Effects of obesity treatment on female

reproduction: results do not

match expectations
Richard S. Legro, M.D.
Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

The adverse effects of obesity of female reproduction have been extensively documented. However, there are few prospective studies
that have examined preconception weight loss interventions. There is a need to develop successful interventions with signicant weight
loss and compliance and most importantly document the effects of preconception interventions on important perinatal outcomes such
as live birth and the health of the infant and mother. The existing data from randomized trials that come closest to meeting these criteria
have failed to document improved live-birth rates after the intervention compared with control groups. There is a tendency to equate
favorable weight change both before and during pregnancy with a direct qualitative improvement in all perinatal outcomes, yet the
results from the most successful treatment of morbid obesity, that is, bariatric surgery, with on average 40% weight loss, suggest a
mixed risk-benet ratio on perinatal outcomes. Although interventions to control gestational weight gain have been more completely
studied than preconception ones, and have documented successful interventions to achieve appropriate weight gain, there is no clear
evidence that controlling gestational weight gain actually improves any important perinatal outcome. Future studies must develop more
successful and effective interventions, capture perinatal outcomes instead of weight change as the primary outcomes, use, at least pre-
conception, new antiobesity drugs (in combination with other therapies), and study bariatric surgery in prospective trials to improve our
understanding of the effectiveness of obesity treatment before pregnancy. (Fertil Steril 2017;107:8607. 2017 by American Society
for Reproductive Medicine.)
Key Words: Infertility, lifestyle modication, bariatric surgery, pharmacotherapy, gestational weight gain
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
16110-fertility-and-sterility/posts/15173-23610

T
he adverse effects of female harm. Higher rates of operative delivery obesity on reproduction is still being
obesity on reproduction have including cesarean section, wound in- described.
been exhaustively documented fections, and thromboembolic events Given this mountain of evidence,
(1). The epidemiologic literature pro- characterize the peripartum period. Dif- can we do anything for an obese
vides overwhelming and consistent ev- culty initiating and maintaining woman other than strongly advocate
idence that female obesity is associated lactation continue into the puerperium, weight loss if she is contemplating
with ovulatory dysfunction; increased and the vicious circle continues with pregnancy and if she is currently preg-
time to pregnancy; increased preg- higher rates of infant obesity among nant, to at least slow gestational weight
nancy loss from rst trimester to last, obese mothers. Never in the eld of hu- gain (GWG) to some modest margin?
including increased rates of stillbirth; man reproduction have so many obese Yet as this article will argue, based on
and increased risk of major pregnancy women attempted and achieved preg- level 1 randomized clinical trial evi-
morbidities such as gestational dia- nancy, often with iatrogenic multiple dence, there is little proof that such in-
betes, preterm labor, and preeclampsia pregnancy further worsening the situa- terventions to control weight before or
with associated maternal and fetal tion, such that the full scope of female during pregnancy effectively improve
the perinatal outcomes of interest to
Received December 21, 2016; revised January 25, 2017; accepted February 21, 2017. the patient or clinician, such as
R.S.L. has nothing to disclose. improved live-birth rates, term deliv-
Supported in part by the National Institutes of Health (NIH) (grant no. U10 HD38992).
The content is solely the responsibility of the authors and does not necessarily represent the ofcial eries, appropriate for gestational age
views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development babies, and above all the preservation
or the NIH.
Reprint requests: Richard S. Legro, M.D., Department of Obstetrics and Gynecology, Pennsylvania
of the health of infant or mother. In
State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033 fact, there is emerging evidence that
(E-mail: RSL1@psu.edu). such interventions counterintuitively
Fertility and Sterility Vol. 107, No. 4, April 2017 0015-0282/$36.00 may actually worsen some of these
Copyright 2017 Published by Elsevier Inc. on behalf of the American Society for Reproductive desired outcomes. Potential reasons
Medicine
http://dx.doi.org/10.1016/j.fertnstert.2017.02.109
for the discrepancy between treatment

860 VOL. 107 NO. 4 / APRIL 2017


and outcome will be explored. This review will focus on the
obese reproductive woman, that is, the obese woman who is
seeking pregnancy or is pregnant. A disclaimer is also neces-
sary. This article focuses on the effects of weight loss in the
obese woman on reproduction. There is no argument that
weight loss in an obese woman will improve diabetes or car-
diovascular risk and disease, but this review will focus on the
shorter term personal and public goal of a healthy baby and a
healthy mother.
WEIGHT IS A SURROGATE MARKER FOR
REPRODUCTIVE FITNESS
Surrogate markers, which tend to track with a health outcome of
interest, are not the end of treatment, but often only a means to a
successful outcome. Weight loss preconception or weight main-
tenance during pregnancy should be sought in the obese repro-
ductive woman only if an outcome of health signicance is
favorably impacted, that is, the achievement of a healthy normal
weight full-term baby with the avoidance of undue harm to the
mother and infant (2, 3). Let us explore the rst part of this
clause: to assume that weight loss will automatically improve
the desired outcomes is to make the fundamental aw of
confusing association with cause and effect. Epidemiological
studies show that increasing weight, in a dose-response relation-
ship, is associated with increasing reproductive failure in women
(4, 5). But that does not necessarily mean that increasing weight
loss before pregnancy or controlling weight gain during
pregnancy proportionately restores normal outcomes. It is
possible that other factors than weight contribute to or cause
reproductive failure, which are differentially impacted by
therapy. To clearly answer this question, prospective dose-
response weight loss studies are needed. They would provide
proof of concept not only of increasing weight loss improving
perinatal outcomes but also of establishing the optimal amount
of weight loss. Without them, we are seeing through a glass
darkly.
