Clinical Opinion
org
Prevention of obesity and diabetes in pregnancy:
is it an impossible dream?
Oded Langer, MD, PhD
T he continuing epidemic of obesity
and diabetes has led to an increase
in type 2 diabetes as well as gestational
diabetes mellitus (GDM) for women of
childbearing age. The proportion of
pregnant women who are overweight or
obese in pregnancy is >58.5% between
the ages of 20e39 years with a body mass
index (BMI) >25 kg/m in the United
States.1-3 Obesity is one of the most
common metabolic disorders of women
of reproductive age. It constitutes a major
risk factor for maternal and fetal
complications. For example, subfertility,
miscarriage, thromboembolism, hyper-
tensive disorders, and metabolic
syndrome are potential maternal com-
plications while preterm delivery, intra-
uterine death, congenital anomalies, and
macrosomia adversely affect the fetus.
Moreover, obesity, diabetes, and cardio-
vascular diseases may well extend beyond
fetal life into childhood and adulthood.4
The obesity epidemic is an unintended
consequence of economic, social, and
technological changes. The food supply is
low in cost, abundant, tasty, and highly
caloric. Labor-saving technologies have
virtually eliminated requirements for
physical activity as part of everyday life.
Preventing diabetes mellitus and obesity
has the potential to halt the trans-
generational disease cycle by reducing the
incidence of the disease, impaired
glucose tolerance, and obesity.5,6
From Knoxville, TN.
Received Jan. 24, 2018; revised March 8, 2018;
accepted March 15, 2018.
The author reports no conflict of interest.
Presented as a keynote address at the Diabetes
in Pregnancy Study Group of North America,
Washington, DC, October 28, 2017.
Corresponding author: Oded Langer, MD, PhD.
odlanger@gmail.com
0002-9378/$36.00
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.03.014
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ajog.
The obesity and diabetes epidemic is an unintended consequence of economic, social,
and technological changes. In nonpregnancy, people identified as high risk to develop
type 2 diabetes may delay progression by 30e70% with lifestyle interventions and
pharmacological agents. In pregnancy, lifestyle interventions have been the primary
focus to prevent fetal short- and long-term complications that may evolve into substantial
weight gain and gestational diabetes mellitus. The dilemma for obstetricians is whether
diabetes and obesity can be prevented and not simply treated after the fact. Interventions
after women become pregnant may be too late to see the kinds of meaningful im-
provements in child and maternal health because there is a short interval from gesta-
tional diabetes mellitus diagnosis to delivery. Therefore, future efforts need to incorporate
quality research, lifestyle interventions that designate time of initiation and duration
during pregnancy, the preventative intervention of a prepregnant “fourth trimester,”
coupled with the concept of precision medicine so that there is the potential to make the
impossible dream a reality.
Key words: gestational diabetes prevention, lifestyle interventions, patient compliance,
pregnancy outcomes
Prevention is defined as any activity involving diet and enhanced physical
that reduces the burden of mortality or activity helps to delay or prevent the
morbidity from disease. Primary pre- progression of impaired glucose toler-
vention avoids the development of a ance to diabetes even with a modest
disease. Secondary prevention targets loss of weight through diet and exer-
early disease detection to increase op- cise. However, it should be noted that
portunities for intervention (eg, anom- the duration of intervention in these
alies). Tertiary prevention reduces the studies was >3 years. Thus, the effect
negative impact of already established of preventative measures and weight
disease (diabetes, hypertension).7 loss had sufficient time to impact
The goal of prevention in nonpreg- change in the nonpregnant subjects8-14
nant women is to mainly address pri- (Table 1).
mary and secondary prevention of In pregnancy, the main focus is
type 2 diabetes and impaired glucose related to the fetal perspective for short-
toleranceealong with obesityeand sec- and long-term complications. The
ondary and tertiary prevention of med- mother, however, may have veiled
ical complications such as cardiovascular metabolic disturbances in the presence
risk, myocardial infarction, and hyper- of normal glucose tolerance 5 years
tension. The scientific basis of preven- postpregnancy. When women with
tative health is the premise that chronic previous GDM were compared to
illnesses are incremental in nature. The healthy controls, it was shown that there
best health strategy is to change the slope was a 48% higher risk to develop dia-
of progression of a disease from the rate betes and hyperglycemia. In addition,
at which illness develops. these subjects exhibited insulin resis-
Prospective randomized controlled tance, decreased adiponectin, increased
studies such as the Diabetes Prevention C-reactive protein, and cardiovascular
Program in the United States and the risk.15 The scope of the problem that
Finnish Diabetes Prevention Study faces the pregnant woman and her
have shown that lifestyle modification care provider is to address potential
JUNE 2018 American Journal of Obstetrics & Gynecology 581
Clinical Opinion
TABLE 1
Preventative measures that positively impacted outcome in nonpregnant
women
Intervention
Lifestyle 8,13,14
12
Metformin
Tiazolidinedione
Troglitazone12
Rosiglitasone 9
Payoglitazone10
11
Acarbose
Langer. Prevention of obesity and diabetes in pregnancy. Am J Obstet Gynecol 2018.
preventative measures that may posi-
tively affect pregnancy outcome.
Motivation and compliance in
pregnancy
Pregnancy offers a critical window of
opportunity for assessing and improving
women’s health. Pregnant women with
and without GDM are considered to be
highly motivated. They may, perhaps, be
even more receptive to advice concern-
ing lifestyle choices especially if phrased
as being for the benefit of the baby. Thus,
pregnancy has been suggested to repre-
sent a teachable moment in women’s
lives during which physician advice
regarding healthy lifestyle behaviors may
have lasting beneficial effects.16,17
An associated factor to lifestyle
changes is the improvement of the
motivation and compliance relationship
between the woman’s health and her
sense of control. Compliance in the
patient is defined as the willingness
and ability to perform in a prescribed
manner. Care providers define
noncompliance as behavior deviating
from their expectations. However, a pa-
tient’s everyday personal reality not
meeting medical expectations does not
equate with noncompliance.
