Nutrition and Reproduction in Women: The ESHRE Capri Workshop Group

Human Reproduction Update, Vol.12, No.3 pp. 193–207, 2006 doi:10.
1093/humupd/dmk003
Advance Access publication January 31, 2006
Nutrition and reproduction in women
The ESHRE Capri Workshop Group1

1
To whom correspondence should be addressed at: P.G.Crosignani, Il Department of Obstetrics and Gynaecology, University of Milano,
Via Commenda 12, 20122 Milano, Italy. E-mail: piergiorgio.crosignani@unimi.it
Malnutrition is a major problem in developing countries, and obesity and eating disorders are increasingly common
Downloaded from https://academic.oup.com/humupd/article/12/3/193/554114 by guest on 13 May 2021

in developing as well as developed countries. The reproductive axis is closely linked to nutritional status, especially
undernutrition in the female, and inhibitory pathways involving detectors in the hind brain suppress ovulation in
subjects with weight loss. Recovery may occur after minimal reacquisition of weight because energy balance is more
important than body fat mass. Anorexia nervosa and bulimia nervosa affect up to 5% of women of reproductive age
causing amenorrhoea, infertility and, in those who do conceive, an increased likelihood of miscarriage. Obesity can
affect reproduction through fat cell metabolism, steroids and secretion of proteins such as leptin and adiponectin and
through changes induced at the level of important homeostatic factors such as pancreatic secretion of insulin, andro-
gen synthesis by the ovary and sex hormone-binding globulin (SHBG) production by the liver. WHO estimates that 9
to 25% of women in developed countries are severely obese, and obese mothers are much more likely to have obese
children, especially if they have gestational diabetes. Obesity-associated anovulation may lead to infertility and to a
higher risk of miscarriage. Management of anovulation with obesity involves diet and exercise as well as standard
approaches to ovulation induction. Many obese women conceive without assistance, but pregnancies in obese women
have increased rates of pregnancy-associated hypertension, gestational diabetes, large babies, Cesarean section and
perinatal mortality and morbidity. Among contraceptors, the fear of weight gain affects uptake and continuation of
hormonal contraceptives, although existing trials indicate that any such effects are small. For all methods of hormo-
nal contraception, weight above 70 kg is associated with increased failure rates.
Key words: contraception/miscarriage/nutrition/obesity/reproduction
Introduction disorders and obesity), although obesity is on the increase even in

developing countries. Malnutrition is associated with 55% of
Nutrition problems are strikingly different in developing nations deaths among children under the age of five. Over 4 million of the
(deprivation and undernutrition) and developed nations (eating 12 million annual deaths are in sub-Saharan Africa alone, where
every third child is underweight and two out of five are stunted.
A meeting was organized by ESHRE (Capri, 3–4 September 2005) with an Iron deficiency anaemia is a contributing factor in over 20% of
unrestricted educational grant from Institut Biochimique SA to discuss the post-birth maternal deaths in Africa and Asia. Nearly 67 million
above subjects. The speakers included D.T. Baird (Centre for Reproductive
children are wasted (weigh less than they should for their height);
Biology, University of Edinburgh, Simpson Centre for Reproductive Health,
51 Little France Crescent, Edinburgh EH16 4SA, UK), S. Cnattingius
(Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, (Il Department of Obstetrics and Gynecology, University of Milano, Italy),
PO Box 281, S-171 77 Stockholm, Sweden), J. Collins (McMaster University, P. Devroey (Centre for Reproductive Medicine, AZ-Vrije Univ. Brussel,
Faculty of Health Science, Hamilton, Ontario, Canada), J.L.H. Evers Laarbeeklaan 101, B-1090 Brussels, Belgium), E. Diczfalusy (Rönningvägen
(Department of Obstetrics and Gynecology, Academic Hospital Maastricht, 21, S-144 00 Rönninge, Sweden), K. Diedrich (Klinikund Frauenheilkunde
P. Debeyelaan 25, P.O.Box 5800, 6202 AZ Maastricht, The Netherlands), und Geburtshilfe, Univ. zu Lübeck, D-2400 Lübeck, Germany), L. Fraser
A. Glasier (Director of FP & WW Services, 18 Dean Terrace, Edinburgh, EH4 (Endocrinology and Reproductive Research Group, School of Biomedical Sci-
1NL, Scotland Edinburgh), B.L. Heitmann (Research Unit for Dietary Stud- ences, New Hunt’s House, Kings College London, Guy’s Campus, London
ies, Copenhagen Centre for Prospective Population Studies, Copenhagen Uni- Bridge, London SE1 1UL, U.K.), L. Gianaroli (S.I.S.M.E.R., Via Mazzini 12,
versity Hospital, Denmark), R. Norman (Research Centre for Reproductive 40138 Bologna, Italy), I. Liebaers (Academic Hospital, Vrije Univ. Brussels,
Health and Repromed, Deptartment of Obstetrics and Gynecology, Academic Laarbeeklaan 101, B-1090 Brussels, Belgium), G. Mautone (Institut Bio-
Head, Repromed Pty. Ltd., Australia 5 005), K.K. Ong (Department of Paedi- chimique SA, Pambio Noranco, Switzerland), G. Ragni (U.O. Ostetricia e
atrics, University of Cambridge, Addenbrooke’s Hospital, Box 116, Hills Road, Ginecologia III, Sterilità di Coppia e Andrologia, Milano, Italy), B. Tarlatzis
Cambridge CB2 2QQ, U.K), A. Sunde (University Hospital, Department of (Infertility & IVF Center, Geniki Kliniki, 2 Gravias Street, Thessaloniki 546
Obstetrics and Gynecology, N-7006 Trondheim, Norway). The discussants 45, Greece), A. Van Steirteghem (Academic Hospital, Vrije Univ. Brussel,
included: J. Cohen (8, rue de Marignan, 75008 PARIS, France), B. Cometti Laarbeeklaan 101, B-1090 Brussels, Belgium). The report was prepared by
(Institut Biochimique SA, Pambio Noranco, Switzerland), P.G. Crosignani J. Collins (Hamilton) and P.G. Crosignani (Milano).
© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For
Permissions, please email: journals.permissions@oxfordjournals.org 193
The ESHRE Capri Workshop Group
and about 183 million weigh less than they should for their age.
Unfortunately, reducing poverty and increasing food production
by themselves cannot solve the nutrition problems of the poor in
developing countries (Bekele, 1998). Major public health and
social expenditures are needed to address these devastating condi-
tions that at present cannot be remedied substantially by medical
practice.
In contrast, developed nations experience little deprivation,
but eating disorders and obesity are increasingly common and
may be amenable to medical intervention. For females, repro-
duction involves much greater energy expenditure than for
males, and as a protective mechanism against undernutrition, the
reproductive axis is closely linked to nutritional status. As one Figure 1. Partitioning of metabolic fuels by priority (Wade and Jones, 2004).