For example, elevated low-density lipoprotein cholesterol
(LDL-C) levels are associated with an increased risk for pri-
mary and secondary cardiovascular events, and lowering
these levels is generally associated with lowering event rates,
that is, LDL-C levels are a surrogate marker for cardiovascular
events (6). Statin therapy was initially approved by the Food
and Drug Administration (FDA) on this basis (LDL-C
lowering) without evidence of lowering event rates (which
was subsequently demonstrated by the publication of the
Scandinavian Simvastatin Survival Study [4S] 7 years later
[7]). However, this direct correlation between marker and
events is not always the case. There are multiple examples
of drugs that signicantly lowered LDL-C levels but resulted
in increased cardiovascular events in patients, for example,
the use of hormone replacement therapy in the Women's
Health Initiative (8) or the use of torcetrapib, a potent choles-
teryl ester transfer protein, in the ILLUMINATE trial (9). We
can argue that the adverse event rates here were likely unre-
lated to the decline in LDL-C but rather related to the adverse
effects of the drug on other organ systems, but it harkens to
the importance of capturing all related events to identify
collateral benets and harms.
VOL. 107 NO. 4 / APRIL 2017
Fertility and Sterility
THE LIMITATIONS OF CURRENT OBESITY
THERAPY WITH REGARD TO FEMALE
REPRODUCTION
The prevalence of obesity and extreme obesity continues to
increase among women in the United States, while it has
plateaued in men (10). Currently, 40% of women are obese
and 10% have class 3 obesity (body mass index [BMI] >
40 kg/m2). It is equally as concerning that obesity rates
continue to rise among adolescents age 1219 years (11) in
the United States, ensuring a steady pipeline of obese
reproductive-age women in the future.
Obesity treatment guidelines adapted by multiple soci-
eties advocate that all obese patients should be offered
comprehensive lifestyle intervention as a rst step; however,
additional therapies may also be indicated based on degree of
obesity and presence of comorbidities (12). As little as 3%5%
weight loss can reduce circulating triglycerides, blood
glucose, hemoglobin A1c, and the risk of developing type 2
diabetes. However greater amounts of weight loss are required
to reduce blood pressure, improve LDL-C and high-density li-
poprotein cholesterol, and reduce the need for medications to
control hypertension and diabetes (12). However, while it is
often cited that as little as 5% weight loss can improve fertility
(13), there is no clear dose-response relationship between
weight loss in an obese patient and fertility, given the lack
of published dose-response weight loss studies. Current med-
ical therapies for obesity result in relatively modest weight
loss over 612 months, ranging from 5%10% with lifestyle
modication to 10%15% with the combination of lifestyle
modication and pharmaceutical agents (12). Currently there
are a number of drugs available in the United States for the
treatment of obesity, most of which have only limited data
on reproductive toxicity in women due to their relatively
recent FDA approval (Table 1). Some of the newer drugs
such as the combination of phentermine (an appetite suppres-
sant) and topiramate (an antiepileptic adapted to obesity
treatment) lack long-term safety data or have a known poten-
tial for teratogenicity (topiramate). They have rarely been
used in preconception weight loss interventions in women.
Similarly, the most effective therapy for severe obesity,
that is, bariatric surgery, is invasive and expensive, with a
high initial morbidity related to surgical complications. Addi-
tionally, pregnancy is relatively contraindicated during the
rst 612 months after surgery due to the inability of the re-
constructed gastrointestinal tract to accommodate the need
for the increased nutrition that a developing pregnancy re-
quires. Long-term malabsorption after some procedures may
further exacerbate vitamin and specic nutrient needs after
surgery. Although bariatric surgery is the recommended
weight loss treatment for those with a BMI > 40 kg/m2 (12,
15), only about 1% of individuals in the United States who
meet this BMI criteria elect to undergo surgery (16).
POPULAR MISCONCEPTIONS ABOUT WEIGHT
LOSS
The two most popular misconceptions about weight loss are
[1] that exercise alone can signicantly lead to weight loss
861
862

VIEWS AND REVIEWS

TABLE 1

Summary of currently approved weight loss drugs for the treatment of obesity in the United States.
