Successful weight loss interventions

before in vitro fertilization:

fat chance?
Robert J. Norman, M.D.a,b and Ben Willem J. Mol, M.D., Ph.D.c
a
Robinson Research Institute, School of Medicine, University of Adelaide, and b Fertility SA, Adelaide, South Australia;
c
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia

Most expert opinions and guidelines indicate the necessity for weight loss before in vitro fertilization (IVF) in women who are
overweight or obese. This is based on the documented impact of obesity on pregnancy rates and pregnancy complications and the
long-term impact on the child in natural conceptions. Some clinicians and authorities refuse to treat patients unless they are below
a certain body mass index. In the past this advice has been hindered by a lack of opportunity for patients to join lifestyle programs
and the high dropout failure before treatment. However, the ideal has remained in the search for effective methods for weight loss.
New clinical trials have evaluated a lifestyle program before IVF treatment and compared the results with those who were merely given
advice and allowed to proceed directly to other fertility treatments or IVF. No compelling evidence of the value of lifestyle intervention
for weight loss on live-birth rates was gained from these well-conducted studies. The research and medical and ethical opinions may
now favor moving to fertility treatment earlier than originally recommended for patients who are overweight or obese. (Fertil SterilÒ
2018;110:581–6. Ó2018 by American Society for Reproductive Medicine.)
Key Words: Fertility, IVF, lifestyle, obesity, weight loss
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-
sterility/posts/33447-26293

T
he increasing obesity rates world- overweight should undertake efforts to patients' participation. A number of
wide have important implications lose weight before embarking on cohort studies from Adelaide and
for health in general and repro- treatment. Guidelines from some elsewhere in patients with PCOS have
ductive health in particular. There is clinical societies as well as some health suggested that group lifestyle programs
considerable evidence that being over- funding bodies recommend dedicated may play a big role in helping patients
weight adversely impacts fertility, preg- efforts to get lifestyle changes before to lose weight and are indicated before
nancy, and the health of children born treatment (1, 11). Indeed, some any ART takes place (13, 14). Limited
to parents who are greatly above the countries impose weight limits on resources have also led to health care
recommended body mass index (BMI) patients before public funding for IVF providers clamping down on
levels (1–5). There is a substantial and will not allow facilitated treatment subsidised treatment of patients going
literature on the association between unless the patient's BMI is below a through IVF. This approach has been
body weight on fertility and pregnancy certain level (National Institute for criticized on ethical and medical
outcomes both in women with and Clinical Excellence UK) (12). grounds (12, 15), although it is
without polycystic ovary syndrome The prominent debate up until defended by others (16).
(PCOS) (6–10), suggesting a beneficial recently has not been on whether Until recently, clear evidence has
effect of weight reduction. As a result, weight loss will make a difference to as- been lacking with regard to the
one of the commonly held dogmas in sisted reproductive technology (ART) effectiveness of lifestyle interventions
the treatment of in vitro fertilization outcomes but rather how best to deliver and other forms of weight loss before
(IVF) patients is that women who are it in a way that will encourage the ART interventions, despite the benefits
for other forms of fertility treatment
Received May 15, 2018; accepted May 23, 2018. (17, 18). The scene has changed
R.J.N. is a minor shareholder of Fertility SA (IVF unit), has received nonfinancial support from Merck,
and has received grants from Ferring, outside the submitted work. B.W.J.M. is supported by a
dramatically in the past 2 years after
NHMRC Practitioner Fellowship (GNT1082548) and is a consultant for ObsEva, Merck, and two excellent clinical trials appeared
Guerbet. to show no effect of introducing a
Reprint requests: Robert J. Norman, M.D., Fertility SA – Level 9, 431 King William Street, Adelaide SA
5000, Australia (E-mail: robert.norman@adelaide.edu.au). lifestyle intervention before IVF
versus starting immediate fertility
Fertility and Sterility® Vol. 110, No. 4, September 2018 0015-0282/$36.00
Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc.
treatment (19, 20).
https://doi.org/10.1016/j.fertnstert.2018.05.029

VOL. 110 NO. 4 / SEPTEMBER 2018 581

VIEWS AND REVIEWS
Epidemiologically, there appears to be a clear link be-
tween weight at either extreme and the chances of fertility
in patients who are seeking natural conception (5, 21, 22).