consequence, eating disorders leading to loss of weight are asso-
ciated with reduced frequency or cessation of ovulation. Since
energy balance more than absolute weight loss is the key factor,
there may be a return of ovulation after no more than a small per-
Energy balance and ovulation
centage change in body weight recovery. Obesity, however, is a
less reliable risk factor of infertility except among obese women Approximately 1–5% of women suffer from ‘weight-related amen-
who also have polycystic ovarian disease. This review of nutri- orrhoea’ (Laughlin et al., 1998). Because many girls with delayed
tion and reproduction will address the clinical conditions that are puberty are relatively thin during adolescence it has been sug-
associated with underweight and overweight in developed coun- gested that a certain critical body weight (47 kg) or body fat con-
tries. It will outline the physiological mechanisms and clinical tent is required for onset of cyclical ovarian activity (Frisch and
conditions associated with undernutrition first and then those McArthur, 1974; Frisch, 1987). However, although ovarian activity
associated with obesity. and fat content are correlated they are not causally linked. It is rel-
atively easy to dissociate fatness and reproductive function. Thus,
for example, menstrual cycles return in some female athletes when
Undernutrition energy expenditure is reduced such as after an injury long before
there is any change in body weight or an increase in body fat
Physiological mechanisms (Loucks, 2003).
The reproductive system is extremely sensitive to influences from Reproductive function, like appetite, is responsive to short-term
the external environment (Martin et al., 2004). Most animals changes in metabolic food oxidation. For example, many breeds of
adjust their pattern of reproduction so that the chances of their off- sheep are capable of altering their ovulation rate and hence the
spring surviving are maximal. A common strategy involves timing number of lambs they carry depending on body condition (Martin
of conception by photoperiod and/or rainfall which usually et al., 2004). Feeding underweight sheep high-calorie supplement
ensures that birth takes place in a season when food and climatic of lupins or clover hastens the onset of the breeding season
conditions are favourable, such as spring. (‘flushing’) and increases the ovulation rate. A similar effect can
Reproduction involves much greater energy expenditure in the be produced by administration of a glucogenic ‘drench’ (Downing
female than in the male. The nourishing of the offspring during et al., 1995).
pregnancy and lactation and their subsequent rearing to adulthood The mechanisms involved in this adjustment of reproductive
are the biggest expenditure of energy that a female mammal will function involve the availability of calories. When Syrian ham-
make in her lifetime. Hence, the female reproductive system is sters are administered 2 de-oxy-D-glucose (DG), which limits glu-
much more sensitive to disruption than the male. cose oxidation, ovulatory cycles are interrupted rapidly (Schneider
Because reproduction involves energy expenditure, it is sensi- and Wade, 1990). It is likely that this involves both central and
ble that the physiological control mechanisms are linked to those peripheral mechanisms. In sheep and rats infusion of DG directly
involved with appetite and nutrition (Wade and Jones, 2004). into the lateral ventricles depressed LH secretion (Murahashi
Food is used as a source of energy for a variety of essential and et al., 1996; Ohkura et al., 2000). Subsequent experimentation has
non-essential functions. In times of deprivation it is necessary to helped define the pathway by which calorie deprivation leads to
ration available oxidizable substrate in favour of those essential short-term inhibition of reproductive function. It appears that in
functions involved in staying alive, e.g. keeping warm (Bronson, the rat the metabolic signals are detected by chemoreceptors in an
1989). Reproduction is expendable at least in the short term and area of the hind brain area [postrema (PA)]. The signals involved
can be deferred until times are more favourable (Figure 1). Dur- in this are not entirely clear but probably include leptin and insulin/
ing lean times animals have devised a number of strategies to glucose (Clarke and Hendry, 1999; Foster and Nagatani, 1999)
reduce energy output such as huddling together in insulated nests (Figure 2). Epinephrine, nor-epinephrine and neuropeptide Y
(houses), daily torpor or hibernation. Very little energy is (NPY) neurones connect to the forebrain to influence GnRH
diverted to storage of fat. Rather, calories are mobilized from fat secretion in the hypothalamus (Sawchenko et al., 1985). When the
stores in an attempt to maintain energy balance. Thus, it is animal is replete, the system is free running. The ‘brake’ is only
energy balance not fatness per se that regulates reproductive applied during times of negative energy balance and involves
function. NPY neurons (Sawchenko et al., 1985; Li and Ritter, 2004).
194
Nutrition and reproduction
developed countries it is most commonly found in women with

eating disorders.
Although records of undernutrition from developing countries
are scarce, the experience from the Dutch famine in 1944–1945 is
relevant to modern countries with a high prevalence of malnutri-
tion. In the Western Netherlands, average daily intake fell from
1500 to less than 700 kilocalories from October 1944 to January
1945 and the birth rate fell 9 months after October 1944. Future
reproductive life was affected among women who were severely
affected by famine at 3 to 13 years of age: they had a 1.9 fold
higher risk (95% CI = 1.3–1.8) of having fewer than the desired
number of children in their lifetime (Elias et al., 2005).
Undernutrition due to eating disorders may affect ovulation and

fertility, alter the response to conventional treatment and assisted
reproduction technology for infertility and have effects on preg-
nancy and the newborn.
The relevant eating disorders are bulimia nervosa (excessive
eating and compensatory activities such as vomiting or laxative
Figure 2. Nutrition and reproduction (Wade and Jones, 2004). NE, nor-epinephrine;
NPY, neuropeptide Y; PA, postrema. abuse) and anorexia nervosa [low body mass index (BMI) and fear
of weight gain]. Both commonly onset in adolescence and occur in
3% of young women (Becker et al., 1999).
Recent observations in women with ‘hypothalamic amenor- Milder eating disorders (not otherwise specified) occur in a further
rhoea’ have suggested that these experimental studies are relevant 3–5% of women (Stewart et al., 1990). Anorexia nervosa (1% of
to clinical disorders. Women with anovulation associated with young women) is defined as body weight less than 85% of
strenuous exercise or who are underweight, have low levels of leptin, expected weight or BMI less than 17.5 kg/m2, coupled with intense
LH and estradiol (Welt et al., 2004). The frequency of gonadotro- fear of weight gain and an inaccurate perception of body image.
pin pulses is too low to sustain development of antral follicles to Bulimia nervosa (1–5% of young women) involves recurrent binge
the point of ovulation. When leptin was injected to restore levels eating, compensated by recurrent purging, excessive exercise or
to normal, there was an immediate increase in the frequency of LH fasting, excessive concern about body weight or shape and the
pulses within 2 weeks, followed by growth of large ovarian folli- absence of anorexia nervosa (Becker et al., 1999). Full recovery
cles. Ovulatory cycles were restored in three out of eight women. with bulimia nervosa is more likely (74%) than with anorexia ner-
Whether leptin acts directly on the hypothalamus or increases the vosa (33%), but to achieve these recovery rates required a median
availability of oxidizable metabolic substrates or both is unknown. of 90 months of follow-up with treatment and relapses occurred in
It is likely that leptin plays a significant role in mediating this about one third of full recoveries (Herzog et al., 1999).
event although it should be noted that when nutritionally starved
Effects on fertility
animals are refed the frequency of LH pulses increases long before
there is an increase in circulating leptin (Schneider, 2004). Menstrual periods often cease after a 10–15% decrease in normal
body weight. In theory the mechanisms include altered regula-
Energy balance and implantation tion of gonadotropin-releasing hormone secretion and changes in
Nutrition not only influences ovulation and fertilization but also the dopaminergic and opioid systems. Amenorrhoea occurs in
implantation and early fetal development. Paradoxically overfeed- 15–30% of women with anorexia nervosa (Watson and
ing of sheep in the first few weeks of pregnancy results in an Andersen, 2003; Miller et al., 2005). Amenorrhoea is also a
increase in embryonic mortality associated with low levels of pro- component of the female athletic triad, along with osteoporosis
gesterone (Parr, 1992). The level of nutrition during pregnancy and milder versions of the eating disorders (Rome, 2003). Oli-
has a profound effect on fetal development and subsequent goamenorrhoea may occur with bulimia nervosa even in women
susceptibility in adulthood to disease. When ewes were underfed with BMI in the normal range. The amenorrhoea persisted in
during mid pregnancy there was an increase in the incidence of 30% of patients who had regained their normal weight during
pre-term birth (Bloomfield et al., 2003). The concept of fetal pro- recovery from anorexia nervosa with amenorrhoea (Falk and
gramming in utero which was originally derived from epidemio- Halmi, 1982).
logical studies in man has been confirmed in a number of With respect to fertility, anorexia nervosa or bulimia nervosa
experimental studies in animals (Barker, 2001; Gluckman and was present in 5 (8%) of 66 consecutive infertility clinic patients;
Hanson, 2004). Thus there is little doubt that nutrition plays an non-specified eating disorders were found in a further six (9%)
important role during pregnancy as well as in determining the tim- (Stewart et al., 1990). Seven of the 11 women with eating disor-
ing and quality of reproductive activity. ders were among the 12 of 66 with oligoanovulation; thus, in this
small group, eating disorders were present in about 60% of women
with oligoanovulation. Although women with anovulation are
Eating disorders unlikely to conceive, fertility may be normal in later years among
Undernutrition implies inadequate food intake or faulty assimila- women who achieve normal weight after recovery from eating dis-
tion due to low-caloric intake or limited nutritional diversity. In orders (Finfgeld, 2002; Rome, 2003). Women with a history of
195
anorexia nervosa and community controls had similar rates of Among women with eating disorders, postponement of concep-
pregnancy, mean number of pregnancies per woman and age at tion until remission is recommended because of the impact of low
first pregnancy (Bulik et al., 1999). After 11.5 years of follow-up nutrition, but all pregnant women with past or current eating disor-
in 173 women with bulimia nervosa, 75% had been pregnant at ders should be viewed as being at high risk and should be moni-
least once and only 2% reported that they were unable to conceive tored closely both during and after pregnancy to ensure optimal
(Crow et al., 2002). maternal and fetal outcomes (Becker et al., 1999; Fedorcsak et al.,
2004)
Effects on treatment for infertility
Undernutrition is not a reliable predictor of conception among
Overnutrition
infertile women. In 244 cycles of GnRH treatment for oligoamen-
orrhoea in 48 women, pregnancy rates were not affected by Epidemiology of obesity
patients’ weight or weight loss (Braat et al., 1991). With assisted
Obesity trends
reproduction (ART) treatment, BMI was <20 kg/m2 in 22% of 398

