Infertility: a marker of future health

risk in women?
Suneeta Senapati, M.D., M.S.C.E
Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania
Perelman School of Medicine, Philadelphia, Pennsylvania

Infertility, may be a harbinger for future health risk in women, including early mortality. Fertility status itself could serve as an early
biomarker, (present in a woman's reproductive years) for risk stratification later in life. The relationship between infertility and early
mortality involves the impact of nulliparity on future adverse health events, potential sequelae from the underlying cause(s) of infer-
tility, the risks of fertility treatments, as well as the potential for risk reduction from a healthy pregnancy. This complex interplay
coupled with difficulties ascertaining infertility on a population level has presented unique challenges to assessing infertility and early
mortality risk. With further study, a better understanding the role of fertility status in health at various stages of life may provide unique
opportunities for surveillance and risk reduction. (Fertil SterilÒ 2018;110:783–9. Ó2018 by American Society for Reproductive
Medicine.)
Key Words: Infertility, IVF, mortality, cardiovascular risk, cancer

Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/38187-26725

F
ertility has long been associated The interplay between fertility, women <35 years-old, and for at least
with vitality, longevity, and gen- parity, and long-term health is complex 6 months in women R35 years-old).
eral well-being. While Kirk- and multi-faceted. While we have While the association between nulli-
wood's Disposal Soma Theory and looked to historical population cohorts parity and mortality has been exam-
William's antagonistic pleiotropy hy- to analyze birth and mortality trends, ined, the assumption that nulliparity
pothesis both postulate a tradeoff be- with the advent of assisted reproductive is an appropriate surrogate for infer-
tween fertility and longevity (1, 2) technologies in the 20th century, pat- tility is overly simplistic. An examina-
humans appear to have superceded terns in family building have shifted, tion of in the association of infertility
expectations with multiple cohort and and with it, the ripple effect on long- and early mortality involves consider-
population-based studies suggesting a term health in both women and men re- ation of not only of the impact of nulli-
positive correlation between fertility mains to be seen. A better understand- parity on future adverse health events,
and longevity in both historical and ing of this relationship between fertility but also potential sequelae from the un-
contemporary settings (3). Just as status and future health risk is critical derlying cause(s) of infertility, the risks
fertility may be a marker of longevity as more women seek guidance to un- of fertility treatments, as well as the po-
for women, infertility, may be a derstand their fertility and general tential for risk reduction from a healthy
harbinger for future health risk, health status, and as the generation of pregnancy. Indeed, understanding the
including early mortality. While there children born after IVF come to adult- role of fertility status in health at
are multiple contributors to health sta- hood and move through their reproduc- various stages of life may provide
tus including genetics, epigenetics, tive years. To date, there are no studies unique opportunities for surveillance
environmental influences, concomitant that examine the relationship between and risk reduction.
co-morbidities, and lifestyle factors, infertility and mortality on a popula- Perturbations in both female (4)
fertility status itself could serve as an tion level likely due to challenges as- and male (5–7) reproductive function
early biomarker, (present in a woman's certaining infertility as the exposure have been linked to cancer,
reproductive years) for risk stratifica- of interest (defined as attempting cardiovascular disease, and mortality.
tion later in life. conception for at least 12 months in Several epidemiological studies have
suggested that nulliparity is associated
with an increased risk of all-cause mor-
Received July 28, 2018; revised August 26, 2018; accepted August 27, 2018.
S.S. has nothing to disclose. tality (8–13). A recent meta-analysis
Correspondence: Suneeta Senapati, M.D., M.S.C.E., Penn Fertility Care, University of Pennsylvania, of 18 studies including 2,813,481