The fault with weight-loss and exer-
cise programs may lie almost as much
with care providers as with their pa-
tients. Most physicians have little to no
training in how to counsel patients who
need to lose weight. Instead of being
motivated to exercise or lose weight,
many patients feel stigmatized by their
582 American Journal of Obstetrics & Gynecology JUNE 2018
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Duration, y Risk reduction
3.2 29e58%
3.0 26e31%
55%
2.5 60%
3.0 60%
2.2 72%
3.3 25%
perceived provider’s attitude toward
people with weight problems. An online
survey at the Rudd Center for Food Policy
and Obesity at Yale University revealed
that people considered terms such as
“obese,” “fat,” and “morbidly obese” as
blaming language used by doctors. At
least 20% of survey participants said they
would either avoid future medical ap-
pointments or seek new doctors.17
The motivation/compliance relation-
ship of women with GDM was evaluated
using memory self-monitoring blood
glucose monitors. The study sought to
investigate adherence and reliability of
testing. The results revealed that more
than two thirds of the patients altered the
glucose measurements.18 Similar findings
of poor reliability and adherence as being
common in diabetes in pregnancy were
reported.19 In a large study of women in
San Antonio, TX, and New York, NY,
subjects (n ¼ 1102) were required to
test blood glucose 7 times/d with the
knowledge of the memory capabilities of
the reflectance meters. The women
actually tested on average 4.3 times/d and
only 70% improved patient performance
and compliance to the diabetic regimen
that included diet and insulin therapy
when indicated. Social, ethnic, and
geographic location did not affect patient
performance.20
The effectiveness of exercise training
and the level of physical activity for
preventing excessive gestational weight
gain and GDM among women who
are overweight or obese is still uncer-
tain.21-23 Since there is a lack of detailed
ajog.org
descriptions of physical activity patterns
during pregnancy in women who are
normal weight, overweight, or obese, we
examined (unpublished data) the rela-
tionship between motivation and
compliance in women with GDM in an
exercise regimen. Women were counseled
to exercise 30 min/d. For obese subjects
(BMI 30), 4% reported exercising daily
and/or every other day. In all, 22%
claimed to exercise weekly, while 62%
rarely exercised. In contrast, 80% of the
nonobese (BMI 18e25) subjects followed
the exercise recommendations. It may be
unrealistic to expect most overweight and
obese patients to comply with an exercise
regimen. Patients most likely to benefit
are the least likely to exercise. Developing
new strategies on diet and exercise guid-
ance at all weight levels for use by care
providers may enhance compliance.
Can diabetes and obesity be prevented
during pregnancy and not simply
treated after the fact?
Behavioral weight-management pro-
grams should last a minimum of 12e15
weeks. The standard length of most
commonly commissioned diet in-
terventions in nonpregnancy is 12
weekse3 years.24 Moreover, at least
40e60% of women reported that their
pregnancies were unplanned. Maternal
health status before pregnancy is a
decisive factor for pregnancy outcomes
and for risk for maternal and infant
complications. Still, maternity care does
not start until the pregnancy is estab-
lished and, in many cases, not until more
than half of the pregnancy has pro-
gressed, which often is too late to impact
outcomes. The Barker hypothesis25
demonstrated that much of an adult’s
health is programmed during his/her
experience as a fetus and in early child-
hood. There is now evidence that the
pattern that is laid down during early
fetal life might provide a mechanism to
explain how intrauterine stress could
impact adult health status and the pro-
pensity for obesity and diabetes in the
next generation. Thus, interventions for
all women after they become pregnant
are too late to see the kinds of mean-
ingful improvements in child and
maternal health due to the short interval
ajog.org
from GDM diagnosis to delivery.26-30
Therefore, there is a need to reevaluate
nearly everything that has been accepted
about the conventional wisdom of diet
and exercise and their effects on health,
and in particular, in pregnancy. High-
lighting the instances of the limits of our
medical knowledge is to demonstrate
that we are at a crossroads in our
approach to prevention and lifestyle in-
terventions. Will the repercussions of
decision-making on lifestyle in-
terventions be significant or trivial? Will
the evidence supporting a given decision
be overwhelming, minimal, or some-
where in between? Will the evolution of
the concept and protocols for a fourth
trimester forestall some of the negative
impact of the complications of obesity
and diabetes?
Although studies are publicized
weekly, they do not provide the answers
to such questions as: what to eat and how
much to exercise and which type. The
problem is one of signal-to-noise ratio.
This relationship compares the level of a
desired signal to the level of background
noise. One cannot discern the signal (less
diabetes and/or obesity) because of the
abundance of so much noise. The enor-
mous uncertainty in the measurement of
diet, exercise, and weight gain in preg-
nancy is overwhelming. As a result, the
signal is often weak, meaning that if
there is an effect on lifestyle, it is often
small. In addition, there is no gold
standard for measurement, ie, nothing
that everyone agrees upon and uses to
measure aspects of lifestyle. Adding to
the confusion is the discordance of
poorly designed research, use of different
measurements, diverse reporting of
outcomes, and selective reports of posi-
tive or interesting results that produce
“whipsaw” literature, ie, one week coffee
is good for you and the next week it is
lethal.
Literature addressing prevention of
complications in pregnancy using meta-
analysis has proliferated. However, it is
susceptible to several sources of bias
since it often includes randomized
controlled trials (RCTs) of questionable
quality. There is a clinically important
and statistically significant 30e50%
exaggeration of treatment efficacy when
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results of lower-quality trials were
pooled.31-35
Effects of individual lifestyle change
components in pregnancy
While there is little doubt about the as-
sociation of lifestyle and pregnancy
outcome, there is considerable doubt
about the net value of lifestyle adjust-
ments during pregnancy. Traditional
lifestyle choices are: staying active; exer-
cising regularly with the goal of at least
30 minutes of daily moderate exercise
such as walking or swimming; and,
eating well-balanced meals that are low-
fat and rich in fiber to prevent excessive
weight gain. However, advice alone on
nutrition in pregnancy has not been
demonstrated to improve outcome, and
may, in itself, have adverse effects.
Beneficial effects may occur when advice
is accompanied by a program of social
support.36,37
Many news stories on lifestyle
researchewhat types of food and drink
are associated with healthy outcomes,
whether trans fats are healthier than
saturated fats, or the healing powers of
certain foods such as acai berries or
beetseare not of any genuine contribu-
tion to health education. Readers
invariably walk away with wildly skewed
notions of what they need to do to
improve their health, which accounts in
part for the repeated waves of fad diets or
trendy foods that dominate the health
consumer market. Only when health
care guidelines, programs, industry, care
providers, and academicians work in
tandem with the media is there the po-
tential for a joint effort in educating the
public. Their collaboration as to what,
why, and how to read and apply the in-
formation may enhance the public’s
ability to incorporate positive lifestyle
interventions into their lives.
Diet and weight loss: are there
opportunities for intervention?
The National Health and Nutrition
Survey involving >4700 people showed
that only 38% of US adults eat a healthy
diet and 10% exhibited normal body fat
percentage.38 A review of the literature
discloses a lack of consensus on the
effectiveness of diet on weight gain.