French women: the delivery rates per started cycle were 21% in The prevalence of overweight defined as BMI 25.0–29.9 and
underweight women and 15% in those with BMI 20–25 kg/m2 obesity defined as BMI ≥ 30 kg/m2 is increasing around the world
(Wittemer et al., 2000). Among 2860 Norwegian women having (Cnattingius and Lambe, 2002). WHO considers that obesity is an
ART, BMI was <18.5 kg/m2 in 3%; the live birth rates per started epidemic, as more obese people are found in developed and devel-
cycle were 21%, both in underweight women and in those with oping countries, among children as well as adults and elderly and
BMI 18.5–25 kg/m2 (Fedorcsak et al., 2004). among men and women (World Health Organisation, 1997). In
Western countries increases in obesity prevalence range from
Effects on pregnancy
1–6% per year among adults and for most countries the increases
Women with a history of being anorexic may have more abor- are greater among men than women (Heitmann, 2000). Using the
tions: 27% in a cohort of 66 anorexics versus 13% in a control classification of BMI, 60% of the adult population in Australia are
group (Bulik et al., 1999). In contrast, a larger follow-up study of overweight and 21% are obese. This proportion in Australia and
246 women with either anorexia or bulimia reported that 54 the western world is increasing and has doubled over the past 20
women had 82 pregnancies of which 46 (56%) were live births, 25 years. This trend of increasing obesity is likely to spread and lead
(31%) were therapeutic abortions and only 11 (13%) were sponta- to a clear association with impaired psychosocial health, type 2
neous abortions (Blais et al., 2000). diabetes, cardiovascular disease (CVD), osteoarthritis, sleep
During pregnancy, women with eating disorders have higher apnoea and various reproductive conditions (Pasquali et al., 2003).
rates of hyperemesis gravidarum, anaemia, impaired weight gain The Heart, Lung and Blood Institute concluded that the public
and compromised intrauterine fetal growth (Becker et al., 1999; health burden caused by obesity resembles that of smoking, which
Kouba et al., 2005). Premature delivery is more likely in under- previously was the most important cause of preventable death
weight women (Figure 3). A case control study found that BMI (Anonymous, 1998).
<20 kg/m2 was associated with a four-fold higher likelihood of Denmark is one country where information on obesity develop-
pre-term labour (OR = 3.96, 95% CI = 2.61–7.09) after adjusting ment has been collected from entire population groups, such as all
for other known factors (Moutquin, 2003). Rates of cesarean school children or all young men at the compulsory draft board
delivery, post-natal complications and post-partum depression are examinations. Recent data on obesity prevalences during almost six
higher among mothers with anorexia nervosa (Bulik et al., 1999; decades from Danish school health examinations show that obesity
Franko et al., 2001). Undernutrition is associated with low birth- was 20-fold and 115-fold higher, among 6–8 year old girls and
weight (3233 g compared with 3516 g for normal controls) boys, respectively, in 2003 compared to 1947 (Pearson et al., 2005).
(Kouba et al., 2005). Similarly, over the past 30 years the prevalence of obesity among
young Danish men is consistently increased (5 per 1000 obese draft-
ees in the mid-1970 to 73 per 1000 in 2004) (Sorensen et al., 1997;
Forsvaret, 2004) (Figure 4). These dramatic increases among Dan-
ish children and young men are unparalleled by any other country.
As Danes are among the leaner populations in the Western world,
however, information from other countries on trends in obesity
prevalence may be greatly underestimated (Heitmann, 2000).
Underestimation of the trends may arise from bias in self-reporting.
In a comparison of trends for obesity from measured and self-
reported data the figures for the self-reported information are 50–
100% lower (Richelsen et al., 2002). Also, studies have shown that
those who never turn up at health examinations to have their height
and weight measured are generally much more obese than those
who do turn up (Sonne-Holm et al., 1980).
Determinants for obesity
Figure 3. Factors associated with premature delivery (Moutquin, 2003). OR,
odds ratio; CI, confidence interval; body mass index Kg/m2 (standing at work Overweight and obesity are attributed to social changes with more
>2 h/day, stress score: arbitrary scale. sedentary lifestyle, decrease in physical activity and changes in
196
8% nature should take care to remove it from the gene pool since it is
no longer an advantage. The question is whether survival of the
7%
fittest dictates that if obesity is no longer an evolutionary advant-
age, decreased fertility perhaps may be nature’s remedy.
Prevalence of BMI > 30 kg/m2
6%
A recent review focused on converging data supporting the
5% hypothesis that, in addition to the thrifty gene inheritance, individ-
uals with metabolic syndrome—combining disturbances in glu-
4%
cose and insulin metabolism, excess of predominantly abdominally
3% distributed weight, mild dyslipidemia and hypertension, with the
subsequent development of obesity, type 2 diabetes mellitus and
2%
CVD—have suffered improper ‘epigenetic programming’ during
1%
their pre- and post-natal development due to maternal inadequate
nutrition and metabolic disturbances. Moreover, as seen for obes-