As an example, the Nurses' Health Study, which enrolled
several thousand women, indicated that women with a BMI
above the normal range had a statistically significantly
higher chance of being infertile and that this could not be
solely attributed to lack of ovulation as indicated by
menstrual disturbances (23). Several other studies have
supported this observation, and various interventions such
as ovulation induction appear to be less successful per cycle
in women who are overweight (18, 24, 25). However,
provided there is sufficient time, overweight ovulatory
women probably have the same chance of spontaneous
pregnancy in their lifetime as other women who are of
normal weight, indicating that while the chance per cycle
may be reduced, over time this is compensated for by a
cumulative pregnancy rate that approaches normal
pregnancy desires.
Compared with women who have a normal BMI, over-
weight and obese women appear to require higher doses of
medication, whether it is oral or injectable (1). There has
also been concern that there may be greater difficulties
with egg recovery and an increased risk of miscarriage and
other complications of pregnancy, although a systematic re-
view has disputed this (26). Given the fact that most inter-
ventions to restrict weight gain during pregnancy are
unsuccessful, many obstetricians would like fertility experts
to ensure that prospective patients lose weight before
entering a pregnancy. They cite the alleged increased risks
of hypertension, preeclampsia, gestational diabetes, and sur-
gical interventions at delivery, and the potential long-term
impact on the health of any child that is born to an over-
weight mother. There has been emerging evidence of a
paternal contribution in terms of obesity to the health of
the offspring as well (27), which has given rise to increasing
concern with optimizing the weight and health of prospec-
tive fathers as well (28). Because an overweight woman is
often partnered with an overweight man, lifestyle interven-
tions before fertility treatment have been advocated for both
partners as an ideal opportunity to maximize both the wom-
an's and the baby's health early in pregnancy. However, data
are lacking to show that a reduction of paternal weight helps
to improve the health of the offspring.
Much of the literature concerning female obesity and ART
outcomes as indicated by the pregnancy and live-birth rates
has suggested inferior outcomes compared with women of
normal weight (2,29–33). However, the Society for Assisted
Reproductive Technology (SART) database finds an only
marginal effect of BMI on IVF outcomes across tens of
thousands of cycles (34). Koning et al. (26) showed only a
slightly lower rate for overweight women. Given that
obesity is increasing in many populations, women are
seeking pregnancy at later ages, patients are demanding
more rapid treatment, and pressure is being placed on
medical providers to institute therapy quickly, there have
been suggestions that placing a weight loss delay on
women who are overweight and need fertility treatment is
unethical (15).
582
So is there a compelling body of evidence to show that
weight reduction will significantly increase the chance of
pregnancy? There have been two small and two large ran-
domized controlled trials that have examined the issue of
whether diet and exercise with the aim to lose weight have
an impact on IVF outcomes. Moran et al. (30) randomized
46 overweight and obese women to a nutritionally adequate
reduced energy diet (5368 kj) by using the CSIRO Total
Well-Being Diet together with one meal replacement of Opti-
fast (Novartis Consumer Health). Patients underwent an exer-
cise component consistent with a home-based physical
conditioning and walking program. The control group
received standard advice on appropriate diet and lifestyle fac-
tors at a single face-to-face interview with no follow-up eval-
uations. Women in the lifestyle group lost on average 3 kg
more weight, but the study was not powered to assess the
impact on pregnancy or live-birth rates, or pregnancy
outcomes.