Relative weight loss compared
Generic name(s) Mechanism of action with other drugs (14) Contraindications and cautions Common side effects
Orlistat Gastric lipase inhibitor; inhibits fat Less 1. Reduced gallbladder function 1. Steatorrhea
absorption 2. Use with caution with pancreatic or liver 2. Diarrhea
disease 3. Flatulence
4. Increased stooling
Phentermine Central appetite suppressant, Better, intended as short-term 1. History of cardiovascular disease 1. Feeling restless
sympathomimetic amine agent (<6 mo) 2. During or within 2 wk following the 2. Headache
administration of monoamine oxidase 3. Dizziness
inhibitors 4. Tremors
3. Hyperthyroidism 5. Poor sleep
4. Glaucoma 6. Dry mouth
5. Agitated states
6. History of drug abuse
Lorcarserin Central appetite suppressant, a Less Caution if 1. Hypoglycemia
serotonin 2C receptor agonist 1. Renal failure 2. Mental issues
2. Congestive heart failure, bradycardia, 3. Bradycardia
or heart block 4. Headache
3. Diabetes mellitus 5. Dizziness
4. Depression 6. Drowsiness
7. Fatigue
8. Nausea
9. Dry mouth
10. Constipation
11. Painful erections
Liraglutide Central appetite suppressant, Better 1. Personal or family history of medullary 1. Nausea/vomiting
long-acting glucagon-like peptide-1 thyroid carcinoma or in patients with 2. Hypoglycemia
receptor agonist multiple endocrine neoplasia syndrome 3. Diarrhea
type 2 4. Constipation
2. Avoid in patients with history or 5. Headache
pancreatitis 6. Fatigue
3. Monitor for depression or suicidal 7. Dizziness
thoughts 8. Increased lipase
Phentermine/topiramate Phentermine is central appetite Best 1. History of cardiovascular disease 1. Mild dizziness
suppressant, sympathomimetic amine; 2. During or within 2 wk after the admin- 2. Anxiety
topiramate is an anticonvulsant that has istration of monoamine oxidase 3. Fatigue or irritability
weight loss side effects inhibitors 4. Constipation
3. Hyperthyroidism. 5. Memory problems
4. Glaucoma. 6. Poor sleep
5. Agitated states 7. Numbness of tingly feeling
VOL. 107 NO. 4 / APRIL 2017

6. History of drug abuse 8. Altered sense of taste

9. Dry mouth
Naltrexone/buproprion Naltrexone is an opioid antagonist; Better 1. History of seizures 1. Nausea
bupropion is a relatively weak inhibitor 2. History of an eating disorder 2. Headache
of the neuronal reuptake of dopamine 3. Taking opioid pain medicines 3. Vomiting
and norepinephrine 4. Taking medicines to stop opioid 4. Constipation
addiction 5. Diarrhea
5. Taking an MAOI within 2 wk. 6. Dizziness
6. Abrupt termination of alcohol, benzo- 7. Poor sleep
diazepines, barbiturates, or antiepileptic 8. Dry mouth
drugs
Legro. Obesity treatment and female reproduction. Fertil Steril 2017.

and [2] that restricting caloric intake by 500 kcal a day will
result in the loss of a pound per week (that is, a weekly
3,500 kcal decit 1 pound), ad innitum. How many pa-
tients when confronted with weight gain vow as a rst step
to join a gym? Yet exercise alone (and here is meant vigorous
exercise) results in minimal weight loss (2%4% over a year)
and is often associated with weight gain or maintenance due
to caloric replacement after exercise (17). Exercise may be
most useful in the context of maintaining weight loss after
caloric restriction (6).
The second myth views the relationship between caloric
restriction and weight loss as a straight never bending line,
when in reality it is asymptotic. Thus while caloric restriction
can result in progressive weight loss, weight loss will slow
over time due to both counterregulatory effects to maintain
weight and the need to reduce absolute caloric intake as
body weight decreases. One of the most perplexing and frus-
trating biologic phenomenon is that the hypothalamic-
pituitary-obesity axis resets at higher body weights to accept
the higher body weight as the new norm and ghts to main-
tain weight through myriad mechanisms, such as reducing the
resting metabolic rate and increasing the production of cen-
tral and peripheral orexigenic signals to increase food intake
(18, 19). The reasons for this are beyond the scope of this
review, but the ability to maintain weight in the face of
diminished caloric intake had clear survival benets for that
organism favoring the perpetuation of those genes.
When the full effects of caloric restriction and exercise
are quantitatively and dynamically modeled based on physi-
ologic adaptation, weight loss over time is much less (20). The
amount of weight loss at 1 year is about half as much with this
projected model as with the 1 pound a week diet rule. Further,
the amount of time to reach steady state is measured in years
not months, and the time increases for patients with
increasing obesity (Fig. 1B). Such a prolonged period of
caloric restriction may not be possible in a patient with
advanced maternal age or diminished ovarian reserve. Further
diets with severe caloric restriction (<800 kcal/day) have been
shown to have high failure rates, adverse health effects, and
potential harm to oocytes (12). The hypothalamus may never
accept the lower weight as normal, as studies have
demonstrated increased production or orexigenic signals
2 years and beyond in obese patients who have lost weight
through caloric restriction as well as increased subjective
appetite compared with weight stable controls (21). We should
consequently counsel our patients realistically, that even the
most compliant patients will experience less weight loss than
projected by current expectations with the recommended
500750 cal/day caloric restriction (12) and that time, more
than expected, is necessary to achieve signicant weight
loss with diet and exercise alone.
EFFECTS OF PRECONCEPTION WEIGHT LOSS
THROUGH LIFESTYLE AND MEDICAL
THERAPIES ON FERTILITY
There have been several meta-analyses that have examined
preconception weight loss intervention through lifestyle
modication and the effect on subsequent fertility (22, 23).