JUNE 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
There are approximately 38 top-rated
diets currently in vogue in the United
States today. They strive to be safe, rela-
tively easy to follow, nutritious, and
effective for weight loss. They attempt to
prevent diabetes and cardiovascular dis-
ease. However, there is paucity of evi-
dence of the overall benefits of these diets
on pregnancy outcome. The hope has
been that by following some simple,
practical, and achievable lifestyle advice,
pregnant women will improve their
health and pregnancy outcomes. To
whatever extent possible, lifestyle dietary
changes should be adopted before
women become pregnant. The key to
success seems to have more to do with
the amount of time to affect change,
monitor caloric intake, and adherence to
any weight-loss plan. This could poten-
tially represent the concept of treatment
prior to pregnancy, ie, the fourth
trimester.
There is extensive literature on the
effects of diet on nonpregnant subjects.
In a study by Johnston et al39 that
comprised a meta-analysis of 59 ran-
domized trials (n ¼ 7286), they found
that weight-loss differences between in-
dividual diets were minimal. A study
conducted by Shai et al40 randomly
assigned 322 moderately obese subjects
to 1 of 3 diets: low-fat, restricted-Medi-
terranean, and low-carbohydrate that
included instructional sessions for 2
years. The authors concluded that all 3
diet protocols may be effective. In addi-
tion, they reported more favorable
effects on lipids and glycemic control
with the low-carbohydrate diet. These
results suggest that personal preferences
and metabolic considerations might
inform individualized tailoring of
dietary interventions. In a randomized
trial conducted by Sacks et al,41 811
overweight adults received instructional
sessions for 2 years to evaluate change in
body weight for several diet groups: low
vs high fat, average vs high protein, and
low vs high carbohydrate content. The
authors reported that none of the diets
elicited substantial weight loss and none
was better than the others.
Differential sensitivity to particular
dietary regimens (based on genotype)
may also contribute to GDM
583
Clinical Opinion
management. Macrobiotics may suc-
cessfully lower postmeal blood glucose
and its long-term metabolic conse-
quences. Personalized nutrition may
predict glycemic responses, ie, people
eating identical meals present high vari-
ability in postmeal blood glucose.42
Can exercise enhance pregnancy
outcome?
In 2015, only 21% of nonpregnant in-
dividuals were compliant in a physical
activity routine based on the Physical
Activity Guidelines Advisory.43 Physical
activity estimates vary substantially
depending on whether self-reported or
measured via accelerometer.44 At the
same time, only 20.3% (95% confidence
interval [CI], 15.50e26.10) of the
women complied with American
Congress of Obstetricians and Gynecol-
ogists criteria. Women aged 30 years
old and those with a university degree
tended to devote more time to exercising
according to both recommendations. It
is necessary to encourage physical ac-
tivity, mainly among those who are
younger, and those with lower levels of
educational attainment.45
In pregnancy, the rationale for rec-
ommending physical activity is to pre-
vent or decrease the prevalence of GDM
and control weight gain. In a systematic
review and meta-analysis, Tobias et al46
showed a 24% lower risk to develop
GDM with physically active subjects.
The results indicated that greater total
physical activity before pregnancy or
during early pregnancy was significantly
associated with a lower risk of GDM. The
magnitude of this association was
greatest for prepregnancy physical ac-
tivity with women in the highest quan-
tiles of activity experiencing a 55%
reduction in risk, compared with that for
women with the lowest activity. The
heterogeneity of the studies included in
the analysis was substantial, suggesting
that differences among study pop-
ulations or methodology may have
affected the results. In a systematic
review and meta-analysis among exer-
cising subjects, with inclusion restricted
to studies that randomized participants
to an exercise-only-based intervention,
Russo et al47 demonstrated a 28% lower
584 American Journal of Obstetrics & Gynecology JUNE 2018
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risk to develop GDM. Using a meta-
analysis with regular moderate-
intensity exercise during pregnancy,
Sanabria-Martınez et al48 demonstrated
a 31% lower risk for GDM (relative risk,
0.69; P ¼ .009) and decreased maternal
weight gain (weight mean difference,
1.14 kg; P < .001) in the intervention
group. No serious adverse fetal and
maternal effects were reported.
In contrast, in a RCT (n ¼ 255  2) of
healthy gravidas, Barakat et al49 evalu-
ated the effect of regular moderate in-
tensity exercise (3 training sessions/wk of
50- to 55-minute duration) on the inci-
dence of GDM. The authors demon-
strated no reduction in the risk for
developing GDM (odds ratio, 0.84; 95%
CI, 0.50e1.40) for both groups. In a
randomized clinical trial (n ¼ 855) of
women recruited at 18e22 weeks, Stafne
et al50 compared moderate-/high-in-
tensity exercise vs standard antenatal
care. The duration of the trial was 12
weeks. The authors reported 7% rate of
GDM with the intervention and 6% in
the control. Further findings revealed
that insulin resistance showed no dif-
ference between the groups and only
55% of intervention subjects followed
the exercise protocol. A study by Han
et al51 evaluated the effect of exercise in
pregnancy to prevent GDM (Cochrane
database). At the conclusion of 5 trials
with 1115 subjects, the authors found no
significant difference in BMI, insulin
sensitivity, incidence of GDM (RR, 1.10;
95% CI, 0.66e1.84), cesarean delivery (2
trials, RR, 1.33; 95% CI, 0.97e1.84), or
operative vaginal birth (2 trials, RR, 0.83;
95% CI, 0.58e1.17). In addition, they
reported a moderate risk of bias for the
included studies. The FitFor2 study by
Oostdam et al52 randomized pregnant
women at risk for GDM into exercise vs
standard care. They demonstrated that
exercise performed over the second and
third trimesters of pregnancy had no
effect on fasting blood glucose, insulin
sensitivity, and birthweight, most prob-
ably because of low compliance. In
studying exercise during pregnancy with
overweight and obese women, Garnæs
et al53 demonstrated that this interven-
tion did not influence birthweight or
other neonatal and maternal outcomes
ajog.org
at delivery in either group. The study was
limited by a small sample size and poor
adherence to the exercise protocol.
Ramírez-Vélez,54 in a 12-week exercise
program undertaken during the second
trimester of pregnancy, randomized par-
ticipants into exercise (n ¼ 429) and no
exercise (n ¼ 426). The authors reported
that the intervention did not reduce the
prevalence of GDM (7% intervention vs
6% control) in pregnant women with
BMI in the normal range (Table 2).
The ability of a study to reproduce
similar findings is the gold standard in
science. Thus far, the lack of consensus
in study findings on exercise in preg-
nancy to reduce/prevent the develop-
ment of GDM challenges the
conventional wisdom of its efficacy. The
introduction of an exercise program
during pregnancy does not have the time
needed to affect change. However, when
exercise and/or diet protocols are incor-
porated during preconception, they may
be efficacious preventative components.