3701 Market St, Ste 800, Philadelphia, PA 19104 (E-mail: suneeta.senapati@uphs.upenn.edu).
participants demonstrated a pooled
Fertility and Sterility® Vol. 110, No. 5, October 2018 0015-0282/$36.00 relative risk of all-cause mortality of
Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. 1.19 (95% confidence interval [CI]
https://doi.org/10.1016/j.fertnstert.2018.08.058

VOL. 110 NO. 5 / OCTOBER 2018 783

VIEWS AND REVIEWS
1.03–1.38) among nulliparous women compared to those with
1 or more live births (4). These findings are likely driven by the
increased risk of cardiovascular disease-related death
observed amongst nulliparous women when compared to
their parous counterparts (hazard ratio 2.43, 95% CI 1.49–
3.96) (13). As cardiovascular disease is intimately related to
circulating levels of reproductive hormones as well as hor-
mone replacement (14) it is plausible that unique disruptions
of these hormones by disease processes that lead to infertility,
and for some, unintended nulliparity, may explain the unique
risk of cardiovascular disease-related mortality observed.
Beyond cardiovascular health, abnormal estrogen and pro-
gesterone profiles have been implicated in hormone-
sensitive cancers including breast, ovarian, and endometrial
cancer (15–18); thus, it is likely that altered profiles
observed amongst nulliparous women may be implicated in
cancer-related mortality. Additionally, nulliparity has been
associated with limitation of activity for health reasons and
faster acquisition of those limitations suggesting an adverse
effect on functional status in addition to specific disease pro-
cesses (19). It is plausible that the relative risks attributable to
nulliparity and infertility are different depending upon the
underlying etiology of why a woman may have chosen not
to bear children versus been unable to bear children due to
either lack of access to treatment or unsuccessful treatment.
As nulliparity is a state that describes a heterogenous cross-
section of the population and may include heterosexually
partnered women who have elected to not have children,
women who are not in a relationship with a male partner,
transgender female-to-male as well those with a history of
infertility, it is important to consider both parity and fertility
status as related but potentially independent contributors to
the assessment of future health risk. In an interesting parallel
to these findings, several studies have observed an association
between later maternal age at birth and exceptional
longevity. An analysis of New England Centenarian Study
cohort demonstrated that women who gave birth to a child af-
ter the age of 40 had four times greater odds of being a cente-
narian compared to women from the same birth cohort who
had their last child at younger ages (20). A nested case-
control study using Long Life Family Study data found that
women who had their last child beyond the age of 33 years
had twice the odds of survival to the top 5th percentile of sur-
vival of their birth cohorts compared to women who had their
last child by 29 years of age (odds ratio [OR] 2.08, 95%CI
1.13–3.92 for age between 33 and 37 years and OR 1.92,
95% CI 1.03–3.68 for age>37 years) (21). In contrast an anal-
ysis of over 20,000 women from the Women's Health Initia-
tive cohort demonstrated that while odds of longevity were
significantly higher in women with later age at first childbirth
(adjusted OR 1.11, 95% CI 1.02–1.21 for age 25 years or older
vs. younger than 25 years) there was no difference in
longevity based on age at last birth (22). While some have in-
terpreted these findings to suggest that pregnancy at
advanced maternal ages is not only possible, but may be asso-
ciated with increased longevity, it should be noted that these
studies were performed amongst women in population-based
cohorts and may not reflect the longevity or health status of
women who have pregnancies at advanced maternal ages
784
made possible by fertility treatments; certainly, further study
of in contemporary cohorts are needed to understand these
associations.
To understand the mechanisms of infertility's potential
association with early mortality one need only look to the
most common causes of infertility for biologic plausibility.
There are several pathologic processes associated with
infertility whose systemic effects can lead to chronic
morbidity and adverse events later in life. Indeed, amongst
the most common causes of infertility including polycystic
ovary syndrome (PCOS), endometriosis, fibroids, and dimin-
ished ovarian reserve there are disruptions in systemic path-
ways that may be implicated in future morbidity. PCOS is
the most common endocrine disorder amongst women of
reproductive age and is associated with chronic anovula-
tion, androgen excess, and metabolic perturbations (23).