VOL. 107 NO. 4 / APRIL 2017
Fertility and Sterility
Unfortunately they consist largely of underpowered trials
with modest weight loss that have failed to capture key
outcomes of perinatal health, such as live birth, birth
weight, and adverse maternal and fetal effects. In this
section, the focus will be on the recent high-quality and larger
studies. The largest study of preconception weight loss (the
LIFEstyle Study) was conducted in the Netherlands and ran-
domized close to 600 obese infertile women (mean baseline
BMI 35) to two groups: [1] either a 6-month evidence-
based National Institutes of Healthpromoted lifestyle inter-
vention program preceding 18 months of infertility treatment
(intervention group) or [2] prompt infertility treatment for
24 months (control group) (24). The primary outcome was
the vaginal birth of a healthy singleton at term within
24 months after randomization. This outcome captures the
ultimate goal of infertility treatment for patients. Against
expectation, the primary outcome (as well as live birth) was
signicantly less common in the weight loss intervention
group (27.1%) compared with the control group, which
went straight to treatment (35.2%; rate ratio in the interven-
tion group, 0.77; 95% condence interval [CI], 0.600.99).
There were several critiques of the LIFEstyle Study. One was
the high dropout rate of 21% among women in the lifestyle
modication group, although much higher rates have been re-
ported in other such studies (25, 26). Second, the amount of
weight lost in the intervention group was modest (4.4. kg),
and only a fraction of the randomized patients obtained the
minimum weight loss goal of at least 5% (38%). Third, the
study included female patients with a variety of infertility
diagnoses, including unexplained, anovulation, mild male
factor, and so on. The investigators have subsequently
published a post hoc analysis based on predetermined
subgroup analyses and found that in the intervention group,
again against expectation, women with anovulation
(presumably mainly women with polycystic ovarian syndrome
[PCOS] as ovarian insufciency was an exclusion) compared
with women with ovulatory cycles had similar pregnancy,
live-birth, and healthy live-birth rates over the 24-month period
(27). However, women with anovulation did have more sponta-
neous pregnancies in the intervention group compared with
those who were ovulatory, causing the investigators to recom-
mend counseling obese anovulatory patients about an improved
chance for natural pregnancy with weight loss.
We randomized a total of 149 anovulatory women with
PCOS to either a 16-week preconception intervention consist-
ing of caloric restriction with meal replacements, an antiobe-
sity medication (rst sibutramine and then orlistat), and
increased physical exercise and activity; continuous low-
dose oral contraceptive pills (OCPs); or the combination of
the two (the OWL PCOS study) (28). We recommended contra-
ception (in the non-OCP group) during the weight loss phase,
and patients went immediately from weight loss to ovulation
induction with clomiphene, so we did not have any natural
pregnancies. In contrast with the LIFEstyle Study, the average
weight loss in the OWL PCOS study, over a much shorter
period, was about 50% higher, likely due to the more intense
and multifocal intervention of lifestyle and pharmacotherapy
(29). We found a signicantly higher ovulation rate with
clomiphene after weight loss compared with oral
863
VIEWS AND REVIEWS
FIGURE 1
Predicted long-term bodyweight change trajectories. (A)
Bodyweight time course of a 100-kg man after a step decrease
in dietary energy intake of 2 MJ per day. The dashed curves
indicate the expected interindividual variability of weight loss
due to imprecise estimates of the initial state of energy balance
(arising solely from an initial uncertainty in the energy
expenditure rate of 300 kJ per day or about 5%). (B)
Differences of weight change between people with different
initial body composition. People with a higher initial body fat
mass lose more weight, but the time to reach the plateau is
longer. (C) Predicted effect of a step change of physical activity
compared with an energy equivalent step change of dietary
energy intake. Physical activity has an effect on both the
magnitude and the timescale of bodyweight change. Adapted
from Hall et al. (20).
Legro. Obesity treatment and female reproduction. Fertil Steril 2017.
864
contraceptive pretreatment and a trend toward improvement
in pregnancy and live-birth rates.
In fact, in a post hoc study we compared ovulation rates
and pregnancy rates between age- and BMI-matched women
with PCOS who had undergone immediate treatment with
clomiphene citrate in our Pregnancy in Polycystic Ovary Syn-
drome II study (PPCOS II) (30) with those who had 16 weeks of
pretreatment with lifestyle and weight loss in our OWL PCOS
study and found a signicant two- to three-fold improvement
in live-birth rates with weight loss and delayed infertility
treatment (31). We also found no benet to pretreatment
with OCP versus immediate treatment with clomiphene in
PPCOS II, as both studies had nearly identical ovulation and
live-birth rates (31). Thus we see no fertility benet to OCP
pretreatment in obese women with PCOS. However, the post
hoc study from the Dutch study included 260 women with an-
ovulation, signicantly larger than our trial. The common
thread may be that certain obese women, such as women
with PCOS, may derive greater benet from preconception
weight loss, whether it be in terms of restoration of ovulation
and natural conception or improved ovulation rates and
improved fecundity per ovulation with assisted conception
with ovulation induction. Further prospective rather than
post hoc studies are clearly needed to address the effects of
weight loss in anovulatory women as opposed to other infer-
tility diagnoses.
