately half of the fuel and oxygen delivered to the
uterus. A third of the oxygen consumed by the placenta is used for the de
novo generation of peptides, while another third is used to maintain the
cation gradient needed for transmembrane transport. The placenta uses
different mechanisms for transport, depending on the substrate, including
flow-mediated diffusion, active transport, facilitated transport, and endo-
cytosis and exocytosis.
The placenta controls the transfer of nutrients and has adaptive
responses to changes in supply. It plays a role in regulating maternal
metabolism so that substrates are released for transport (i.e., the supply of
nutrients), and it appears to be involved in fetal growth and development
(i.e., the demand for nutrients). The placenta can also change the flow of
nutrients to the fetus by altering the expression of various transporters.
With the ability to store certain nutrients, the placenta may also serve as a
buffer. From an evolutionary standpoint, Myatt suggested that the placenta
likely developed adaptive mechanisms in response to altered nutrient sup-
plies. These mechanisms appear to include altering regulatory signals and
promoting epigenetic changes.

Sexual Dimorphism in Fetal Outcomes

“It’s good to be a girl in utero … conversely it’s not so good to be a
boy in utero,” said Myatt to preface his discussion of sexual dimorphism in
fetal outcomes. Animal studies have shown that changing maternal nutri-
tion can alter the ratio of male-to-female fetuses. Feeding mice omega-3

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110 NUTRITION DURING PREGNANCY AND LACTATION

pol­yunsaturated fatty acids can increase the ratio of male pups born, added
Myatt. In humans, female fetuses appear to grow at a rate to optimize sur-
vival, whereas male fetuses tend to continue growing throughout gestation.
Rates of adverse outcomes—including preterm births, placenta previa, pre-
eclampsia, lagging lung development, macrosomia, and late stillbirths—are
higher among pregnancies with male fetuses. Male fetuses also appear to
affect maternal beta-cell function, increasing risk of gestational diabetes.
The sexual dimorphism also occurs in the placenta (see Box 8-2).

Placental Growth and Development

Placental growth, structure, and function is dynamic and increases in
substrate transport efficiency over the course of gestation. There are several
critical periods of placental development, and the placenta appears to adapt
to insults in an effort to keep the fetus alive. The same insult occurring at
different times of gestation can exert different effects. Although difficult to
study in humans, this concept has been demonstrated with hyper­glycemia.
Women with insulin-dependent diabetes who entered pregnancy with ele-
vated blood glucose concentrations tended to have large-for-gestational-
age infants and had alterations to placental glucose transport. In contrast,
women who developed gestational diabetes and experienced hyperglycemia
later in pregnancy did not experience the placental changes.
The epigenome is responsive to changes in the timing and availability
of nutrients. For instance, DNA methylation was found to be different
depending on whether a woman was in her first or third trimester dur-

BOX 8-2
Evidence for Sexual Dimorphism in Placental Function

• Differences in gene expression, first trimester and term, linked to escape from
X chromosome inactivation
• Inflammatory, hypoxia, apoptosis, and autophagy responses
• Expression of antioxidant defense enzymes
• Fatty acid transporters
• Fatty acid oxidation
• Response to maternal adiposity and inflammatory status
• MicroRNA expression in normal pregnancy
• Steroid synthesis
• All linked to difference in outcomes male versus female

SOURCE: Presented by Leslie Myatt.

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MATERNAL NUTRIENT INTAKE AND EARLY-LIFE PROGRAMMING 111

FIGURE 8-1  Links between nutrition and epigenetic changes.

NOTE: TCA = tricarboxylic acid.
SOURCES: Presented by Leslie Myatt. Reprinted from Myatt L and Mitsuya,
K. 2015. Epigenetics and the placenta: Impact of maternal nutrition. In Human
­placental trophoblasts, edited by Asim K. Duttaroy and Sanjay Basak: CRC Press,
pp. 37–52.

ing the Dutch Hunger Winter.1 The citric acid cycle is affected by various
nutritional factors, and the resulting epigenetic changes can have implica-
tions for placental gene expression, placental function, and developmental
programming (see Figure 8-1). As the placenta is fetal tissue, it is likely that
epigenetic changes are also taking place in the fetus, but the extent of this
is currently unknown, added Myatt.