Sim et al. (35) undertook a similar study with 49 women
of whom 27 were randomized to a low-energy diet for 6 weeks
followed by a hypocaloric diet, combined with a weekly group
multidisciplinary program. The control group of 22 women
received recommendations for weight loss and the same
printed material as the intervention group. The groups that
underwent intensive lifestyle change lost 6.6 kg in weight
and 8.7 cm off their waist while the control group lost
1.6 kg and 0.6 cm, respectively. The intervention group had
a clinical pregnancy rate of 48% compared with 14% in the
control group (odds ratio [OR] 5.88; 95% confidence interval
1.4–24.6) and live-birth rates of 44% and 14%, respectively.
This underpowered study advocated intensive lifestyle
change before fertility treatment.
The field changed substantially after the publications of
Mutsaerts et al. (19) and Einarsson et al. (20). Both these
studies were examples of well-planned and evaluated clinical
trials seeking to establish whether a lifestyle change before
ART is beneficial to live-birth outcomes. Both produced the
surprising result that under the terms of the trials there was
no convincing evidence that introducing diet and exercise in-
terventions for overweight and obese women before IVF as
fertility treatment resulted in higher pregnancy or birth rates.
The Dutch LIFESTYLE program randomized 577 women
aged between 18 and 39 years with a BMI of 29 or higher
(19). The intervention group underwent a 6-month program
with the goal of losing 5% to 10% of their body weight,
with six outpatient visits and four telephone consultations
included during this 24-week period. The objective was to
reduce the caloric intake by 600 kcal per day while maintain-
ing a minimum caloric intake of 1,200 kcal per day. Moderate
intensive energy was prescribed with a target of 10,000 steps
per day. If a pregnancy had not resulted within 6 months they
were assigned to receive fertility treatments based on local
protocols, which could vary between the different centers.
In this group, 63% received subsequent fertility treatment,
roughly divided one-third between ovulation induction, in-
trauterine insemination, and IVF. More than 20% of the inter-
vention group discontinued treatment. The control group
received prompt treatment in accordance with Dutch infer-
tility guidelines with approximately the same proportions of
VOL. 110 NO. 4 / SEPTEMBER 2018

types of fertility treatment. Although there was statistically
significant weight loss (4.4 kg), the primary outcome of
singleton live births delivered vaginally at term was less in
the lifestyle group (27%) than that in the control group
(35%) (rate ratio 0.77; 95% confidence interval[CI], 0.60–
0.99). In this study, the intervention arm showed a higher
spontaneous pregnancy rate, but as the patients were given
6 months before permitting ART and the control group waited
less time, the result was not surprising and does not neces-
sarily indicate a subgroup that will respond to lifestyle treat-
ment. The study could be criticized as not having a
sufficiently intensive lifestyle component and not encour-
aging sufficient weight loss before treatment, but it reflected
a real-life situation. The number who went for IVF were quite
low, thereby reducing the power to examine this component
of study.
The issues in the Dutch study were well addressed by a
Swedish study in which 317 women were randomized to a
lifestyle component before IVF treatment or immediate IVF
(20). Eligibility was 18 to 29 years of age with a BMI of be-
tween 30 and 35. The aim of the weight reduction arm was
to achieve as much weight loss as possible in a time period
of 16 weeks with a strategy of a strict low-calorie liquid for-
mula diet with a daily energy intake of 880 kcal. This was a
slightly more intensive intervention than the Dutch study,
and ongoing dietary advice was provided for 1 year after
randomization (although it is uncertain as to whether exercise
was a component of the intervention). The primary outcome
of live births was 29.6% in the weight reduction before IVF
group and 27.5% in the immediate IVF group. In this study
the mean weight change was 9.44 kg in the intervention
arm as opposed to a weight gain of 1.19 kg in the IVF only
group. Similar to the Dutch study, there appeared to be no sta-
tistically significant difference in miscarriage rates or obstet-
ric outcomes between the two groups. Subgroup analysis
showed no statistical differences in live-birth rates between
the patients with PCOS who were randomized and those
who reached a BMI of 25 or less. As in the previous study,
spontaneous pregnancies were more common among the
intervention group, but this again may reflect the delay of
active fertility treatment in the lifestyle group.