0% ity and type 2 diabetes, the metabolic syndrome tends to appear
1974 1984 1994 2004
earlier in childhood, to be more severe from generation to genera-
Year of Birth
tion and to affect more pregnant women (Junien et al., 2005). This
Figure 4. Prevalence of obesity among young Danish men (Sorensen et al., leads to the conclusion that obesity and related metabolic distur-
1997; Forsvaret, 2004).
bances are major health issues.
dietary energy density and composition, but the underlying cause Prenatal predictors of obesity
is complex involving cultural, psychological and genetic factors Rising rates of obesity and overweight in young people and chil-
that may interact with both energy intake and expenditure to affect dren have shifted research efforts towards the very early preven-
obesity development. For instance, obesity is known to carry a tion of excess weight gain in subjects identified to have high risk
clear social disadvantage, and among those from lower social eco- of developing obesity.
nomic groups, the prevalence of obesity is three to five times Maternal obesity predicts a four-fold increased risk in offspring
higher than among individuals from higher socioeconomic groups obesity (Reilly et al., 2005). Whether this is driven by genetic or
(Heitmann, 2000). Studies show that obesity not only influences behavioural factors, much of this risk is due to increased childhood
social class placement, but is also a predictor of social class place- weight gain. Indeed, this relationship is likely to be multifactorial
ment (Stunkard and Sørensen, 1993). Interestingly, adoption stud- because of a combination of shared lifestyles and genetic influ-
ies have shown a very strong negative association between social ences; in addition, maternal obesity may lead to fetal macrosomia
class of the adoptive parents and the BMI of the child, whereas associated with gestational diabetes (Sermer et al., 1995). Overall,
associations between BMI in the adoptive parents and BMI in the greater birthweight is positively correlated with higher BMI in
adopted child were non-significant, suggesting that social class childhood and later life, although the relationship is complex.
may modify the expression of the genes responsible for obesity Weighing more at birth is subsequently associated with more lean
development (Teasdale et al., 1990). Studies also show that life- mass rather than fat mass (Loos et al., 2001, 2002). In contrast,
style factors, such as dietary fat, physical activity, alcohol and lower birthweight is associated with a subsequent higher fat mass
smoking (Heitmann et al., 1997) may modify the expression of the to lean mass ratio and also with more central fat and insulin resist-
obesity promoting genes, making the development of obesity a ance (Valdez et al., 1994). This paradoxical effect of lower birth-
much more complex issue than a simple imbalance between weight is at least partly explained by the observation that low
energy intake and expenditure. birthweight infants, who have been growth restrained in utero,
tend to gain weight more rapidly, or ‘catch-up’, during the early
Genetic factors
post-natal period (Ong et al., 2002).
The thrifty gene hypothesis (Neel, 1962) considers that a specific Apart from the mother’s current body size, factors associated
gene fosters survival in both feast and famine conditions. Eating with intra-uterine growth restraint include first pregnancies, smok-
food whenever possible and storing the energy helped early ing during pregnancy and lower birthweight of the mother, which
humans—hunters and gatherers—to survive conditions of famine. likely reflects maternal genetic factors. The greatest risk of child-
Thus, fatter individuals were more likely to survive. In modern hood obesity, and in particular obesity-related disease risk mark-
life, however, feast and famine conditions do not apply in the ers, may therefore be seen in babies born small relative to parental
developed part of the world, which suffers more ‘feast only’ con- size, who have been more restrained in utero. Such infants grow
ditions. Evolutionary theory implies that species evolve over time more rapidly during infancy, and this appears to be associated with
to fit their environment best, a process that depends on variation increased central fat deposition, insulin resistance and CVD risks
among individuals which must be inheritable. Not all individuals in later life (Fagerberg et al., 2004; Ong et al., 2004).
in a population survive to reproduce. Some individuals can cope Prevention of offspring obesity requires preventing maternal
with selective pressures better than others. People who possess the obesity and also needs to take into account the interactions
thrifty gene are at an advantage in the time of famine: they can between maternal genes that regulate the supply of fetal nutrition
store energy; a thrifty gene, however, is a disadvantage in times of and post-natal genes that regulate infant appetite.
feast: their carriers grow too fat. If the thrifty gene provided an Particular risks for offspring obesity and long-term health are
advantage to early humans, but a disadvantage to present day man, associated with obese mothers who have gestational diabetes and
197
possibly also gestational hypertension. As these conditions are Table II. Examples of receptors expressed in adipose
increased in obese mothers, efforts should be made to screen, tissue (Kershaw and Flier, 2004)
monitor and intervene early in these mothers. How to safely inter-
vene to prevent over-rapid infant weight gain is as yet unclear, and Receptors for traditional endocrine hormones
it is likely that any future advice will need to be tailored to each Insulin receptor
Glucagon receptor
specific circumstance. The current WHO recommendation encour-
Growth hormone receptor
ages breast-feeding and delayed introduction of solids or comple- Thyroid stimulating hormone receptor
mentary foods until age 6 months. In addition to avoiding excess Gastrin/cholecystokinin B gastrin receptor
infant nutrition, this approach has advantages for infection and Glucagon-like peptide-1 receptor
allergy risks (Anonymous, 2003). Angiotensin II receptors type I & 2
Nuclear hormone receptors
Glucocorticoid receptors
Endocrine activities of fat tissue
Vitamin D receptor
Although under-nutrition is the dominant factor regulating repro- Thyroid hormone receptor