Women with PCOS, as compared with age- and body mass
index-matched women without the syndrome, appear to
have a higher risk of insulin resistance, hyperinsulinemia,
glucose intolerance, dyslipidemia, and an increased pro-
thrombotic state, possibly resulting in a higher rate of
type 2 diabetes mellitus, fatty liver disease, subclinical
atherosclerosis, vascular dysfunction, obstructive sleep ap-
nea, cardiovascular disease, and endometrial hyperplasia
(24). Interestingly, in a United Kingdom cohort study of
women with PCOS, while there was an increased risk of
death from diabetes (OR 3.6, 95% CI 1.5–8.4, there was no
difference in all-cause mortality noted (standardized mor-
tality ratio 0.90, 95% CI 0.69–1.17). Notably, this was rela-
tively small cohort (data based on 59 deaths) suggesting
there may have been insufficient sample size to detect
meaningful associations (25).
Similar correlations with systemic disease have been sug-
gested in endometriosis and uterine fibroids. Endometriosis, a
chronic benign gynecologic disease characterized by endo-
metrial glands and stroma present outside the uterine lining,
affects 10% of women and is a major cause of chronic pelvic
pain and infertility (26, 27). Both underlying inflammation
and molecular alterations of multiple organ systems have
been implicated in the role of endometriosis in other
chronic diseases (28). Endometriosis has been associated
cardiovascular risk factors including increased endothelial
dysfunction and atherosclerosis (29, 30). Additionally,
endometriosis has been linked to an increased risk of
certain subtypes of ovarian cancer (specifically
endometrioid and clear cell ovarian carcinoma) (16, 31).
Interestingly, while several reports have hypothesized a
potential link between endometriosis and cardiovascular
risk, there are no studies that have interrogated these
questions on a population level. Similarly, uterine fibroids
(also known as leiomyomas or myomas) are benign uterine
tumors with an estimated incidence of 20% to 40% in
women during their reproductive years (32). More than 70%
of women with symptomatic fibroids will report symptoms
of heavy menstrual bleeding, and are these women are 2.3
times more likely to experience chronic anemia than
women without fibroids (33). As chronic anemia has been
associated with an increased risk of mortality from acute
coronary syndromes, stroke, and all cause-mortality, fibroids
VOL. 110 NO. 5 / OCTOBER 2018

maybe associated with an increased risk for all-cause mortal-
ity for women later in life (34–36).
Finally, as early menopause has been linked to increased
risk of osteoporosis and cardiovascular disease, diminished
ovarian reserve and premature ovarian insufficiency may be
associated with increased risk of early mortality. Diminished
ovarian reserve which is diagnosed based on high follicle
stimulating hormone levels, low antim€ ullerian hormone
levels, low antral follicle count, or poor response to fertility
treatment (37), is thought to be on a spectrum of ovarian
dysfunction that may culminate in premature ovarian insuf-
ficiency for some women (38–40). While most women
experience menopause between the ages of 45 and 55 years,
approximately 5% of women will enter menopause between
the ages of 40 and 45 years, and 1% of women will enter
menopause before the age of 40 (41, 42). With respect to
osteoporosis-related fracture risk, the data are inconsistent
and time-dependent. While early menopause compared to
natural menopause is associated with an increase in fracture
rates compatible with the associated bone loss (43, 44) one
cohort study demonstrated 50% more fractures with early
menopause until 70 years old, while another suggested
increased fracture risk only after age 70 years (45, 46). With
respect to cardiovascular health, multiple studies have
demonstrated that menopause before 45 years is associated
with increased risk of cardiovascular disease (47), angina
(48), heart failure (49), and early mortality (50, 51). Notably,
much of the data regarding early menopause and
cardiovascular risk is extrapolated from studies including
women with surgical menopause which may be a different
pathogenic process than the more indolent diminished
ovarian reserve or premature ovarian insufficiency. While
hormone replacement therapy in women with premature
ovarian insufficiency has been shown to restore endothelial
dysfunction and reduce the impact of relative estrogen
deficiency on bone health (52, 53), the impact on early
mortality has not been well established. Furthermore, while
diminished ovarian reserve has been shown to correlate
with markers of cardiovascular disease risk (54, 55) the
association of diminished ovarian reserve with
cardiovascular events and early mortality has not been
established. Indeed, this will become increasingly relevant
in the era of direct-to-consumer medical testing, as more
women both with and without a history of infertility seek
fertility testing. Further study of the role of surrogates for
ovarian reserve as biomarkers for future health risk with
consideration of infertility and parity is warranted to identify
which women with infertility or abnormal parameters may be
at greatest risk.