Factors That Affect the Placenta and Early-Life Programming

Nutrients such as betaine, choline, folate, vitamin B6, and vitamin B12,
which are involved in one-carbon metabolism, affect epigenetic modifica-
tions. A host of other nutrients and dietary factors also appear to play a
role. Butyrate and curcumin, for instance, affect histone conformation.
More broadly, various states and conditions can also have implications for

1 The Dutch Hunger Winter was a famine that took place in the Netherlands during the

winter of 1944–1945.

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112 NUTRITION DURING PREGNANCY AND LACTATION

the placenta and early-life programing, including obesity and gestational

diabetes, oxidative stress, and substrate use, said Myatt.

Obesity and Gestational Diabetes

Obesity and gestational diabetes both have implications for early-life
programming. For instance, obesity alters placental DNA methylation. A
recent analysis found a 15 percent increase in DNA methylation and a cor-
responding decrease in hydroxymethylation in the placentas of obese women,
as compared to lean women (Mitsuya et al., 2017). These changes often trans-
lated into differences in gene expression. Many of the 262 genes affected were
found on chromosomes 17 and 19. Increasing maternal a­ diposity can also
decrease mitochondrial respiration, which is potentially related to increased
risk of stillbirth, noted Myatt. Mitochondrial respiration is also decreased in
women who develop gestational diabetes. In an effort to generate energy, the
placenta adapts by increasing in size and increasing glycolysis.

Oxidative Stress
Pregnancy is a state of elevated oxidative stress, with the placenta being
a major source of reactive oxygen species. Pathological pregnancies, such
as those with obesity and gestational diabetes, further increase placental
oxidative stress and can deplete antioxidant defenses, often in a sexually
dimorphic manner. The highest antioxidant defenses are found in placentas
of male fetuses carried by lean women, whereas the lowest antioxidant
defenses are found in the placentas of male fetuses carried by women with
obesity (Evans and Myatt, 2017). There are different types of antioxidant
defenses, including extracellular antioxidants and intracellular reducing
elements, such as superoxide dismutase and glutathione peroxidase. Mecha-
nisms to handle reactive oxygen species within a cell are likely context and
location specific. “Perhaps it is not surprising, with our failure of things like
vitamin C and vitamin E to actually be able to effectively reduce oxidative
stress if they are actually not reaching the site of reactive oxygen species
production,” said Myatt.

Substrate Use
Glucose, fatty acids, and glutamine are substrates used in placental
mitochondrial respiration. Different cell types prefer different substrates,
but they have metabolic flexibility to switch between substrates, should one
become limited. In lean women, the three substrates are used in approxi-
mately equal proportions and there are differences between male and female
fetuses. Women who have hyperglycemia and hyperlipidemia stemming

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MATERNAL NUTRIENT INTAKE AND EARLY-LIFE PROGRAMMING 113

from obesity and gestational diabetes have a greater reliance on glucose

and fatty acids and decreased metabolic flexibility but only among women
carrying male fetuses (Wang et al., 2019).
Docosahexaenoic acid (DHA) and arachidonic acid (AA) are two key
fatty acids that are essential for brain development, particularly as the brain
undergoes dramatic growth in the third trimester of pregnancy and in early
childhood. Male infants of women supplemented with these brain-specific
fatty acids during pregnancy had increased brain size (Ogundipe et al.,
2018). Expression of different fatty acid oxidation enzymes in the placenta
shows sexually dimorphic differences. In women with obesity, there is an
increase in expression of enzymes specific to short-chain fatty acids among
male placentas, whereas female placentas show a preference for long-
chain fatty acids. The male placentas of women who developed gestational
diabetes also showed a decrease in triglycerides containing DHA. These
differences result in more medium- and short-chain fatty acids enzymes in
the placentas for male fetuses. Aligned with these findings, O’Neill et al.
(2018) reported the diabetic women had higher concentrations of medium
chain fatty acids in their amniotic fluid, and more long-chain fatty acids if
the fetus was female.

Summarizing Key Points

Myatt ended his remarks by summarizing select key points from his
presentation. He emphasized that the placenta influences maternal metabo-
lism to support fetal growth and development. The placenta is responsive
to changes in nutrient supply, and these adaptations may lead to fetal
programming via epigenetic mechanisms. Given the responsiveness of the
placenta, Myatt suggested that, “at delivery, the placenta can be used as
a diary of fetal exposure.” Finally, he underscored that there is a sexual
dimorphism in placental function and effect that should be considered and
further studied. It is currently unknown if interfering with the adaptive
effects is potentially harmful or if interventions are addressing a primary
dysfunction of the placenta.