How early these components need to be
introduced has yet to be studied.
The effectiveness of interventions to
limit excessive weight gain
The incorporation of diet and exercise
programs in lifestyle interventions were
introduced to address the problem of
excessive weight gain during pregnancy.
Today, excessive weight gain is more
prevalent than inadequate weight gain. It
is now recognized that excess maternal
weight gain during pregnancy is very
common in the United States, and is
associated with an increased risk of
pregnancy complications, especially in
women who start pregnancy already
overweight or obese. Excess maternal
weight gain has also been associated with
higher rates of obesity in children later in
life. Although some previous trials have
had success with interventions to limit
weight gain during pregnancy, there are
mixed results as to whether subsequent
complications were reduced.
While it might have been expected
that healthier eating and increased
physical activity during pregnancy
would be associated with differences in
weight gain, findings have highlighted
that the current criteria for weight gain
ajog.org
in pregnancy is not an ideal measure of
pregnancy health. Comparing the effec-
tiveness and safety of weight-loss diets is
frequently limited by short follow-up
times and high dropout rates. A study
conducted by Deputy et al55 found that in
44,000 women from 28 states, 20e25%
were below the National Academy of
Medicine (NAM) recommendations and
42e47% above these recommendations.
Overweight or obese women were 2e3
times above weight gain recommenda-
tions. Race, ethnicity, level of education,
and health (diabetes or nausea) affected
weight gain. In another study, only 26%
of women reported receiving NAM-
consistent advice. Not remembering or
not receiving advice was associated with
both inadequate and excessive weight
gain.56 If approximately 60e70% of
subjects did not achieve NAM criteria for
weight gain in pregnancy, the results
challenge either the use of the NAM
criteria to evaluate pregnancy weight gain
or the efficacy of lifestyle interventions of
diet and exercise.
In a meta-analysis of 10 randomized
trials on the effect of lifestyle advice vs
standard care on gestational weight gain
(kg), Oteng-Ntim et al57 reported a pro-
tective effect after lifestyle intervention
counseling of a loss of 2.2 kg (e2.86 to
1.57 kg). Of interest is that of the 10
studies included, only 2 reached a level
of significance for a protective effect
individually. The MOMFIT study, a ran-
domized trial of 276 nondiabetic over-
weight and obese women to prevent
excess gestational weight gain, compared
lifestyle intervention to usual care
(Peaceman et al58). The authors demon-
strated weight gain 19.1 vs 23.7 lb
(P <.001), respectively. Cesarean delivery
rate 40% vs 27% (P <.02), and exceeding
NAM criteria 68% vs 86% (P < .001),
respectively. No significant differences for
adverse pregnancy outcomes including
GDM, preeclampsia, gestational hyper-
tension, and macrosomia were reported.
Are the results of the above studies of a
reduction in weight gain from 23.7e19.1
lb considered a success and if there is a
statistical significance, is there also a
clinical significance?32
Whether prevention of excessive
gestational weight gain in the first weeks
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TABLE 2
Effect of exercise on the reduction of gestational diabetes mellitus
in pregnancy
Design
Tobias et al46 Meta- analysis
Russo et al 47
Meta- analysis
48
Sanabria-Martınez et al Meta- analysis
Han et al51 Meta- analysis
Barakat et al49 RCT
Ramı́rez-Vélez54 RCTs
Stafne et al50 RCT
GDM, gestational diabetes mellitus; n.s., nonsignificant; PA, physical activity; RCT, randomized controlled trial.
Langer. Prevention of obesity and diabetes in pregnancy. Am J Obstet Gynecol 2018.
of pregnancy is associated with a reduced
risk for GDM is currently unclear. A
study by Brunner et al59 addressed this
possible association by conducting a
systematic review and a meta-analysis of
observational studies. A total of 8 studies
involving 13,748 participants were
included (from 1990 through 2014). The
results suggest that excessive gestational
weight gain prior to a GDM screening
test is associated with an increased risk of
GDM compared with nonexcessive
gestational weight gain. These results
emphasize the need for appropriate
preconception care and for better pre-
vention of early excessive gestational
weight gain.
Therapeutic lifestyle interventions: do
they work?
The fundamental question is whether
“big ideas” have improved the quality of
GDM/obesity prevalence and pregnancy
outcome: by how much; for how many;
for whom? Brown et al,60 evaluating
lifestyle interventions for treatment of
women with GDM in a meta-analysis of
15 trials in 45 reports (4501 women,
3768 infants), demonstrated that life-
style interventions included a wide
variety of types: education, diet, exercise,
self-monitoring blood glucose, and 10%
received pharmacological therapy. The
control group received the standard
JUNE 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
GDM risk Method and
reduction recruitment
24% Early pregnancy self-reported
28% Only exercise based
31% Low levels of PA
<20 min
<3 d/wk
n.s. 4/5 Small sample sizes
n.s. 3 Times/wk
50e55 min
7% vs 6% 12-wk Program
7% vs 6% 18e22 wk
antenatal care or diet alone. They used
the GRADE methodology to determine
the quality of evidence, which has a
range from high to very low. The main
reasons for downgrading evidence in the
study were inconsistency and risk of bias.
The influence of lifestyle intervention
protocols remains unclear due to low
and moderate quality of evidence.
Furthermore, although the data
compared lifestyle modification vs stan-
dard care, the data were only generated
from some of the original 15 studies.
Some examples are hypertensive disor-
ders of pregnancy (preeclamptic toxemia
[PET]) data generated from 4/15 trials
(RR, 0.70; 95% CI, 0.40e1.2); data
showing the development of type 2 dia-
betes (up to 10-year follow-up) from 2/15
trials (RR, 0.98; 95% CI, 0.54e1.76); data
of the composite of serious infant out-
comes from 2/15 trials (RR, 0.57; 95% CI,
0.21e1.55); and reduction of the number
of large-for-gestational-age (LGA) infants
from 6/15 trials (RR, 0.60; 95% CI,
0.50e0.71). The net effect of the contri-
bution of individual components of life-
style interventions could not be assessed.
Longer-term benefits or drawbacks
remained unclear (limited reporting).
Evaluation of long-term outcomes for
the mother and child should be a priority
when planning future trials. There has
been no in-depth exploration of the
585
Clinical Opinion
costs saved from reduction in risk of
LGA/macrosomia and potential longer-
term risks for the infants. Future
research could focus on which specific
interventions are most useful (as in-
terventions without pharmacological
treatment), which care providers should
dispense this counseling, and the
optimal format for providing the
information.