EFFECT OF PRECONCEPTION WEIGHT LOSS
THROUGH BARIATRIC SURGERY ON FERTILITY
Clearly, bariatric surgery is the most successful for treating
class 3 obesity and weight loss at 12 months, with Roux-en-
Y gastric bypass averages close to 40% of the initial body
weight. Vertical sleeve gastrectomy, which is growing in popu-
larity due to its lower operative morbidity, has slightly less
weight loss over the same time period. There are likely multiple
mechanisms behind the purported benets of bariatric surgery
on fertility including improved ovulatory function (even in
ovulatory women) (32), shorter follicular phases and thus
more ovulations over a given period of time (33), and improved
self-esteem and well-being with accompanying improvements
in sexual function and intercourse frequency (34).
This is sadly an area where randomized trials are lacking,
although we note multiple randomized trials have docu-
mented the superiority of bariatric surgery versus conven-
tional medical therapy for the control of type 2 diabetes (35,
36). However in the area of human fertility, we are left with
glowing case reports and case series about the restoration of
fertility after bariatric surgery. One recent meta-analysis
(based on 589 women) of the effects of bariatric surgery on
fertility concluded that 58% of obese infertile women
conceived after bariatric surgery (37). Again the most impor-
tant outcome of interest is the birth of a healthy normal
weight infant by a healthy mother, which is rarely captured
in these publications.
The best available epidemiologic data from Sweden offer
a mixed risk-benet ratio of pregnancy outcomes after bar-
iatric surgery (38). These investigators linked up multiple
VOL. 107 NO. 4 / APRIL 2017

Swedish medical registries including obstetric and bariatric
registries to perform a case-control study of all women who
conceived singleton pregnancies after bariatric surgery over
a 5-year period compared with weight-matched women
who conceived without surgery. Pregnancies after bariatric
surgery, as compared with matched control pregnancies,
were associated with a higher risk of small for gestational
age (SGA) infants (15.6% vs. 7.6%; odds ratio, 2.20; 95% CI,
1.642.95; P< .001) and shorter gestation. These investigators
also noted an increased risk of moderately preterm birth (be-
tween 32 completed weeks and 36 weeks, 6 days of gestation)
among women who had undergone bariatric surgery than
among women who had not (7.3% vs. 5.7%; odds ratio,
1.30; 95% CI, 1.051.60). The risk of stillbirth or neonatal
death was 1.7% versus 0.7% (odds ratio, 2.39; 95% CI,
0.985.85; P .06). Benecial effects after bariatric surgery tive analysis of the effect of diet and exercise on GWG and
included lower risks of gestational diabetes and large for
gestational age infants (8.6% vs. 22.4%; odds ratio, 0.33;
95% CI, 0.240.44; P< .001). There was no signicant
between-group difference in congenital anomalies. These re-
sults after bariatric surgery, especially the SGA rates and the
trend toward increased neonatal mortality, are concerning.
One might conclude that perhaps pregnancies conceived
early after surgery, especially those during the exponential
weight loss phase in the rst 6 months after surgery, were at
greatest risk for SGA and shorter term pregnancies. However,
the Swedish investigators did not see a relationship with the
time from surgery and poor fetal growth. Interestingly, they re-
ported a signicant inverse association between obesity after
bariatric surgery and the risk of preterm birth (P .03). This
possibility suggests that there may be nutritional or restrictive
components that impact the pregnancy independent of weight
itself that will persist after surgery. For example, those women
who had conceived longer after bariatric surgery or had greater
weight loss were at greater risk for these adverse sequelae (38).
A greater decrease in BMI after surgery was associated with a
lower risk of large for gestational age infants and a higher
risk of preterm birth, and a longer surgery to delivery interval
was associated with a higher risk of SGA infants. These data are
sobering and challenge our assumptions about the unmitigated
benet of weight loss in extremely obese women.
EFFECTS OF INTERVENTIONS TO PREVENT
EXCESSIVE GESTATIONAL WEIGHT GAIN
The approach to excessive weight gain during pregnancy is
different, since weight loss during pregnancy is currently
contraindicated and many methods that induce weight loss
such as pharmacologic therapy or bariatric surgery are also
contraindicated. However, examining the effects of lifestyle
modication on GWG serves as a useful comparator of the ef-
fects of lifestyle modication on perinatal outcomes. Like pre-
conception obesity, excessive GWG during pregnancy is
associated with increased rates of gestational diabetes, pre-
eclampsia, and large for gestational age infants and increased
operative and cesarean deliveries (39). It is worthwhile here to
examine the integrated results of these multiple lifestyle in-
terventions during pregnancy, because there has been a
much more concentrated effort to address this issue in preg-
VOL. 107 NO. 4 / APRIL 2017
Fertility and Sterility
nant women as opposed to preconception intervention to
lose weight in obese women. Studies have also included
much larger cohorts of women, in the thousands in some
studies compared with in the hundreds in the select precon-
ception studies (and most meta-analyses of preconception in-
terventions cited above). For example, the Australian LIMIT
study randomized 2,214 overweight/obese pregnant women
from 1020 weeks of gestation to a comprehensive dietary
and lifestyle intervention delivered by research staff or to
standard care throughout pregnancy (40). This intervention
did not reduce the risk of delivering a baby weighing above
the 90th centile for gestational age and sex or improve other
maternal pregnancy and birth outcomes. This study is a
harbinger of the systematic reviews of this intervention.