PANEL DISCUSSION
After Myatt’s presentation, Kjersti Aagaard of the Baylor College of
Medicine and Michael Goran of Children’s Hospital Los Angeles and Uni-
versity of Southern California joined him for a panel discussion. Moderator
Oken had the panelists consider upcoming, applied, and future innovations
and considerations related to each of their work.
Oken asked the panelists to first share their ideas on what they thought
were clear next-step, highest-yield interventions. From his perspective,

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114 NUTRITION DURING PREGNANCY AND LACTATION

Goran thought sugar is a dietary culprit that should be addressed, given its
caloric, metabolic, and developmental effects. He admitted that investigat-
ing different sugar exposures would be complicated, time-consuming, and
costly, but he emphasized that sugar is a dietary factor frequently found to
be related to maternal and infant outcomes. Reducing sugar intake would
shift dietary intakes toward a more wholesome diet, suggested Goran, who
cautioned the focus should be reducing the craving for sweetness rather
than displacing intake with artificial sweeteners.
Aagaard stated that there is some data to suggest the periconception
period is a key time for intervention, but acknowledged that this approach
would be difficult to use at a population level, as approximately half of
pregnancies are unplanned. Taking a more global view, she thought that
current dietary patterns are not sustainable and locally and regionally
grown nutritious food should be made more available. She also believed
a clear next step would be to improve maternal diets, thereby improving
breast milk composition. With approximately half of the maternal popu-
lation affected by obesity and/or gestational diabetes, Myatt underscored
that these two conditions are critically important to address, especially
given the implications for the placenta. He noted that placental research is
difficult, as samples only become available at term and thought that being
able to get tissue samples earlier could help identify important time points
for intervention. Findings from the few studies that have been able to assess
placentas earlier in gestation have aligned with animal studies, suggesting
changes in the preconception period and early gestation could have implica-
tions for the entire pregnancy, he added. Given this, Myatt suggested that
there should be greater focus on diet and care in the preconception period
and that gestational diabetes should be screened for sooner than 26 weeks
gestation.
In her second question, Oken asked if any of the research the panel-
ists presented is ready for clinical application. From Myatt’s perspective,
he thought the amount of testing a woman undergoes during pregnancy is
fairly minimal and suggested the time is right for more testing of placental
health. He mentioned that, as a result of efforts like the Human Placenta
Project, two biomarkers of placental health (PlFG and soluble Flt-1) have
recently entered clinical practice in the United Kingdom. Used as a screen-
ing in the third trimester, the biomarkers are used to identify women at
increased risk for adverse outcomes in the last portion of their pregnancies.
Myatt indicated additional biomarkers are emerging but need improve-
ments in their sensitivity and specificity.
Aagaard thought that, in general, women undergo a number of screen-
ings during pregnancy. She was concerned about the undue stress positive
screening tests can cause, especially when there is no readily identifiable
therapeutic but a known adverse outcome in the end, and suggested any

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MATERNAL NUTRIENT INTAKE AND EARLY-LIFE PROGRAMMING 115

screening that that is implemented should be tied to clinical management

that would lead to a change or improvement in an outcome. Aagaard
also raised the issues of cost and patient burden related to additional
screenings. Shifting her remarks to the microbiome and epigenomics,
Aagaard did not think either was ready for clinical applications at this
time. She stated that she supported the American College of Obstetri-
cians and Gynecologists statement that inoculation with vaginal swabs is
reserved for the setting of a clinical trial and research purposes only, and
cautioned that the risks of such transfers are not fully understood nor is
benefit demonstrated.
From his perspective, Goran thought oligosaccharides were not ready
for clinical applications yet. The existing clinical trials on oligosaccharides
have limitations, including study design and short durations, he indicated.
Given the state of the science, Goran suggested high-quality trials supple-
menting infant formulas and supplementing lactating women were war-
ranted. “We’re talking about turning breast milk into a more individual,
precision-type of nutrition that can be individualized for the infant to offset
any problems such as environmental toxins,” he said. Goran emphasized
the importance of diet quality, to shift intakes away from sugar, environ-
mental toxins, and contaminants. He remarked, “The question is how to
get people there and how to modify the food system to make that more
broadly available to more people.”
To conclude the panel discussion, Oken asked for ideas on where the
research on these topics should go. Myatt indicated there should be a move-
ment toward determining individualized, optimal nutrition. From a practi-
cal perspective, Aagaard suggested that synchronizing and linking well-child
and postnatal visits in the same time and space could be incredibly informa-
tive. She also thought that there is a need for locally sourced diets specific to
each region of the world across seasons, in an effort to reduce the need for
supplementation. Until the information is digestible, however, personalized
nutrition will not be fully embraced, she suggested. Myatt added, “We need
to get the message across that pregnancy and lactation is an important time
of life in development and [give] it the attention and funding it needs.” To
make strides toward personalized nutrition, research needs to tease apart
differences, he remarked, adding that a common set of data across different
populations could facilitate much more rapid comparisons.