In a study by Koivusalo et al61 a RCT
(n ¼ 144) vs control (n ¼ 125) investi-
gated if moderate lifestyle interventions
reduced GDM. The authors concluded
that in the intervention group, the rate of
GDM was 13.9% (95% CI, 8.7e20.6) vs
control (standard care) 21.6% (95% CI,
14.7e29.8). Additionally, the weight
change loss for the intervention group
was greater by only 0.58 kg (P ¼.04) with
a physical activity total weekly median
increase of 15 minutes. Pregnancy
outcomes were nonsignificant for:
chronic hypertension and preeclampsia
(PET)/pregnancy-induced hypertension,
cesarean delivery, macrosomia (4500 g),
respiratory distress, and anomalies.
In an examination of drug trials, there
are a variety of questions each dealing in
whole or in part with uncertainty that
affect our perception of the value of a
drug. First, what will be the yardstick by
which we will measure a drug’s efficacy?
Will it be something indisputable or
something subject to interpretation and
thus more difficult to measure? How big
will any potential observed benefit need
to be before we consider it a success?
What are the potential harms of the
treatment? Every type of treatment we
offer our patients involves consideration
of each of these factors.
A recent review article by Romero
et al62 discussed the mechanisms of
action and potential benefits of metfor-
min as a therapeutic agent. Experimental
studies suggest that metformin could
have a place in the treatment and/or
prevention of prediabetes mellitus,
GDM, and polycystic ovarian disease. In
addition, there are claims for pre-
eclampsia prevention of cancer and
prolonging life and mitigating the effects
of aging. A study by Aroda et al63 studied
the effect of lifestyle interventions and
metformin on the prevention or delay
586 American Journal of Obstetrics & Gynecology JUNE 2018
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of diabetes in 3 groups (Diabetes Pre-
vention Program study). In women with
no history of GDM, lifestyle in-
terventions reduced the progression to
diabetes by 30%. The metformin-treated
group showed no change and the group
of women with a history of GDM had a
48% higher risk to develop diabetes. A
study by Syngelaki et al64 sought to
evaluate the role of metformin to prevent
GDM and improve pregnancy outcome
in a randomized double-blind placebo-
control trial (202 metformin [3 g/d] vs
198 control) in nondiabetic obese (BMI
>35, median weight 107.7 kg [95.7-
116.2]) pregnant women. There was no
significant difference in the primary
(LGA) and secondary (incidence of
GDM and adverse neonatal outcome)
outcomes. There was a statistically sig-
nificant difference in gestational weight
loss of approximately 2 kg (in the women
whose median weight was almost 108 kg:
4.6 vs 6.3 kg). Does this weight reduction
in obese patients make a clinical differ-
ence? On the other hand, the rate of
preeclampsia in the metformin-treated
patients was 3.0% compared to 11.3%
in the control group. This difference
does make a clinical difference. These
latter 2 studies are examples of how a
drug such as metformin can decrease the
rate of one complication yet fail to
positively effect change in another
complication. Therefore, we need to
determine if in this instance, do the ends
justify the means and for whom?
In a randomized trial of a lifestyle
intervention in infertile obese women
preceding infertility treatment as
compared with prompt infertility treat-
ment, Mutsaerts et al65 found that life-
style intervention did not result in a
higher rate of vaginal births. In addition,
the authors found no significant differ-
ences in perinatal outcome (eg, LGA,
PET, and diabetes). Vinter et al,66 in a
RCT of 304 obese nondiabetic women
for lifestyle intervention (Lifestyle in
Pregnancy study), demonstrated a
weight gain of 7.0 vs 8.6 kg (P <.01). The
NAM criteria for weight gain was
exceeded in 35% (lifestyle intervention
group) vs 47% (standard care). Physical
activity was difficult to maintain in the
weekly frequency protocol. There was
ajog.org
no significant difference in: rates of
GDM, LGA, macrosomia, PET, neonatal
intensive care unit admission, and
cesarean delivery rates. The LIMIT
(RCT, n ¼ 2212)67 and UPBEAT (RCT,
n ¼ 1525)68 studies on intervention in
overweight/obese women demonstrated
no reduction in the incidence of: GDM
(risk ratio, 0.96; 95% CI, 0.79e1.16;
P ¼ .68), LGA (risk ratio, 1.15; 95%
CI, 0.83e1.59; P ¼.40), and weight gain,
to translate into clinical benefits (mean
difference e0.2 kg).
In a systematic review, Thangar-
atinam et al69 studied the effect of life-
style interventions on fetal size (LGA/
small for gestational age). They found
that the contribution of individual
components of lifestyle intervention
such as diet, physical activity, and mixed
approach had no protective effect. A
Cochrane Review70 of 13 RCTs found no
clear differences in risk for GDM and
excessive weight gain. Overall, the
moderate quality of the studies on the
effects of interventions limited the ability
to draw firm conclusions due to the
intervention type, populations assessed,
and outcome definitions between trials
(Table 3).
The whole is equal to the sum of its
parts but not all parts are equal
The conventional wisdom that lifestyle
interventions will have a significant
impact on the incidence of GDM, weight
gain, and pregnancy outcome has not
been clinically proven. It is clear, how-
ever, that the concept of one size fits all in
prevention of obesity and GDM is sim-
ply wrong. Overweight and obesity are a
precursor to but not a single disease.
There are many types of obesity. For
example, metabolically healthy obese
phenotypes have a 9e16% prevalence.
Metabolically healthy obese is charac-
terized by high levels of insulin sensi-
tivity; no hypertension; favorable lipid,
inflammation, hormonal, liver enzyme,
and immune profile; and greater ability
to adapt to a caloric challenge.71,72
However, 30% of this group may
convert to metabolically unhealthy obese
with cardiometabolic complications
over a 5- to 10-year span. Conversion is
associated with aging and weight gain.
ajog.org
TABLE 3
Lifestyle intervention and perinatal outcome
Reduction of GDM
Koivusalo et al 61
n.s.
Syngelaki et al 64
n.s.
Mutsaerts et al65 n.s.
Vinter et al66 n.s.
67
LIMIT n.s.
68
UPBEAT n.s.
GDM, gestational diabetes mellitus; LGA, large for gestational age; n.s., nonsignificant.
Langer. Prevention of obesity and diabetes in pregnancy. Am J Obstet Gynecol 2018.
There is a high likelihood to preserve the
metabolically healthy obese status with
maintenance of physical activity and
weight loss.73 The analysis of factors
such as disease phenotypes, marker
types, and biological treatments will help
clarify the multidimensionality of the
complications in pregnancy. While pur-
suing the use of multiple levels of in-
formation including genetics, clinical
data, environmental, and lifestyle fac-
tors, examining the interaction between
these multiple dimensions represents a
challenge.