The Cochrane Systematic Review included in its quantita-
pregnancy outcomes, 49 randomized controlled trials encom-
passing 11,444 women (39). Diet or exercise, or both, inter-
ventions reduced signicantly the risk of excessive GWG on
average by 20% overall. However, there was no major peri-
natal morbidity that was improved by this intervention, that
is, in the intervention groups there was no decreased rate of
caesarean delivery overall, no decrease in preterm births, no
decrease in infant macrosomia, and no decrease in the risk
of poor neonatal outcomes including shoulder dystocia,
neonatal hypoglycemia, hyperbilirubinaemia, or birth
trauma. If there was a saving grace (by a thin margin) to
the overall lack of benet of these interventions on perinatal
outcomes, it was in a subgroup analysis by risk, where high-
risk women (overweight or obese women or women with or at
risk of gestational diabetes) receiving combined diet and ex-
ercise counseling interventions experienced a 15% reduced
risk of infant macrosomia (average relative risk, 0.85; 95%
CI, 0.731.00; participants 3,252; studies 9; P .05;
moderate-quality evidence). To echo a previous statement,
never has so much time, effort, and money been directed to-
ward so many obese pregnancies with so little public health
benet.
Some have advocated that the 2009 National Academy of
Medicine revised Institute of Medicine (IOM) GWG guidelines
are too generous (41), especially for obese women (59 kg
recommended weight gain during pregnancy). However, a
recent meta-analysis examined nine cohort studies where
obese pregnant women gained less than the
IOM-recommended amount (42). They found this group
with relative weight loss, compared with women who met
weight gain recommendations, had higher odds of SGA
<10th percentile (adjusted odds ratio [AOR], 1.76; 95% CI,
1.452.14) and SGA <third percentile (AOR, 1.62; 95% CI,
1.192.20) but lower odds of larger than gestational age
>90th percentile (AOR, 0.57; 95% CI, 0.520.62). Thus the
birth weight results of less than recommended weight gain
during pregnancy in obese women was very similar to the ef-
fects of bariatric surgery before pregnancy in obese women.
FUTURE DIRECTIONS
The results of interventions to control weight preconception
and during pregnancy have been disappointing on many
865
VIEWS AND REVIEWS
levels: achieving clinically signicant weight loss or control-
ling weight gain, encouraging continued participation and
high rates of compliance with therapies, and most impor-
tantly failing to demonstrate a clear benet of the effects of
these interventions on perinatal outcomes (for preconception
weight loss studies this is partially due to failure to capture
and/or report these). These studies suggest that the degree
of weight loss (or weight change) after an intervention cannot
be used as a surrogate marker of perinatal benet. Future
studies must capture not just the effects of the intervention
on weight, but more importantly, the effects on outcomes of
maternal, fetal, and infant health. While the time period of
intervention to control GWG is limited by the length of preg-
nancy and the late presentation of patients for care, the pre-
conception period of intervention is much longer and offers
greater opportunity for change. The rate of weight loss during
this preconception period and the timing of weight loss in re-
gards to infertility treatment remain unknown (that is, com-
plete the intervention before treatment or when weight
plateaus or conduct both concurrently, etc.?). The cornerstone
of pharmaceutical studies are phase II dose ranging studies to
identify the optimal dose before phase III testing of this
optimal dose. No such studies of dose or duration of treatment
exist for preconception weight loss. The timing of the inter-
vention to fertility treatment is also unclear, although there
is evidence both from bariatric surgery (43) and lifestyle
modication (44) that severe caloric restriction and overall
energy decit immediately before or concordant with infer-
tility results are associated with poor gamete and embryo
quality and implantation failure. There may be a theoretical
benet in clearly separating the intervention to lower weight
from the treatment of infertility, given the long time period
from follicular recruitment to ovulation, to allow the oocyte
to recover from the period of relative caloric restriction with
a recovery phase of eucaloric nutrition. Further the results
from bariatric surgery and low GWG in obese women suggest
a higher rate of SGA infants with inadequate nutrition during
pregnancy. Thus concomitant therapy for both weight loss
and infertility should be considered carefully.
There has been little preconception treatment of obesity
with pharmacologic agents in infertile women. While the reluc-
tance of pharmaceutical companies to pursue these studies may
seem reasonable from a liability standpoint, it ignores the real-
ity that most patients who take these drugs are women of repro-
ductive age, and we have effective means of contraception to
prevent pregnancy in women taking drugs with potential
reproductive toxicity if the benet outweighs the risk. With
the elimination of predetermined FDA pregnancy categories
and a mandate to report human data on the reproductive
toxicity on the package insert of drugs, there is now opportu-
nity to obtain human data on the preconception use of these
drugs to achieve weight loss. Obesity, like other chronic dis-
eases such as diabetes and hypertension, often requires multiple
therapies of varying mechanisms to achieve optimal control,
what in the obesity literature is often referred to as a toolbox
approach. These pharmaceutical tools are relatively untouched.
We need prospective data from clinical trials about the
relative perinatal risks of bariatric surgery versus other treat-
ments or no treatment. We have learned from past failures of
866
TABLE 2
Future research priorities for treating obesity preconception.
1. Primary outcomes of practice changing studies should focus on
perinatal health and not weight change.
2. Establish an optimal dose of weight loss by dose-response studies.
3. Identify the optimal initiation of infertility therapy in relation to
weight loss.
4. Expand studies to use pharmacologic agents with acceptable
perinatal risk.
5. Perform prospective randomized trials of bariatric surgery.
6. Explore the utility of establishing weight or BMI cutoffs for
receiving infertility therapy.