Beyond individual infertility diagnoses, it is important to
consider the temporal effect of a pathogenic process on the
development of disease later in life. Ideally, a screening test
for detection or surveillance of disease should be inexpensive,
easy to administer/detect, reliable, valid, and detect disease in
a pre-clinical phase to have greatest utility. Having a marker
of future disease like fertility status that manifests well before
the onset of disease, may offer a unique opportunity for sur-
veillance and potential risk reduction. A systematic review
integrating genomics and data from the literature to analyze
VOL. 110 NO. 5 / OCTOBER 2018
Fertility and Sterility®
common genes and molecular mechanisms shared by diseases
demonstrated that known causes of infertility not only share
particular genes and/or molecular pathways with other dis-
ease processes associated with long-term morbidity, but
they have distinct clinical relationships with other diseases
appearing after infertility is manifested. These relationships
include but are not limited to: an association between osteo-
porosis, mood disorders, dementia, and premature ovarian
failure; breast/ovarian cancer and diminished ovarian
reserve, specifically in those with BRCA1/2 mutations;
ovarian cancer (clear cell, endometrioid, and low-grade se-
rous), melanoma, and non-Hodgkin's lymphoma and endo-
metriosis; and endometrial/ovarian cancer and unexplained
infertility (56). These findings were the result of a novel
approach that aims to search common pathogenic mecha-
nisms that link diseases together in a single meta-disease
instead of the traditional approach of splitting phenotypes
attributable to sequence variation in the human genome
and specific environmental influences) into discrete disease
entities. As such, the findings, while intriguing, are largely
hypothesis generating, and require validation from larger
studies. Thus, while there is a dearth of population-based
data on the long-term outcomes of women with infertility
and its underlying causes, there is convincing biologic plau-
sibility for increased risk of early mortality attributable to
infertility. Further population-based studies are needed to
better characterize this potential risk.
The 21st century has also seen a shift in population trends
in family building as well as utilization of assisted reproduc-
tive technologies which may have a profound impact on pop-
ulation health in the years to come. In 2017 the Center for
Disease Control reported that 2016 had the lowest fertility
rate since the inception of the National Vital Statistics System
with an overall fertility rate of 62.0 births per 1,000 women
ages 15 to 44 (57). While these findings were largely driven
by a decline in birthrates amongst adolescents and women
in the third decade of life, rising birthrates amongst women
in the 4th and 5th decade of life were also noted, reflecting
the shifting characteristics of women giving birth in the
U.S. Paralleling these trends has been an uptick in utilization
of fertility services including assisted reproductive technolo-
gies. In data from the National Survey of Family Growth
(1982-2010) 12% of women 15-44 in the US reported utilizing
fertility services (58); indeed, this assessment is likely an un-
derestimate of the true burden of infertility as a disease due to
the underlying challenges of access to care and services for
women with infertility (59). The reasons for pursuing fertility
treatment are vast and include medical diagnoses (diminished
ovarian reserve, endometriosis, PCOS, hypothalamic amenor-
rhea, tubal factor resulting from prior infections/inflamma-
tion, male factor, recurrent pregnancy loss, etc), fertility
preservation, and pre-implantation genetic testing for peri-
conception genetic risk reduction. Notably, the birth rate
among women R35 years has increased to 3.5-fold for sin-
gletons, and 4-fold for multiple pregnancies, the latter largely
attributable to a rise in utilization of assisted reproductive
technologies (60). While women who deliver later in life are
more likely to be better educated, have private health insur-
ance, and begin prenatal care earlier in pregnancy than their
785
VIEWS AND REVIEWS
younger peers, they are also more likely to be overweight/
obese, have pre-existing medical conditions, and develop
pregnancy complications, some of which (ie. gestational dia-
betes, pre-eclampsia) may have a long-term impact (61–65). It
is likely that these population trends may extend to those
seeking fertility care; indeed, those with infertility may
present as a uniquely susceptible subpopulation in whom
both the absence of pregnancy and parity, once achieved,
can alter the trajectory of future health.