ductive activity under natural conditions, obesity is an important Androgen receptor
cause of sub-fertility in many modern societies. Adipose tissue is a Estrogen receptor
Progesterone receptor
complex and highly active metabolic and endocrine organ. In
Cytokine receptors
addition to adipocytes there are immune cells, connective tissue Leptin receptor
matrix, nerve tissue and stromovascular cells which together func- Interleukin 6 receptor
tion as an integrated unit. White and brown types of fat tissue dif- Tumour necrosis factor α receptor
fer in composition, appearance and function. White adipose tissue Catecholamine receptors
is 60–85% lipid and 90–99% of this lipid is triglyceride. White fat β1, β2, β3 receptors
tissue provides heat regulation, body cushioning and energy stor- α1, α2 receptors
age (triglycerides). Brown fatty tissue derives its colour from rich
vascularization and densely packed mitochondria. The cells are
polygonal in shape, have a considerable volume of cytoplasm and specific expression of steroid hormone receptors to other hormones
contain multiple lipid droplets of varying size. Their nuclei are while tissue specific pre-receptor steroid hormone metabolism
round and almost centrally located. Brown fatty tissue may make also occurs. The relative contribution of adipose tissue to whole
up 5% of body weight in neonates but disappears by adulthood. It body steroid metabolism is substantial. Up to 50% of circulating
is the site of non-shivering thermogenesis or metabolic heat pro- testosterone in pre-menopausal women comes from fat and up to
duction without rapid contraction of muscles. 100% of circulating estrogen in the post-menopausal women
Fat tissue responds to signals from circulating hormones, but (Weisberg et al., 2003; Wellen and Hotamisligil, 2003).
also produces its own hormones and receptors (Kershaw and Flier, Enzymes involved in the metabolism of glucocorticoids
2004). Therefore the traditional view that fat tissue is a passive
reservoir for lipids and has no other function is incorrect (Ahima Glucocorticoids can be metabolized through 11β hydroxysteroid
and Flier, 2000). Many proteins with endocrine functions are syn- dehydrogenase1 which is highly expressed in adipose tissue.
thesized by adipocytes (Table I), and adipose tissue expresses a Tissue-specific disregulation of this hormone has been implicated
broad range of key cytoplasmic and nuclear receptors (Table II). in a variety of common medical diseases including disturbances in
Among the many synthetic processes in adipose tissue, perhaps, reproductive mechanisms.
the most important with respect to reproduction are intrafat modi- Adipose tissue secreted proteins
fication of steroid hormones and secretion of adipokines (Ahima
and Flier, 2000). (i) Leptin: Leptin is the classic adipose secreted protein and is
secreted in direct proportion to adipose tissue mass as well as
Enzymes involved in the metabolism of steroid hormones nutritional status. Regulation of expression and secretion is under
Adipose tissue contains a large number of enzymes for activation, the control of a variety of other factors while leptin’s effect on
interconversion and inactivation of steroid hormones. Steroid hor- energy intake is well documented. Leptin may have an action on
mones from the circulation can be converted through tissue- the endometrium and the ovary in addition to its classical action
on the hypothalamic pituitary access with regard to eating.
(ii) Tumour necrosis factor (TNF α): TNF has been implicated
in the pathogenesis of obesity and insulin resistance while having
Table I. Examples of adipocyte-derived proteins
with endocrine functions
significant effects on other metabolic components of fat and the
liver. Increases in TNFα are associated with decreased food
Other immune-related proteins
uptake, increased energy expenditure, more lipolysis and decreased
Proteins involved in the fibrinolytic system lipogenesis and decreased insulin sensitivity.
Complement and complement-related proteins (iii) Interleukin (IL-6): This cytokine circulates in concentra-
Lipids and proteins for lipid metabolism or transport tions that are positively correlated with obesity, impaired glucose
Enzymes involved in steroid metabolism tolerance and insulin resistance.
Proteins of the renin angiotensin system (RAS) (iv) Macrophage and monocyte chemoattractant protein (MCP-1):
Other proteins
Activated macrophages secrete inflammatory factors that contribute
Cytokines and cytokine-related proteins
to insulin resistance. MCP-1 recruits monocytes to inflammatory
198
sites and has local as well as endocrine effects (Weisberg et al., (viii) Resistin: Resistin is expressed 15-fold greater in visceral fat
2003; Wellen and Hotamisligil, 2003). as opposed to subcutaneous adipose tissue in rats and links obesity
(v) Plasminogen activator inhibitor (PAI-1): Circulating levels with insulin resistance. Mice carrying a targeted deletion of resis-
of PAI-1 are elevated in obesity and insulin resistance and are tin have significantly improved fasting blood glucose levels and
related to features in the metabolic syndrome and predict future proved glucose tolerance.
risk of type 2 diabetes and cardio-vascular disease. (ix) Proteins of the renin angiotensin system (RAS): These
(vi) Adiponectin: This molecule is produced in very large quan- include renin, angiotensinogen, angiotensin I, angiotensin II and
tities from fat, especially subcutaneous rather than visceral fat. It so on. All of these are involved with metabolic changes. There can
is inversely related to insulin resistance and inflammatory states. be significant effects on blood pressure and adipose tissue devel-
Adiponectin levels are low in obesity. Expression of adiponectin is opment.
much greater in gluteal than in fatty tissue from other subcutane- There are numerous contributing factors to the metabolic and
ous or visceral sites. endocrine activity of fat. Many of these influences are reproduc-
(vii) Adipsin and acylation stimulating protein (ASP): Both these tive hormones, but in turn the secretions of the fat can affect the

positively correlate with adiposity insulin resistance and cardio- appetite and the functioning of the reproductive system (Figure 5)
vascular disease. (Gale et al., 2004).
Figure 5. Appetite, fat and intestine (Gale et al., 2004). POMC/CART = proopiomelanocortin/cocaine- and amphetamine-regulated transcript; NPY = Neuropeptide Y;
AgRP = agouti-related peptide.
199
Health consequences of obesity women are obese and indeed most obese women are able to get
Obesity is a health concern because of the close relationship pregnant easily. However, the general view is that being over-
between obesity and major lifestyle diseases, such as diabetes and weight is correlated with difficulty in getting pregnant (Norman
coronary heart disease (CHD). Obesity is also linked, however, to et al., 2004). This is particularly shown in the Nurses Health Study
hypertension, gall bladder disease, dyslipidermia, cancer (particu- looking at 2527 married infertile nurses. The risk of ovulatory
larly hormone dependent and gastrointestinal; such as endome- infertility increased from 1.3 in a group with a normal BMI to a
trial, ovary, cervix and post-menopausal breast cancer), rate of 2.7 in women with a BMI over 32 (Rich-Edwards et al.,
osteoarthritis, reproductive hormone abnormalities and psychoso- 1994). Treatment of anovulatory infertility of overweight women
cial problems. Abdominal obesity is of particular concern and requires increased concentrations of clomiphene citrate and higher
more clearly associated with ill health and premature death than doses of gonadotrophins to induce an ovulatory follicle. Treatment
peripheral obesity (World Health Organisation, 1997). of overweight women on IVF programs shows a much lower
Several reports have documented that the costs of obesity and pregnancy rate (Crosignani et al., 1994; Wang et al., 2000;
the related comorbidities are substantial and vary between 2 and Fedorcsak et al., 2001). There is also evidence using donor eggs

8% of total health care costs, depending on country. In a number that the body mass of the recipient is more important than the body
of countries prevalence of diabetes type 2 is already increasing as mass of the donor (Figure 6). This is largely due to the miscarriage
a consequence of the obesity epidemic and this increase includes rate which has been shown to increase four-fold in the obese
not only adults, but also children (Pinhas-Hamiel et al., 1996). It is (Bellver et al., 2003).
feared that in less than 10–15 years the increasing diabetes preva- Weight loss management in PCOS
lence will also affect morbidity and mortality from CHD and CVD
if action is not taken. The primary goal of treatment in PCOS is to normalize serum
androgens and to restore reproductive function. This is achieved by
reducing insulin resistance through a decrease in weight and
Fertility in obese women
abdominal fat. Lifestyle modification has been shown overwhelm-
Stein and Leventhal (1934) were the first to recognize the relation ingly to be successful with interventions as little as 3–4 weeks
between obesity and reproductive disturbances. They described inducing weight losses of 5–10% of initial body weight. Caloric
what nowadays is known as syndrome ‘O’: overnourishment, restriction improves insulin sensitivity measured through euglycae-
overproduction of insulin, ovarian confusion and ovulation disrup- mic hyperinsulinemic clamps, fasting glucose insulin ratios, oral
tion. The impact of obesity on reproduction is shown in Table III glucose tolerance test (OGTT) stimulated insulin and fasting insu-
(Pasquali et al., 2003). lin. Weight loss also decreases hyperandrogenaemia and improves
Anovulatory infertility menstrual function, ovulation, fertility and hirsutism. The return of
reproductive function occurs with modest weight loss (<10% of
Obesity and abdominal obesity are especially common in poly- initial body weight) even though the end of study BMI often is over
cystic ovary syndrome (PCOS) with 10–50% of women with 30 kg/m2 (Crosignani et al., 2003; Norman et al., 2004).
PCOS having a BMI outside of the acceptable range of 19–25. Weight loss is not consistent in all patients because discrepan-
This enhances the features of insulin resistance and is associated cies in appetite regulation might exist. Ghrelin is a stomach-
with reproductive dysfunction in a high proportion of cases. derived hormone that increases sharply before feeding onset and
Abdominal obesity particularly worsens the clinical features of decreases after a meal. In obesity, fasting levels of ghrelin are
menstrual irregularity and infertility and is correlated with decreased and the post-prandial decrease might be impaired poten-
increased serum androgens and luteinizing hormone. However, it tially compromising meal termination. Fasting ghrelin increases
is not clear whether it is the visceral or subcutaneous adipose tis- with weight loss. Weight loss is a desirable outcome in overweight
sue that is related to reproductive dysfunction. Many multiparous women with PCOS for short- and long-term improvements in
reproductive and metabolic health. Precise dietary evidence-based
guidelines are needed for the treatment of this group, both in the
Table III. Impact of obesity on reproduction
amelioration of short-term reproductive and metabolic dysfunction
Condition Associated risks
Menstruation Risk of menstrual dysfunction:

60 <20
amenorrhoea, oligomenorrhea and menorrhagia
20-24.9
Body Mass Index Kg/m2
Infertility Risk of ovulatory and anovulatory 50

25-29.9
infertility: anovulation, poor response to fertility drugs ∗
40 ∗ >30
Miscarriage Risk of miscarriage, spontaneously
and after infertility treatment 30
Glucose Risk of impaired glucose tolerance ∗
20
and type 2 diabetes mellitus intolerance
Infertility treatment Requirement for clomiphene citrate/gonadotrophin 10
ovulation induction. Success rate for
0
IVF/ICSI pregnancies
Implantation rate Pregnancy rate (%) Abortion rate (%)
Pregnancy Prevalence of pregnancy-induced hypertension, (%)
gestational diabetes, caesarean section and Down’s
syndrome Figure 6. Body weight (BMI) of recipient is important for oocyte donation
(Bellver et al., 2003). * = p<.05.
200
Table IV. Practical approaches to weight loss Table V. Obesity increases risks of both pre-eclampsia and gestational
hypertension (Ros et al., 1998)
Sensible diet
Smoking cessation Body mass index Pre-eclampsia Gestational hypertension
Effective exercise [OR (95% CI)] [OR (95% CI)]
Avoid crash diets
Use behavioural modification for stress Underweight (<19.8) 1.0 1.0
Minimal role for drugs Normal (19.8–26.0) 1.5 (0.8–2.9) 1.8 (0.8–3.7)
Avoid surgery in the majority Overweight (26.1–29.0) 3.1 (1.4–6.8) 2.0 (0.8–5.3)
Sympathetic physician support Obese (>29.0) 5.2 (2.4–11.5) 4.9 (2.0–11.9)
0.4% in obese women (95% CI = 0.1–0.7) compared with 0.1% in

and for minimizing long-term cardiovascular and diabetic mortal-
women of normal weight (95% CI 0.02–0.2). Although signific-
ity and morbidity.

ant, the difference was not large (Lashen et al., 2004).
There are a number of dietary approaches to the overweight
women with reproductive dysfunction that include high protein, Pregnancy complications
high carbohydrate or low fat diets. There is a paucity of data
examining the relationship between these various approaches but In animals, overfeeding of sheep in late pregnancy leads to preg-
overall low calories are the most important component of a diet nancy complications as well as dystocia at birth (Wallace et al.,
rather than its actual composition. There has been interest recently 2001). Gestational diabetes is far more common in overweight and
in the glycaemic index particularly by introducing a low glycae- obese women compared to women with normal weight. Swedish
mic index diet. Practical approaches to weight loss are summa- data show a doubling in risk of gestational diabetes among over-
rized in Table IV. weight women and a six-fold increase in risk among obese women
(Cnattingius and Lambe, 2002). Similar results have been reported
Pharmacological management from other countries, such as the United States (Baeten et al.,
Administration of insulin sensitizing drugs is controversial 2001). These risks are most likely related to increased insulin res-
although at least one study has suggested that the addition of met- istance among overweight and obese women. Since gestational
formin to a low calories diet and lifestyle change leads to extra diabetes increases the risk of subsequent development of type 2
benefit (Norman, 2004). The adjuvant use of such a drug with diet diabetes, the generally increasing BMI among young women may
and exercise needs investigation. There are few studies of using be specially important in populations with genetic susceptibility
appetite suppressants and lipid anti-resorption drugs in PCOS. for type 2 diabetes, i.e., many Asian populations (Table V).
Gastric stapling and banding may have some value in women who Pregnancy-induced hypertensive diseases, such as gestational
are very obese. hypertension and pre-eclampsia, are also known to occur more often
in overweight and obese women compared to women of normal
weight (Ros et al., 1998; Nuthalampaty and Rouse, 2004). The mech-
Gestation in obese patients
anisms by which overweight increases the risk of pregnancy-induced
The prevalence of overweight in pregnancy is now 35% and one- hypertensive diseases are not clear. The increased risk of insulin res-
fifth of these are obese, thus, risks of miscarriage, pregnancy com- istance among overweight women gives rise to hyperinsulinemia,
plications and adverse pregnancy outcomes related to maternal which may lead to hypertension by vasoconstriction. In addition,
overweight and obesity are important from a public health per- insulin resistance may also increase the risk of endothelial dysfunc-
spective (Andreasen et al., 2004; Cedergren, 2004). tion (Roos et al., 1998).
The risk of cesarean delivery increases with BMI, partly
Bodyweight and abortion
because of weight-related risks of pregnancy complications, which
Several studies have shown that there is an increased risk of spon- increase the likelihood of induced labour. During delivery, over-
taneous abortion in obese women, irrespective of the coexistence weight and obese women also face a substantial risk of dystocia,
of PCOS (Hamilton-Fairley et al., 1992; Wang et al., 2001; Roth which can be explained by increased occurrence of fetal macro-
et al., 2003). In one study involving donor oocyte pregnancies, the somia, but primary and secondary inertia uteri are also more com-
spontaneous miscarriage rate was increased in acceptor women mon among overweight pregnant women (Jensen et al., 1999).
with a BMI over 30 kg per m2 (Bellver et al., 2003) (Figure 6). Cesarean deliveries among obese gravidas are also associated with
The relation between obesity and miscarriage concerns predomi- increased risks of peri- and post-operative complications, includ-
nantly early miscarriage. Lashen et al. (2004) found a significant ing excessive blood loss and post-operative infections (Nuthalampaty
difference between early miscarriage rate in obese patients (n = 1644): and Rouse, 2004).
12.5% (95% CI = 11–14%) and normal weight patients (n = 3288):
Pregnancy outcomes
10.5% (95% CI = 10–12%). There was no increase in late miscar-
riages. Wang et al. (2002) in a retrospective study of 2349 women The risk of stillbirth increases with BMI. Compared to women
confirmed earlier findings by Fedorcsak et al. (2000) in IVF with normal BMI (20.0–24.9), the risk of stillbirth among obese
patients and found a significantly increased spontaneous abortion (BMI ≥ 30.0) mothers is 40–100% higher (Sebire et al., 2001;
rate after IVF in women with a BMI of 25–30 (22% abortions), Cnattingius and Lambe, 2002). The reasons for the weight-related
30–35 (27% abortions) and over 35 kg per m2 (31% abortions). In the increase in stillbirth remain to be determined. One possibility is
Lashen et al. study, the rate of recurrent early miscarriage was that the increased risk may be due to residual social confounding.
201
However, adjusting for maternal education and other social factors Contraception and weight
does not substantially influence the risks of stillbirth related to In most young women, contraception is the earliest reproductive
overweight and obesity (Cnattingius and Lambe, 2002). A second consideration, and obesity influences decisions and effectiveness
possibility is that the association between overweight and obesity of hormonal contraceptives. The relationship between contracep-
and stillbirth risk may reflect that overweight and obesity, in fact, tion and weight is complex. Many women attribute weight gain to
negatively influence fetal environment (gestational diabetes, pre- the method of contraception they are using; it is a common reason
eclampsia and hyperlipidemia) which in turn increase the risk of for method discontinuation and fear of putting on weight deters
stillbirth (Cnattingius and Lambe, 2002). some women from ever starting certain methods. Some hormonal
Obesity is reported to increase the risk of induced pre-term methods may well cause weight gain in susceptible women and
birth, an association most likely caused by obesity-related preg- body weight appears to influence efficacy of most methods.
nancy disease, i.e., pre-eclampsia and gestational diabetes (Hendler Finally, excess body weight can be a contraindication to some
et al., 2005). One study reports that obesity increased the risk of methods of contraception.
infant death (Baeten et al., 2001). Moreover, provided that obesity