Medicine has evolved to accept that
people are born with a set of genetic
traits, and this is the basis of our vari-
ability. The environment in the form of
diet, pathogens, and drugs will interact
with this genetic endowment. Not only
must the care provider seek to under-
stand the immediate cause of an illness
and find a treatment or, better still, a
cure, but the care provider should also
attempt to understand the ethical and
human dimensions of the illness that are
relevant to its etiology and essential to
good management.
To achieve optimal pregnancy out-
comes in the future, which will translate
to better health throughout life, there is a
need for enhanced preconception care
that spans the time periods before, dur-
ing, and between pregnancies and across
generations. “Precision medicine” has
become the new slogan for targeting
disease treatment and prevention based
on an individual’s specific profile. It may
be an additional component in precon-
ception care. This profile takes into
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Weight gain, kg PET
<0.58 n.s.
2.6 vs 6.3 3% vs 11.3%
e n.s.
7.0 vs 8.6 n.s.
n.s. n.s.
n.s. n.s.
account 3 main contributing factors:
genetics, environment, and lifestyle.74,75
Targeting therapies with consideration
given to individual variations in these
factors may ultimately illuminate the
future of diabetes care in pregnancy.
Based on a specific genomic profile, in
the future, some women may have better
tolerance of certain nutrients than others
in maintaining glycemic contro.42 For
example, glyburide failure is associated
with the common E23K variant in
KCNJ11. The GDF15 gene (NAG-1)
positively affects metformin. It activates
the secretory and/or reduces inhibitory
pathways. OCT1 polymorphisms re-
duces the response to metformin in type
2 diabetics. Physical activity is an indi-
vidual genomic response to exercise in
muscle strength and fat distribution.75,76
Preconception counseling is one
element of precision medicine that we can
carry out today; it assists women in setting
the stage for an optimal intrauterine
environment for their infant based on
their own genetics, environment, and
lifestyle history. The combination of these
factors, with consideration given to indi-
vidual variations of the components in the
decision-making process, may improve
maternal-fetal outcomes. The significance
of initiating lifestyle changes during
preconception will override the time
constraints for change during pregnancy.
Thus, preconception care becomes the
fourth trimester of pregnancy and sets the
stage for an improved pregnancy
outcome.
The point of science is not to create
canon but to collect and test evidence
JUNE 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
Macrosomia LGA Cesarean delivery
n.s. e n.s.
e n.s. e
n.s. n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
n.s. n.s. n.s.
that points toward conclusions, which in
turn update approaches, treatments, and
policies based on rigorous research.
However, scientific knowledge is always
provisional. When the evidence changes,
so does the strategy. Lifestyle in-
terventions, coupled with the concept of
precision medicine, and the incorpora-
tion of the preventative intervention in a
prepregnant fourth trimester, have the
potential to inspire quality research to-
ward better approaches and innovations
that will ultimately benefit the target
population. -
REFERENCES
1. Centers for Disease Control and Prevention
(CDC). National diabetes statistics report, 2017.
Estimates of diabetes and its burden in the
United States. Available at: https://www.
cdc.gov/diabetes/pdfs/data/statistics/national-
diabetes-statistics-report.pdf. Accessed April
12, 2018.
2. Lawrence J, Contreras R, Chen W, Sacks D.
Trends in the prevalence of preexisting diabetes
and gestational diabetes mellitus among a
racially/ethnically diverse population of pregnant
women, 1999-2005. Diabetes Care 2008;31:
899-904.
3. Flegal K, Carroll M, Kit B, Ogden C. Preva-
lence of obesity and trends in the distribution of
body mass index among US adults, 1999-2010.
JAMA 2012;307:491-7.
4. Langer O. Obesity in pregnancy: a sign of the
times? In: The diabetes in pregnancy dilemma:
leading change with proven solutions, 2nd ed.
Shelton (CT): People’s Medical Publishing
House; 2015. p .257-77.
5. Office of Disease Prevention and Health
Promotion. Healthy People 2000. Available at:
https://www.cdc.gov/nchs/healthy_people/
hp2000.htm. Accessed: April 12, 2018.
6. Barbour L. Unresolved controversies in
gestational diabetes: implications on maternal
587
Clinical Opinion
and infant health. Curr Opin Endocrinol Diabetes
Obes 2014;21:264-70.
7. Bonita R, Beaglehole R, Kjellstrom T. Basic
epidemiology, 2nd ed. World Health Organiza-
tion; 2006. p. 99-114.
8. The Diabetes Prevention Program (DPP)
Research Group. The Diabetes Prevention Pro-
gram (DPP): description of lifestyle intervention.
Diabetes Care 2002;25:2165-71.
9. Gerstein H, Yusuf S, Bosch J, et al. DREAM
(diabetes reduction assessment with ramipril
and rosiglitazone medication) Trial Investigators.
Effect of rosiglitazone on the frequency of dia-
betes in patients with impaired glucose toler-
ance or impaired fasting glucose: a randomized
controlled trial. Lancet 2006;368:1096-105.
10. DeFronzo R, Tripathy D, Schwenke D. Pio-
glitazone for diabetes prevention in impaired
glucose tolerance. N Engl J Med 2011;364:
1104-15.
11. Chiasson J, Josse R, Gomis R, Hanefield M,
Karasik A, Laakso M. Acarbose for prevention of
type 2 diabetes mellitus: the STOP-NIDDM
randomized trial. Lancet 2002;359:2072-7.
12. Knowler W, Hamman R, Edelstein S, et al.
Diabetes Prevention Program Research Group.
Prevention of type 2 diabetes with troglitazone in
the Diabetes Prevention Program. Diabetes
2005;54:1150-6.
13. Knowler W, Barrett-Connor E, Fowler S,
et al. Diabetes Prevention Program (DPP)
Research Group: description of lifestyle inter-
vention. Diabetes Care 2002;25:2165-71.
14. Lindström J, Louheranta A, Mannelin M. The
Finnish Diabetes Prevention Study (DPS) Life-
style intervention and 3-year results on diet and
physical activity. Diabetes Care 2003;26:
3230-6.
15. Winhofer Y, Tura A, Winzer C, et al. Hidden
metabolic disturbances in women with normal
glucose tolerance five years after gestational
diabetes. Int J Endocrinol 2015;2015:342938.
16. Power M, Schulkin J. Knowledge, attitudes
and practices regarding weight gain during
pregnancy. J Womens Health (Larchmt)
2017;26:1169-75.
17. Puhl R, Peterson J, Luedicke J. Motivating
or stigmatizing? Public perceptions of weight-
related language used by health providers. Int
J Obes 2013;37:612-9.