Several studies have sought to determine the risk of
fertility treatments on long-term health. While there is a po-
tential impact of ovarian stimulation on vascular health due
to venous thromboembolic risk, the risks of ovarian hyper-
stimulation syndrome (66), and surgical complications of
oocyte retrieval including hemorrhage or surgical injury,
these events are uncommon (<1%) and thus the burden on
long-term health is likely minimal. As such, the preponder-
ance of concern has been focused on risks of ovarian cancer
related to fertility medications. Concerns were initially raised
in the 1990s with two studies that demonstrated an increased
risk of invasive ovarian cancer associated with fertility medi-
cation use (67, 68). Subsequent analyses including a meta-
analysis of nine cohort studies with over 100,000 patients
compared the ovarian cancer risk in women receiving fertility
treatment with that in an infertile reference group and the
general population and demonstrated that ovarian cancer
risk in women receiving fertility treatment was increased
compared to the general population (relative risk [RR] 1.50,
95% CI 1.17–1.92), but similar to that of the infertile reference
group (RR 1.26, 95% CI 0.62–2.55) (69). These findings sug-
gest it is more likely the underlying infertility or cause thereof
as opposed to the treatment that may be implicated in inva-
sive ovarian cancer risk. With respect to borderline ovarian
cancers, several studies have demonstrated a significant asso-
ciation between fertility medication utilization and borderline
ovarian cancer with standardized incidence ratios ranging
from 1.79 (95% CI 1.16–2.56) to 3.3 (95% CI 1.1–7.8)
(67, 70, 71) while a recent case-cohort study of over 96,000
subfertile women found no association between borderline
ovarian cancer and fertility medication use (RR 1.00, 95%
CI 0.67–1.51) (72, 73). The discrepancy amongst studies is
likely due to inherent challenges in studying long-term health
including study design (choice of controls, follow-up time,
appropriate consideration of confounding by reproductive
characteristics like parity and concomitant diseases) as well
as the relatively low prevalence of disease with long incuba-
tion period to disease diagnosis. Additionally, what is un-
known, is whether these cases were the ultimate cause of
mortality, and if so, were they associated with earlier mortal-
ity compared to fertile controls.
Importantly, the success of fertility treatments also has a
potential impact on long-term health that is highly dependent
on the definition of ‘‘success.’’ While conventional fertility
treatment outcomes focus on the chances of ongoing preg-
nancy or live birth per initiated cycle or embryo transfer as
the primary metric of success, a growing body of evidence
suggests that some pregnancies after fertility treatments
may be associated with an increased risk of adverse perinatal
outcomes including preterm birth and pre-eclampsia (74–80).
786
Indeed, several studies have noted an increased risk of pre-
eclampsia in both fresh embryo transfers (81, 82) and twin
frozen embryo transfers amongst those with polycystic
ovary syndrome (83). While early studies suggested this
phenomenon may be attributable to the supraphysiologic
hormonal environment seen in fresh embryo transfers, more
recent data implicating an association between pre-
eclampsia and frozen embryo transfers confers added
complexity to our understanding of the impact of IVF on peri-
natal and subsequent maternal outcomes. Pre-eclampsia is
thought to be a disorder of endothelial dysfunction superim-
posed on pre-existing circulatory, metabolic, or immunologic
abnormalities specific to pregnancy and the postpartum
period, it has also been associated with a 2- to 7-fold increase
risk of ischemic heart disease, stroke, arrhythmias, heart fail-
ure, and an increased risk of mortality compared to those
without a history of pre-eclampsia (RR 1.49, 95% CI 1.05–
2.14) (84). Thus, if a woman conceives after fertility treat-
ments and delivers a preterm infant due to pre-eclampsia,
both she and her child's future health trajectory may be
very different from the woman who with an uncomplicated
delivery at term. To what degree this risk extends to women
with infertility specifically remains to be characterized and
will need require consideration of confounders including
maternal age at birth, gestational number, and concomitant
comorbidities.