increases the risk of pre-term birth, a possible association between The influence of weight on uptake and continuation
overweight and obesity and infant mortality may be mediated by
an increased risk of pre-term birth related to high maternal BMI. Most surveys of contraceptive use highlight weight gain as an
Overweight and obesity are consistently associated with important issue for women. In a survey of 967 British women of
increased risk of the delivery of large-for-gestational-age infants. reproductive age nearly half perceived the risk of CVD (45%) or
The reduced insulin sensitivity among obese mothers increases the cancer (41%) as a theoretical disadvantage of oral contraception,
availability of glucose to the fetus, which thereby may increase but almost twice as many (73%) of women were worried about
fetal growth (Surkan et al., 2004). The increasing prevalence of weight gain (Oddens et al., 1994). In a survey of 1466 German
maternal overweight and obesity seems to be the main reason for women, 21% of current users and 32% of past users claimed
the increasing prevalence of infants born with a high birthweight a median weight gain of 5 kg which they attributed to OC use
in North America and Europe (Kramer et al., 2002; Surkan et al., (Oddens, 1999). Weight gain—whether caused by the contraceptive
2004). method or not—is a common reason for discontinuation. In a lon-
Finally, maternal overweight and obesity may also carry a long- gitudinal survey of Swedish women followed up every 5 years,
term risk for the newborn infant. Rates of large-for-gestational-age weight gain was given as the reason for one in five 19-year-old
infants are increasing as a consequence of increasing maternal women stopping the oral contraceptive pill (Larsson et al., 1997).
BMI. Infants born large-for-gestational-age are at a higher risk of Similarly, weight gain was the commonest side effect leading to
being overweight in adulthood (Eriksson et al., 2001). Thus, off- discontinuation of Depo Provera in a cohort of New Zealand
spring to overweight mothers may not only face an increased risk women (Colli et al., 1999).
of being large-for-gestational-age at birth, but may also carry a Fear of weight gain influences acceptability of most hormonal
long-term risk of overweight and overweight-related diseases in methods especially, perhaps, Depo Provera. In two separate stud-
adulthood. ies of contraceptive use among adolescents 25% of young women
preferred to use barrier methods despite their lower efficacy,
Prevention of obesity because they were worried they would gain weight on the pill
The continuing rise in the obesity epidemic calls for immediate (Pratt and Bachrach, 1987; Dusterberg and Brill, 1990).
action. Numerous treatment intervention studies have documented
that secondary prevention is effective: significant weight loss can The influence of contraception on weight
easily be obtained by caloric restriction. Additionally, several Women—and men—gain weight during their reproductive lives.
studies show that although weight loss per se may be modest after In an observational study of 1697 Brazilian women using a copper
intervention with increased physical activity, the addition of activ- intrauterine device (IUD) the mean weight of the cohort was 58.5 kg
ity to dietary interventions generally proves very beneficial, (SD = 0.3) when the IUD was inserted. After 5 years of follow-up
because the resulting increase in lean tissue at the expense of fat mean weight was 61.2 kg (SD = 0.33) and after 7 years 62.4 kg
not only reduces fat mass, but also increases the metabolically (SD = 0.55) (Hassan et al., 2003). It is possible that hormonal con-
active lean body compartments such as muscle mass (Haddock traceptives, through a variety of mechanisms including (among
et al., 2002). others) stimulation of the RAS, altered carbohydrate metabolism
By contrast, there is still unconvincing evidence from the pub- or increased appetite, might cause weight gain.
lished literature that primary community interventions towards In a non-systematic review of the literature on the effect of the
weight gain works. Hence, the general notion that current trends combined pill on weight, Gupta summarized a number of com-
for obesity are consequences of gluttony and sloth only would parative and non-comparative, controlled and blinded or double
seem a major simplification. Rather, a more complicated interac- blind studies (Gupta, 2000). Whatever the study design, most
tion between cultural, psychological, social, familial and genetic demonstrated that roughly one third of women regardless of the
factors seems to operate. Indeed, it is likely that primary interven- method of contraception they were using gained up to 2 kg in
tion trials should focus on high-risk groups, such as lean children weight over 6–12 months of follow-up. A smaller proportion of
from families where obesity is a problem, lean children from low women lost weight. In a more recent Cochrane review, Gallo and
socioeconomy families or children already modestly overweight. colleagues reviewed 570 published reports of weight change
These focused programs may be more effective than previous pre- among users of combined hormonal contraception (Gallo et al.,
vention trials aimed at general population groups. 2004). The quality of reporting of the trials was ‘generally poor’
202
Table VI. Hormonal contraception: weight change in placebo-controlled trials women of lower weight. The risk of failure was inversely related
(Gallo et al., 2003) to the dose of estrogen in the pill (Holt et al., 2002). Similar find-
ings have been demonstrated among users of the contraceptive
Date Estrogen (μg) Cycles Measurement Likelihood patch (Zieman et al., 2002) and of progestogen-only oral contra-
1971 100 EE 4 Gain > 2.3 kg 1.0 (0.5–2.3)
ceptives (POP) (Vessey et al., 1985), and it has become common
1971 100 Mestranol 4 Gain > 2.3 kg 0.6 (0.2–1.3) practice in the United Kingdom to prescribe a doubled dose of
1971 50 Mestranol 4 Gain > 2.3 kg 0.5 (0.2–1.2) POP to women over 70 kg. While other variables, perhaps to do
2001 20 EE 6 Mean difference (kg) 0.3 (−0.2–1.2) with compliance, are often cited as possible confounders, a
2000 Patch (20) 9 Gain > 5% 1.0 (0.3–3.0) number of trials have demonstrated increased failure rates among
2000 Patch (20) 9 Loss > 5% 0.3 (0.0–1.8) heavier women using Norplant when compliance is not an issue
(Glasier, 2002). Since phase three clinical trials designed for the
purposes of licensing drugs often specifically exclude women with
(the description of their shortcomings takes up most of the paper). a BMI over 30 or 35, data are lacking for new methods such as