7. Use personalized medicine approaches to patients for precon-
ception therapy and specic therapies.
8. Initiate obesity prevention therapies in overweight adolescent
females.
Legro. Obesity treatment and female reproduction. Fertil Steril 2017.
prospective trials to match the epidemiologic background to
never accept epidemiology as the nal arbiter of treatment if
it can be tested in a prospective hypothesis-driven trial. We
must accept the possibility that there are some patients whose
weight is beyond the pale, whose degree of obesity may not be
amenable to any form of therapy. However, a priori cutoffs on
treatment should not be imposed by authorities until evidence
provides a clearer picture of the risk-benet ratio. If such cut-
offs are found, and certainly based on the disturbing trend of
increasing adolescent obesity in the United States, trials to pre-
vent obesity in at-risk adolescent females should receive
enhanced priority. We cannot assume one treatment ts all,
and the use of personalized medicine to select patients who
may most benet from individual preconception (and infer-
tility) therapies is necessary to balance competing concerns
about declining ovarian reserve and/or advancing maternal
age versus delay in treatment to obtain weight loss; these
must be the tenets of any preconception weight loss therapy.
To conclude, the opportunity for future innovative and
important studies is as open as Oklahoma was in 1889 (e.g.,
the date of the Land Rush). We should be lining up to conduct
these studies (Table 2) as the settlers did then. We have a pop-
ulation of women eager for change, increasingly aware of the
relation between obesity and reproductive failure, and moti-
vated by perhaps the strongest altruistic impulse in human
nature, to conceive and nurture another human being.
REFERENCES
1. Practice Committee of the American Society for Reproductive M. Obesity
and reproduction: a committee opinion. Fertil Steril 2015;104:111626.
2. Harbin Consensus Conference Workshop Group, Conference Chairs,
Legro RS, Wu X, Scientic C, Barnhart KT, Farquhar C, Fauser BC,
et al. Improving the Reporting of Clinical Trials of Infertility Treat-
ments (IMPRINT): modifying the CONSORT. Hum Reprod 2014;29:
207582.
3. Harbin Consensus Conference Workshop Group. Improving the Reporting
of Clinical Trials of Infertility Treatments (IMPRINT): modifying the CONSORT
statement. Fertil Steril 2014;102:9529.e15.
4. Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R. Female
obesity adversely affects assisted reproductive technology (ART) pregnancy
and live birth rates. Hum Reprod 2011;26:24552.
VOL. 107 NO. 4 / APRIL 2017

5. Aune D, Saugstad OD, Henriksen T, Tonstad S. Maternal body mass index
and the risk of fetal death, stillbirth, and infant death: a systematic review
and meta-analysis. JAMA 2014;311:153646.
6. Tardif JC, Heinonen T, Orloff D, Libby P. Vascular biomarkers and surrogates
in cardiovascular disease. Circulation 2006;113:293642.
7. Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet
1994;344:13839.
8. Writing Group for the Womens Health Initiative Investigators. Risks and
benets of estrogen plus progestin in healthy postmenopausal women:
principal results from the Womens Health Initiative randomized controlled
trial. JAMA 2002;288:32133.
9. Barter PJ, Cauleld M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M,
et al. Effects of torcetrapib in patients at high risk for coronary events. N
Engl J Med 2007;357:210922.
10. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity
among adults in the United States, 2005 to 2014. JAMA 2016;315:228491.
11. Ogden CL, Carroll MD, Lawman HG, Fryar CD, Kruszon-Moran D, Kit BK,
et al. Trends in obesity prevalence among children and adolescents in the
United States, 19881994 through 20132014. JAMA 2016;315:22929.
12. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al.
2013 AHA/ACC/TOS guideline for the management of overweight and
obesity in adults: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines and the Obesity Society.
Circulation 2014;129(25 Suppl 2):S10238.
13. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al.
Improvement in endocrine and ovarian function during dietary treatment
of obese women with polycystic ovary syndrome. Clin Endocrinol 1992;
36:10511.
14. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Associ-
ation of pharmacological treatments for obesity with weight loss and adverse
events: a systematic review and meta-analysis. JAMA 2016;315:242434.
15. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, et al. Ef-
fects of bariatric surgery on mortality in Swedish obese subjects. N Engl J
Med 2007;357:74152.
16. Mainous AG 3rd, Johnson SP, Saxena SK, Wright RU. Inpatient bariatric sur-
gery among eligible black and white men and women in the United States,
19992010. Am J Gastroenterol 2013;108:121823.
17. Swift DL, Johannsen NM, Lavie CJ, Earnest CP, Church TS. The role of exer-
cise and physical activity in weight loss and maintenance. Prog Cardiovasc
Dis 2014;56:4417.
18. Muller MJ, Bosy-Westphal A, Heymseld SB. Is there evidence for a set point
that regulates human body weight? F1000 Med Rep 2010;2:59.
19. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting
from altered body weight. N Engl J Med 1995;332:6218.
20. Hall KD, Sacks G, Chandramohan D, Chow CC, Wang YC, Gortmaker SL,
et al. Quantication of the effect of energy imbalance on bodyweight. Lan-
cet 2011;378:82637.
21. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A,
et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J
Med 2011;365:1597604.