18. Langer O, Mazze R. The relationship between
large-for-gestational-age infants and glycemic
control in women with gestational diabetes. Am J
Obstet Gynecol 1988;159:1478-83.
19. Cosson E, Baz B, Gary F, et al. Poor reli-
ability and poor adherence to self-monitoring of
blood glucose are common in women with
gestational diabetes mellitus and may be asso-
ciated with poor pregnancy outcomes. Diabetes
Care 2017;40:1181-6.
20. Langer O, Langer N, Piper J, Elliot B,
Anyaegbunam A. Cultural diversity and self-
monitoring blood glucose. J Assoc Acad Minor
Phys 1995;6:72-7.
21. Sui Z, Dodd J. Exercise in obese pregnant
women: positive impacts and current percep-
tions. Int J Womens Health 2013;5:389-98.
588 American Journal of Obstetrics & Gynecology JUNE 2018
Descargado para demetrio rufino guarniz capristan (ethangc_66@hotmail.com) en Colegio Medico Del Peru de ClinicalKey.es por Elsevier en julio 24, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
22. Renault K, Norgaard K, Andreasen K,
Secher N, Nilas L. Physical activity during preg-
nancy in obese and normal-weight women as
assessed by pedometer. Acta Obstet Gynecol
Scand 2010;89:956-61.
23. McParlin C, Robson S, Tennant P, et al.
Objectively measured physical activity during
pregnancy: a study in obese and overweight
women. BMC Pregnancy Childbirth 2010;10:76.
24. National Institute for Health and Care
Excellence. Weight management: lifestyle ser-
vices for overweight or obese adults. 2014.
Available at: https://www.nice.org.uk/guidance/
ph53. Accessed April 12, 2018.
25. Barker D, Osmond C, Law C. The intrauter-
ine and early postnatal origins of cardiovascular
disease and chronic bronchitis. J Epidemiol
Community Health 1989;43:237-40.
26. Catalano P, Mcintyre D, Cruickshank K,
et al. The hyperglycemia and adverse pregnancy
outcome study. Diabetes Care 2012;35:780-6.
27. Landon M, Spong C, Thom E, et al.
A multicenter, randomized trial of treatment for
mild gestational diabetes. N Engl J Med
2009;361:1339-48.
28. Crowther C, Hiller J, Moss J, McPhee A,
Jeffries W, Robinson J. Effect of treatment of
gestational diabetes mellitus on pregnancy out-
comes. N Engl J Med 2005;352:2477-86.
29. Langer O, Conway D, Berkus M, Xenakis E,
Gonzales O. A comparison of glyburide and in-
sulin in women with gestational diabetes melli-
tus. N Engl J Med 2000;343:1134-8.
30. Committee on Practice Bulletinse
Obstetrics. Gestational diabetes mellitus. Prac-
tice bulletin no. 180. Obstet Gynecol 2017;130:
e17-37.
31. Frakt A. An observational study goes where
randomized clinical trials have not. JAMA
2015;313:1091-2.
32. American Statistical Association. Statement
on statistical significance and p-values. 2016.
Available at: https://www.amstat.org/asa/files/
pdfs/P-ValueStatement.pdf. Accessed April
12, 2018.
33. Moher D, Pharm B, Jones A, et al. Does
quality of reports of randomized trials affect es-
timates of intervention efficacy reported in meta-
analyses? Lancet 1998;352:609-13.
34. Peinemann F, Tushabe D, Kleijnen J. Using
multiple types of studies in systematic reviews of
health care interventions. PLoS One 2013;8:
e85035.
35. Frieden T. Evidence for health decision
makingebeyond randomized controlled trials.
N Engl J Med 2017;377:465-75.
36. Herring S, Platek D, Elliot P, Riley L,
Stuebe A, Oken E. Addressing obesity in preg-
nancy: what do obstetric providers recom-
mend? J Womens Health 2010;19:65-70.
37. Sanda B, Vistad I, Sagedal L, Haakstad L,
Lohne-Seiler H, Torstveit M. Effect of a prenatal
lifestyle intervention on physical activity level in
late pregnancy and the first year postpartum.
PLoS One 2017;12:e188102.
38. Clarke T, Norris T, Schiller J. Leisure time
physical activity. National Center for Health
ajog.org
Statistics. National Health Interview Survey,
March 2016. Available at: https://www.cdc.
gov/nchs/data/nhis/earlyrelease/earlyrelease
201609.pdf. Accessed April 12, 2018.
39. Johnston B, Kanters S, Bandayrel K.
Comparison of weight loss among named diet
programs in overweight and obese adults: a
meta-analysis. JAMA 2014;312:923-33.
40. Shai I, Schwarzfuchs D, Henkin Y, et al.
Weight loss with a low-carbohydrate, Mediter-
ranean, or low-fat diet. N Engl J Med 2008;359:
229-41.
41. Sacks F, Bray G, Carey V, et al. Comparison
of weight-loss diets with different compositions
of fat, protein, and carbohydrates. N Engl J Med
2009;360:859-73.
42. Zeevi D, Korem T, Zmora N, et al. Person-
alized nutrition by prediction of glycemic re-
sponses. Cell 2015;163:1079-94.
43. Office of Disease Prevention and Health
Promotion. Physical activity guidelines for
Americans. 2008. Available at: https://health.
gov/paguidelines/guidelines/. Accessed April
12, 2018.
44. Tucker J, Welk G, Beyler N. Physical activity
in U.S.: adult compliance with the physical ac-
tivity guidelines for Americans. Am J Prev Med
2011;40:454-61.
45. Amezcua-Prieto C, Lardelli-Claret P,
Olmedo-Requena R, Mozas-Moreno J, Bueno-
Cavanillas A, Jiménez-Moleón J. Compliance
with leisure-time physical activity recommenda-
tions in pregnant women. Acta Obstet Gynecol
Scand 2011;90:245-52.
46. Tobias D, Zhang C, van Dam R, Bowers K,
Hu F. Physical activity before and during preg-
nancy and risk of gestational diabetes mellitus.
Diabetes Care 2011;34:223-9.
47. Russo L, Nobles C, Ertel K, Chasa-Taber L,
Whitcomb B. Physical activity interventions in
pregnancy and risk of gestational diabetes
mellitus: a systematic review and meta-analysis.
Obstet Gynecol 2015;125:576-82.
48. Sanabria-Martınez G, Garcia-Hermoso A,
Poyatos-Leon R, Alvarez-Bueno C, Sanchez-
Lopez M, Martinez-Vizcaino V. Effectiveness of
physical activity interventions on preventing
gestational diabetes mellitus and excessive
maternal weight gain: a meta-analysis. BJOG
2015;122:1167-74.