There were four placebo-controlled trials among pill users and ImplAnonymous. It seems likely that for all hormonal contracep-
one among women using the contraceptive patch. No statistically tives the balance between reducing the dose to improve safety and
significant differences in weight change were identified when thereby jeopardizing efficacy is critical. What often gets forgotten,
contraceptive users were compared with non-users (Table VI). however, is that the absolute risk of failure is still very small and
Five of the 69 trials comparing two different formulations of much less than that associated with less effective methods such as
combined pill did, however, demonstrate significant weight gain condoms.
but the largest mean difference was 1.8 kg (95% CI = 0.7–3.4) The effect of weight on contraceptive effectiveness is also seen
after 1 year. The authors of the review concluded that the evid- with female sterilization. In a multi-centre study of female sterili-
ence is insufficient to rule out any effect of combined hormonal zation using tubal rings, case control analysis revealed three risk
contraception on weight change but that it is unlikely that there is factors for technical failure: obesity, previous use of an IUD and
any large effect. previous abdominal surgery (Chi et al., 1980).
Data for the effect of progestogen-only contraceptives (POC)
The influence of weight on the side effects and safety of contraception
on weight change are less extensive. Although studies have
reported variable effects of Depo Provera on weight, some have The vast majority of women who use contraception are well and
reported weight increase of 3–6 kg. In a review of the topic can use any method with minimal risk of serious side effects. For some
Westhoff (2003) points out that certain groups of women have a women with pre-existing medical conditions, such as hypertension
susceptibility to gain weight (including post-partum adolescents, for example, the risks of some contraceptives, particularly
African Americans, Maori and Navajo Indians) and that these combined hormonal methods, may outweigh the benefits. Obesity
groups often feature in studies of DMPA (Westhoff, 2003). A 5 is one such condition, but additionally being overweight contributes
year prospective study of 103 Brazilian women using DMPA to a list of other conditions (such as smoking) which when taken
reported a mean weight increase of 4.3 kg over 5 years, signifi- together substantially increase the risks of CVD. In the WHO
cantly greater than that typical of a control group of IUD users Medical Eligibility Criteria BMI >30 kg/m2 is considered a cate-
(1.8 kg) matched for age and weight at the start of the study gory 2 condition for all combined hormonal methods indicating
(Bahamondes et al., 2001). In contrast a study of Thai women that the methods can generally be used but more careful follow-up
showed no difference between IUD users and DMPA users, both may be required (World Health Organisation, 2004). The British
gaining approximately 8 kg over 10 years (Taneepanichskul et al., National Formulary regards a BMI of >39 kg/m2 as an absolute
1998). A very recent well-designed study from the United States contraindication to the combined pill. Using the UK Mediplus and
demonstrated a mean increase of 6.1 kg in weight and 24% in General Practice Research databases to identify women with
body fat after 30 months of starting Depo Provera (Clark et al., venous thromboembolism while exposed to the combined oral
2005). contraceptive pill, Nightingale et al. (2000) identified a significant
Most studies of contraceptive implants show an average association with a BMI of over 25 kg/m2 (Nightingale et al.,
increase in weight of 0.4–1.5 kg/year (Brache et al., 2002) but a 2000). The association rose dramatically among women with a
controlled study comparing Norplant users with IUD users dem- BMI > 35 kg/m2.
onstrated no difference between the two groups (Sivin, 1983). An association between weight and safety applies mainly to
combined hormonal contraception; however, a study of over 9000
The influence of weight on contraceptive efficacy
women undergoing sterilization identified obesity as an independent
Hormonal contraceptives, like most drugs, are administered at the risk factor for significant complications (OR = 1.7; CI = 1.2–2.6)
same dose regardless of the weight or BMI of the user. There are (Jamieson et al., 2000).
data to suggest that the efficacy of some methods may be reduced
when used by overweight women. Several mechanisms can be
Conclusions
hypothesized, simple dilution of the steroids in a larger blood vol-
ume, sequestration of steroids in fat cells or different metabolism While deprivation and undernutrition are major causes of disease
of steroids by obese women. In a retrospective cohort analysis of and death in developing countries, eating disorders and obesity are
755 randomly selected women in Washington State, women the nutrition problems most likely to interfere with reproduction in
weighing over 70.5 kg had a significantly increased risk of oral developed countries. Because preservation of female energy expend-
contraceptive failure (RR1.6, 95% CI = 1.1,2.4) compared with iture for reproduction is essential, appetite and the reproductive
203
axis are closely linked to nutritional status. As a safeguard against Practical recommendations for preventive intervention
untimely reproduction due to undernutrition, ovarian activity is (i) Medical education for doctors on the art of preventing obes-
suppressed in women with eating disorders and exercise amenor- ity and managing weight loss in women with established over-
rhoea through pathways in the hindbrain. It is the balance between weight and obesity.
energy consumption and utilization that is crucial more than the (ii) Patient education regarding the role of obesity in reproduction.
body fat mass, thus recovery of ovulation may occur after a small (iii) Promotion of fitness and healthy living for the woman, her
percentage gain in weight. partner and their future family. The emphasis should be on reduc-
The combined prevalence of bulimia nervosa and anorexia ner- ing central adiposity and improving metabolic fitness rather than
vosa is approximately 5% among women of reproductive age, simply on weight and BMI reduction.
and the likelihood of cure is higher with bulimia nervosa. Both (iv) Long-term weight control. It is useless to have a short term
disorders suppress ovulation in severely affected women and very low-calorie diet that fails to induce results in several months
account for up to 60% of women with anovulatory infertility. time.
Pregnancy among underweight women increases the risk of pre- (v) Reduced calorie diets are more important than dietary com-

mature labour. position.
Obesity and its related problems to day are major issues. (vi) Checks for metabolic disorders at the start and at regular
In Western countries among women the obesity rate range is intervals are essential for obese women with PCOS or any other
from about 10–25% and is increasing through mechanisms that obesity-related reproductive disorder.
include genetic, biological, psychological and social factors. (vii) Psychological advice. This is helpful for those committed
The thrifty gene hypothesis may explain why obesity used to be to a long-term change in lifestyle and is often best provided
an advantage in famine conditions but has turned into a disadvan- through group therapy among women with similar problems who
tage in modern society. Nature’s answer may be sub-fertility and meet together on a regular basis.
increased pregnancy complications in essence a natural selection The relationship between contraception and weight is complex
in favour of a profligacy gene. and influences method choice and continuation, efficacy, side effects
Social determinants for obesity are clearly operating and and safety. Since the incidence of obesity is increasing worldwide
results in a much higher prevalence of obesity among the (nearly one third of all Americans are obese), this relationship is
socially disadvantaged. Maternal obesity is a strong predictor becoming increasingly relevant. There is a danger that women and
of offspring obesity but the relationship is complex since the their healthcare professionals loose sight of the fact that contracep-
infant who have been restrained in utero tend to gain weight tion is designed to prevent unwanted pregnancy. Fat women get
and to have more fat mass in childhood. The world-wide pregnant and obesity is associated with an increased risk of compli-
increase in maternal weight is of great public health concern cations for both the mother and the baby. It is vital that concern
and provides further support for the planning of prevention about the relative risk of contraceptive failure and of serious side
strategies aimed at reducing the current trend to large birth- effects does not overshadow the small absolute risks. It is important
weight babies. too for women to understand that weight gain is extremely common
In countries where smoking prevalence has decreased, over- and seldom due to the method of contraception they are using.
weight and obesity may be the most important risk factor for poor
pregnancy outcomes.
Fat tissue is metabolically active and its most important activity Acknowledgements
is intrafat modifications of steroid hormones and secretion of adi-
The secretarial assistance of Mrs Simonetta Vassallo is gratefully
pokines. Many of these factor influences are reproductive hor- acknowledged.
mones, but in turn the secretions of the fat can affect the
functioning of the reproductive system.
Many obese women conceive and go through pregnancy with- References
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Human Reproduction Update, Vol.12, No.3 pp. 193–207, 2006 doi:10.

Nutrition and reproduction in women

The ESHRE Capri Workshop Group1

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Key words: contraception/miscarriage/nutrition/obesity/reproduction

Introduction disorders and obesity), although obesity is on the increase even in

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developed countries it is most commonly found in women with

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Menstruation Risk of menstrual dysfunction:

Infertility Risk of ovulatory and anovulatory 50

0.4% in obese women (95% CI = 0.1–0.7) compared with 0.1% in

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