The Swedish and Dutch studies are complementary in that
one addressed only IVF intervention and the other all fertility
treatments. In addition, one used a moderate lifestyle inter-
vention with less weight loss and the other used a more
aggressive weight loss strategy with a more substantial
outcome in anthropometric parameters. Both used a multi-
center approach in different health systems, and the similar
outcomes make their conclusions more compelling.
Legro et al. (36) showed statistically significantly higher
ovulation and live-birth rates after caloric restriction, anti-
obesity medication, behavioral modification, and exercise in
a randomized trial where patients underwent non-IVF treat-
ment for PCOS. Other studies have also have shown remark-
able efficacy for weight loss and lifestyle programs in non-
IVF procedures (1, 11, 37, 38).
Why then do these two large randomized controlled trials
not show the logical results suggested through epidemiolog-
ical studies, earlier cohort observations, and randomized trials
VOL. 110 NO. 4 / SEPTEMBER 2018
Fertility and Sterility®
of weight loss in patients with PCOS? There are several possi-
bilities that relate to weight loss and lifestyle programs failing
due to poor efficacy or rather due to poor efficiency of weight
loss.
First, we would point out that the stronger evidence pro-
vided by two well-controlled, well-powered randomized trials
trumps the uncontrolled observational studies, thereby sug-
gesting that the evidence for weight-loss efficacy before IVF
is lacking. Despite well-supervised programs with good
weight loss values, there was no evidence of any subgroups
that showed a better response (although one study indicated
a better outcome when the waist-to-hip ratio was <0.8)
(31). These studies suggest that even with well-planned pro-
grams there is little evidence of benefit, at least for pregnancy
and live-birth rates in IVF candidates. Legro (2, 12) has argued
that these results, those of bariatric surgery and a failure to
achieve substantial weight control in pregnancy, indicate
that our current approaches are ill fated.
Second, IVF may repair damage to the oocyte while
potentially improving the endometrium. We made observa-
tions in 2000 of a marked impact of overweight and obesity
on IVF outcomes (29), although this was not confirmed
12 years later in the same laboratory in the same population
(39). The techniques of IVF culture have improved dramati-
cally over the past decade, so it is possible that IVF improves
oocyte quality in compromised gametes in vivo. We and
others have shown in animal and human experiments sub-
stantial damage to the oocyte environment and metabolism,
including lipid deposition, mitochondrial damage, endo-
plasmic reticulum stress, and oxidative damage (40–47).
This translates into worse fertility outcomes and a major
impact on the offspring. It is interesting that the oocyte
damage can be repaired chemically to restore the egg to
near full potential, at least in the mouse (40, 43, 44, 48).
Is it possible that our better culture techniques, whether
media or incubation conditions, are adding a degree of bio-
logical repair that is not seen in natural conception? Bellver
et al. (49) showed metabolic differences in the spent culture
media from embryos derived from overweight women, sug-
gesting that any repair may not be fully achieved. In further
studies they showed that obesity reduced the endometrial
receptivity of oocyte recipients who received donor eggs
(50) and this was reflected in different endometrial gene
expression (51). Other studies have shown a higher miscar-
riage rate for euploid embryos in overweight and obese
women (52). These findings would not support the concept
that IVF improves physiological outcomes, at least for the
uterus.
Third, it is possible that giving patients information about
weight and impaired metabolism leads to significant lifestyle
changes in the control group, even though this is not reflected
by changes in their weight or waist circumference. There is an
emerging literature indicating that dietary composition, inde-
pendent of caloric value, may influence the outcome of IVF
cycles (53). Also, we should realize that the effectiveness of
a lifestyle program depends on two steps: first, the lifestyle
intervention participant reduces weight; second, the weight
loss improves fertility outcomes. Indeed, the Dutch study
showed that in the subgroup of women who reached the
583
VIEWS AND REVIEWS
most weight loss, pregnancy complications such as hyperten-
sion and preterm birth were reduced.