49. Barakat R, Pelaez M, Lopez C, Lucia A,
Ruiz J. Exercise during pregnancy and gesta-
tional diabetes-related adverse effects: a ran-
domized controlled trial. Br J Sports Med
2013;47:630-6.
50. Stafne S, Salvesen K, Romundstad P,
Eggebo T, Carlsen S, Morkved S. Regular ex-
ercise during pregnancy to prevent gestational
diabetes: a randomized controlled trial. Obstet
Gynecol 2012;119:29-36.
51. Han S, Middleton P, Crowther CA. Exercise
for pregnant women for preventing gestational
diabetes mellitus. Cochrane Database Syst Rev
2012;7:CD009021.
52. Oostdam N, van Poppel M, Wouters M. No
effect of the FitFor2 exercise program on blood
glucose, insulin sensitivity, and birthweight in
ajog.org
pregnant women who were overweight and at
risk for gestational diabetes: results of a random-
ized controlled trial. BJOG 2012;119:1098-107.
53. Garnæs K, Nyrnes S, Salvesen K. Effect of
supervised exercise training during pregnancy
on neonatal and maternal outcomes among
overweight and obese women. Secondary an-
alyses of the ETIP trial: a randomized controlled
trial. PLoS One 2017;12:e0173937.
54. Ramírez-Vélez R. A 12-week exercise pro-
gram performed during the second trimester
does not prevent gestational diabetes in healthy
pregnant women. J Physiother 2012;58:198.
55. Deputy N, Sharma A, Kim S, Hinkle S.
Prevalence and characteristics associated with
gestational weight gain adequacy. Obstet
Gynecol 2015;125:773-81.
56. Deputy N, Sharma A, Kim S, Olson C.
Achieving appropriate gestational weight gain:
the role of healthcare provider advice. J Womens
Health 2018 Jan 10. https://doi.org/10.1089/
jwh.2017.6514 [Epub ahead of print].
57. Oteng-Ntim E, Varma R, Croker H,
Poston L, Doyle P. Lifestyle interventions for
overweight and obese pregnant women to
improve pregnancy outcome: systematic review
and meta-analysis. BMC Med 2012;10:47.
58. Peaceman A, Kwasny M, Gernhofer N,
Vincent E, Josefson J, Van Horn L. MOMFIT: a
randomized clinical trial of an intervention to
prevent excess gestational weight gain in over-
weight and obese women. Am J Obstet Gynecol
2017;216(Suppl):S2-3.
59. Brunner S, Stecher L, Ziebarth S, et al.
Excessive gestational weight gain prior to
glucose screening and the risk of gestational
diabetes: a meta-analysis. Diabetologia 2015;58:
2229-37.
60. Brown J, Alwan N, West J, et al. Lifestyle
interventions for the treatment of women with
Descargado para demetrio rufino guarniz capristan (ethangc_66@hotmail.com) en Colegio Medico Del Peru de ClinicalKey.es por Elsevier en julio 24, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
gestational diabetes. Cochrane Database Syst
Rev 2017;5:CD011970.
61. Koivusalo S, Rono K, Klemetti M, et al.
Gestational diabetes mellitus can be prevented
by lifestyle intervention: the Finnish gestational
diabetes prevention study (RADIEL). Diabetes
Care 2016;39:24-30.
62. Romero R, Erez O, Huttemann M, et al.
Metformin, the aspirin of the 21st century: its role
in gestational diabetes mellitus, prevention of
preeclampsia and cancer, and the promotion of
longevity. Am J Obstet Gynecol 2017;217:
282-302.
63. Aroda V, Christophi C, Edelstein S, et al. The
effect of lifestyle intervention and metformin on
preventing or delaying diabetes among women
with and without gestational diabetes: the dia-
betes prevention program outcomes study 10-
year follow up. J Clin Endocrinol Metab
2015;100:1646-53.
64. Syngelaki A, Nicolaides K, Balani J, et al.
Metformin versus placebo in obese pregnant
women without diabetes mellitus. N Engl J Med
2016;374:434-43.
65. Mutsaerts M, van Oers A, Groen H, et al.
Randomized trial of a lifestyle program in obese
infertile women. N Engl J Med 2016;374:
1942-53.
66. Vinter C, Jensen D, Ovesen P, Beck-
Nielsen H, Jorgensen J. The LiP (lifestyle in
pregnancy study): a randomized controlled trial
of lifestyle intervention in 360 obese pregnant
women. Diabetes Care 2011;34:2502-7.
67. Dodd J, Turnbull D, McPhee A, et al. Ante-
natal lifestyle advice for women who are over-
weight or obese: LIMIT randomized trial. BMJ
2014;348:g1285.
68. Poston L, Bell R, Croker H, et al. Effect of
behavioral intervention in obese pregnant
women (the UPBEAT study): a multicenter,
JUNE 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
randomized controlled trial. Lancet Diabetes
Endocrinol 2015;10:767-77.
69. Thangaratinam S, Rogozinska E, Jolly K,
et al. Effects of interventions in pregnancy on
maternal weight and obstetric outcomes: meta-
analysis of randomized evidence. BMJ
2012;344:e2088.
70. Bain E, Crane M, Tieu J, Han S, Crowther C,
Middleton P. Diet and exercise interventions
for preventing gestational diabetes mellitus.
Cochrane Database Syst Rev 2015;4:
CDC10443.
71. Badoud F, Lam K, Perreault M, Zulyniak M,
Britz-McKibbin P, Mutch D. Metabolomics re-
veals metabolically healthy and unhealthy
obese individuals differ in their response to a
caloric challenge. PLoS One 2015;10:
e0134613.
72. Flegal K, Kit B, Orpana H, Graubard B. As-
sociation of all-cause mortality with overweight
and obesity using standard body mass index
categories: a systematic review and meta-anal-
ysis. JAMA 2013;309:71-82.
73. Appleton S, Seaborn C, Visvanathan R,
et al. Diabetes and cardiovascular disease out-
comes in the metabolically healthy obese
phenotype: a cohort study. Diabetes Care
2013;36:2388-94.
74. Collins F. Medical and societal conse-
quences of the human genome project. N Engl J
Med 1999;341:28-37.
75. President’s Council of Advisors on
Science and Technologies. Priorities for
personalized medicine. 2008. Available at:
http://oncotherapy.us/pdf/PM.Priorities.pdf.
Accessed April 12, 2018.
76. Gerstein H, Pare G, McQueen M, et al.
Identifying novel biomarkers for cardiovascular
events or death in people with dysglycemia.
Circulation 2015;132:2297-304.
589