22. Sim KA, Partridge SR, Sainsbury A. Does weight loss in overweight or obese
women improve fertility treatment outcomes? A systematic review. Obes
Rev 2014;15:83950.
23. Anderson K, Norman RJ, Middleton P. Preconception lifestyle advice for peo-
ple with subfertility. Cochrane Database Syst Rev 2010:CD008189.
24. Mutsaerts MA, van Oers AM, Groen H, Burggraaff JM, Kuchenbecker WK,
Perquin DA, et al. Randomized trial of a lifestyle program in obese infertile
women. N Engl J Med 2016;374:194253.
25. Thomson RL, Buckley JD, Noakes M, Clifton PM, Norman RJ, Brinkworth GD.
The effect of a hypocaloric diet with and without exercise training on body
composition, cardiometabolic risk prole, and reproductive function in
overweight and obese women with polycystic ovary syndrome. J Clin Endo-
crinol Metab 2008;93:337380.
VOL. 107 NO. 4 / APRIL 2017
Fertility and Sterility
26. Ladson G, Dodson WC, Sweet SD, Archibong AE, Kunselman AR,
Demers LM, et al. The effects of metformin with lifestyle therapy in polycystic
ovary syndrome: a randomized double-blind study. Fertil Steril 2011;95,
105966.e17.
27. van Oers AM, Groen H, Mutsaerts MA, Burggraaff JM, Kuchenbecker WK,
Perquin DA, et al. Effectiveness of lifestyle intervention in subgroups of
obese infertile women: a subgroup analysis of a RCT. Hum Reprod 2016;
31:270413.
28. Legro RS, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM,
Williams NI, et al. Randomized controlled trial of preconception interven-
tions in infertile women with polycystic ovary syndrome. J Clin Endocrinol
Metab 2015;100:404858.
29. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, et al.
Randomized trial of lifestyle modication and pharmacotherapy for obesity.
N Engl J Med 2005;353:211120.
30. Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, et al.
for the NICHD Reproductive Medicine Network. Letrozole versus clomi-
phene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;
371:11929.
31. Legro RS, Dodson WC, Kunselman AR, Stetter CM, Kris-Etherton PM,
Williams NI, et al. Benet of delayed fertility therapy with preconception
weight loss over immediate therapy in obese women with PCOS. J Clin En-
docrinol Metab 2016;101:265866.
32. Rochester D, Jain A, Polotsky AJ, Polotsky H, Gibbs K, Isaac B, et al. Partial
recovery of luteal function after bariatric surgery in obese women. Fertil
Steril 2009;92:14105.
33. Legro RS, Dodson WC, Gnatuk CL, Estes SJ, Kunselman AR, Meadows JW,
et al. Effects of gastric bypass surgery on female reproductive function. J Clin
Endocrinol Metab 2012;97:45408.
34. Sarwer DB, Spitzer JC, Wadden TA, Mitchell JE, Lancaster K, Courcoulas A,
et al. Changes in sexual functioning and sex hormone levels in women
following bariatric surgery. JAMA Surg 2014;149:2633.
35. Courcoulas AP, Goodpaster BH, Eagleton JK, Belle SH, Kalarchian MA,
Lang W, et al. Surgical vs medical treatments for type 2 diabetes mellitus:
a randomized clinical trial. JAMA Surg 2014;149:70715.
36. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA,
Navaneethan SD, et al, for the STAMPEDE Investigators. Bariatric surgery
versus intensive medical therapy for diabetes3-year outcomes. N Engl J
Med 2014;370:200213.
37. Milone M, De Placido G, Musella M, Sosa Fernandez LM, Sosa Fernandez LV,
Campana G, et al. Incidence of successful pregnancy after weight loss inter-
ventions in infertile women: a systematic review and meta-analysis of the
literature. Obes Surg 2016;26:44351.
38. Johansson K, Cnattingius S, Naslund I, Roos N, Trolle Lagerros Y, Granath F,
et al. Outcomes of pregnancy after bariatric surgery. N Engl J Med 2015;372:
81424.
39. Muktabhant B, Lawrie TA, Lumbiganon P, Laopaiboon M. Diet or exercise,
or both, for preventing excessive weight gain in pregnancy. Cochrane Data-
base Syst Rev 2015:CD007145.
40. Dodd JM, Turnbull D, McPhee AJ, Deussen AR, Grivell RM, Yelland LN, et al.
Antenatal lifestyle advice for women who are overweight or obese: LIMIT
randomised trial. Br Med J 2014;348:g1285.
41. Gilmore LA, Redman LM. Weight gain in pregnancy and application of the
2009 IOM guidelines: toward a uniform approach. Obesity 2015;23:507
11.
42. Kapadia MZ, Park CK, Beyene J, Giglia L, Maxwell C, McDonald SD. Weight
loss instead of weight gain within the guidelines in obese women during
pregnancy: a systematic review and meta-analyses of maternal and infant
outcomes. PLoS One 2015;10:e0132650.
43. Marceau P, Kaufman D, Biron S, Hould FS, Lebel S, Marceau S, et al.
Outcome of pregnancies after biliopancreatic diversion. Obes Surg 2004;
14:31824.
44. Tsagareli V, Noakes M, Norman RJ. Effect of a very-low-calorie diet on
in vitro fertilization outcomes. Fertil Steril 2006;86:2279.
867