QUESTIONS FROM THE AUDIENCE

After the panel discussion, Oken open the discussion to members of the
audience. Questions were raised about collaboration and futures ­studies,
evidence related to the placenta, and dietary quality and components.

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116 NUTRITION DURING PREGNANCY AND LACTATION

Collaboration and Futures Studies

A member of the webinar viewing audience wondered to what extent
toxicologists and nutritionists collaborate, given shared interests in the role
of environmental contaminants on fetal programming. Aagaard acknowl-
edged the interplay between nutrition, environmental contaminants, and
fetal programming. Even nutritious food can be exposed to chemical toxi-
cants depending on how and where it is grown. Proper nutrition helps to
ensure the right microbes are present so they can detoxify these chemical
toxicants, she explained. Agreeing that there is a connection, Goran said
he personally has had such cross-disciplinary collaborations, but thought
more interdisciplinary work is needed.
Referring to remarks made of the continuum of maternal health and
nutrition, Anna Maria Siega-Riz of the University of Massachusetts Amherst
asked for ideas of how best to effectively study long-term outcomes. Oken
said the Environmental influences on Child Health Outcomes (ECHO)
Program is one example in the United States. Building on this, Aagaard
added that the ECHO Program brings together data from different s­ tudies
to help fill in gaps. She suggested that artificial intelligence and the use
of electronic health records could also be valuable. Aagaard viewed the
5-year timeline for National Institutes of Health funding as a limitation to
long-term endeavors, and she thought there was a need to develop funding
mechanisms to support lengthy longitudinal cohorts.

Evidence Related to the Placenta

Siega-Riz wanted to know at what point the placenta starts to play a
more prominent role in delivering nutrients to the fetus. Myatt explained
that blood flow in the placental intervillious space begins at about 12 weeks
gestation and increases over the course of pregnancy. He noted both the fetus
and the surface area of the placenta undergo exponential growth during the
third trimester. On the topic of fetal and placental growth, Aagaard offered
that there are interesting examples in the animal literature. For instance,
marmosets are New World nonhuman primates that do not have singleton
births, but rather birth twins. Approximately 70–80 of the 135 days of
gestation are spent investing in placentation, which is the opposite of what
humans do, she explained. Marsupials can make a choice between gesta-
tions and lactation, depending on nutrient availability. “­Decisions around
investments in placentation and investments in fetal growth are ones that
have different species come up with different solutions for,” said Aagaard.
A webcast audience member asked Myatt about the underpinning for
the sexual dimorphic growth in utero. There is an argument that, from an
evolutionary standpoint, males want to grow larger so they can compete for

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MATERNAL NUTRIENT INTAKE AND EARLY-LIFE PROGRAMMING 117

a mate even though it places them in a stressful situation, suggested Myatt.

“Boys live dangerously in the womb,” he said, in a quote he attributed to
David Barker.

Dietary Quality and Components

With respect to comments made earlier in the workshop, a webcast
audience member asked about the relationship between fiber and the micro-
biome. Indicating fiber serves a beneficial role, Aagaard stated that to
her knowledge there are no pregnancy-specific recommendations for fiber
intake related to supporting the microbiome.
A member of the webcast audience questioned whether quality of fat
should be prioritized over quantity of total fat. Noting that certain fats are
critical for brain growth and development, Myatt indicated that there
are mechanisms to preferentially transport and use different types of fat.
More research is needed to determine the ideal mix of different types of
fat, he said. Goran added that quality should also be considered for the
other macronutrients, as well.

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