Additionally, it has been argued that the best pregnancy
results for spontaneous pregnancy and ovulation induction
with lifestyle intervention have been seen in group interven-
tions whereby participants encouraged each other and built
an emotional rapport with people who were having the
same problems (14, 54, 55). It may be that diet and exercise
by themselves are less effective without the additional
emotional support and encouragement found in a group
environment. In addition, some studies have used weight
loss drugs to good effect (1, 2).
How should clinicians respond to this information? We
recognize that pregnancy rates are not the outcome that we
are seeking but rather a live baby with full potential for health
who has not been compromised by the intrauterine environ-
ment. Although the two large randomized trials indicate
that lifestyle interventions do not improve live-birth rates,
we should remember that a fetus growing in a metabolically
challenging environment may be programmed, either
through its body weight or through epigenetic changes, for
future health and disease (3). The Dutch study showed signif-
icant benefits in the intervention group with respect to blood
pressure, the metabolic syndrome, and several anthropo-
metric parameters including weight and waist circumference
(56). Hypertension in pregnancy and preterm labor were also
reduced in this group (57).
It still makes sense that all patients, whether of normal
weight or overweight, should be given the full information
as to preconception health, which includes advice about
diet, folic acid, ingestion of cigarette smoke or alcohol, avoid-
ance of environmental and dietary contaminants, and
fostering of a healthy emotional environment (58, 59).
Assessment of glucose and lipid metabolism in overweight
patients is essential, together with prescription of a healthy
lifestyle for those who do not have one.
It is increasingly apparent that a prolonged delay of
fertility treatment where IVF is warranted (e.g., tubal factor
infertility, severe sperm problems, or prolonged unexplained
infertility >3 years) is neither medically justified nor ethically
fair. Although not supported by some studies, more natural
conception methods such as through intrauterine insemina-
tion or ovulation induction may be different. The cost-
effective measures of delay versus immediate IVF treatment
may differ among the various approaches (60), but our obstet-
ric colleagues will still demand that we take a longer view
than just obtaining a positive pregnancy test or a fetal heart
on ultrasound scanning. Pediatricians will remain skeptical
that we have not tried our hardest to persuade our infertility
patients to take more drastic action to improve their future
neonatal and infant outcomes before they pursue pregnancy.
Physicians who treat these infants after they become adults
may one day criticize us even more if our ART patients take
shortcuts on the fertility journey rather than investing in
long-term measures for the health of their offspring.
So can we still hold the belief that our patients need to
lose weight before IVF treatment? There is ample incentive
to improve metabolic status and reduce complications in an
anticipated pregnancy for the future health of the mother
584
and baby, and every attempt should be made to optimize
the mother's weight and general well-being before proceeding
further. Dropouts are common from lifestyle programs (61),
and only the very motivated lose significant weight, so phy-
sicians must usually face the reality of determined women
who are still significantly overweight. However, metabolic
improvement can be obtained through lifestyle choices
without necessarily losing weight. Counseling about poten-
tially reduced pregnancy rates, the increased risks of preg-
nancy and labor, and the possible impact on the baby
should precede a final decision.
Obese and overweight infertile women should definitely
be informed, encouraged, and facilitated with respect to life-
style changes and fertility and pregnancy outcomes. Howev-
er, for women who fail to reach their weight targets despite
their best efforts, the patient's free choice to access treatment
should be honored, provided the treatment presents no overt
health risks to her. With the current data available to us, ulti-
mately it is hard to refuse IVF treatment to an overweight pa-
tient who has a genuine need for it, provided she has been well
informed by her medical team. Further research may change
this view, but it is increasingly hard to justify the logical
but increasingly impractical view that women should lose a
substantial amount of weight before treatment. This thereby
challenges the view we have steadfastly held for the past three
decades.
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