In a fascinating paradox, while complications of preg-
nancy can present unique long-term health risks, a healthy
pregnancy, may confer risk reduction for future illness. In a
recent meta-analysis of parity and long-term mortality a
non-linear association between parity and all-cause mortality
was observed such that increased parity was associated with
decreased all-cause mortality with the lowest risk reduction
for all-cause mortality among subjects with 3 to 4 live births
(4). The contemporary predicted model is likely a U-shaped
curve as suggested by Grundy et al. (85), with increased early
mortality risk associated with nulliparity and grand multipar-
ity with early mortality risk reduction observed in women
with two to four children. While the precise mechanisms un-
derlying this observed ‘‘rejuvenation effect’’ of pregnancy are
unknown, animal models suggest that hormonal changes in
early pregnancy may result in molecular changes that stabi-
lize p53, allowing it to repair cumulative DNA damage and
prevent cellular proliferation induced by carcinogens (86).
Furthermore, high levels of endogenous estrogens such as
those present during pregnancy and in preparation for lacta-
tion stimulates terminal differentiation of mammary gland
stem cells rendering breast epithelium resistant to carcino-
genesis, a protective effect that is increased with each subse-
quent pregnancy (87, 88). Thus, while infertility may be
associated with increased risk of future morbidity, treating
infertility in a way that supports delivery of a healthy
pregnancy at term may confer risk reduction for future
morbidity and early mortality. Thus, treating infertility with
attention to both pregnancy rates and potential perinatal
outcomes may improve health status overall.
There is no doubt that our field has made tremendous
strides in the management of infertility in the past 40 years.
Increasing awareness and acceptance of infertility as a
VOL. 110 NO. 5 / OCTOBER 2018

distinct disease process will facilitate access to care and help
identify women with current health care needs as well as po-
tential future health risks. Admittedly, given the relatively
nascent status of IVF technologies and their application in
the reproductive years, we are only starting to learn about
the long-term effects of infertility and its treatments. As we
celebrate in vitro fertilization's 40th birthday, the continued
pursuit of understanding role that infertility plays beyond
the reproductive years is imperative, as it will be increasingly
important to women's health care in the future.
REFERENCES
1. Lithgow GJ, Kirkwood TB. Mechanisms and evolution of aging. Science
1996;273:80.
2. Williams G. Pleiotropy, natural selection, and the evolution of sensescence.
Evolution 1957;11:398–411.
3. Mitteldorf J. Female fertility and longevity. Age 2010;32:79–84.
4. Zeng Y, Ni ZM, Liu SY, Gu X, Huang Q, Liu JA, et al. Parity and all-cause mor-
tality in women and men: a dose-response meta-analysis of cohort studies.
Sci Rep 2016;6:19351.
5. Capogrosso P, Ventimiglia E, Boeri L, Cazzaniga W, Chierigo F, Montorsi F,
et al. Male infertility as a proxy of the overall male health status. Minerva Urol
Nefrol 2018;70:286–99.
6. Eisenberg ML, Li S, Behr B, Cullen MR, Galusha D, Lamb DJ, et al. Semen
quality, infertility and mortality in the USA. Hum Reprod 2014;29:1567–74.
7. Latif T, Kold Jensen T, Mehlsen J, Holmboe SA, Brinth L, Pors K, et al. Semen
Quality as a predictor of subsequent morbidity: a Danish cohort study of
4,712 men with long-term follow-up. Am J Epidemiol 2017;186:910–7.
8. Barclay K, Keenan K, Grundy E, Kolk M, Myrskyla M. Reproductive history
and post-reproductive mortality: a sibling comparison analysis using Swed-
ish register data. Soc Sci Med 2016;155:82–92.
9. Jaffe DH, Eisenbach Z, Manor O. The effect of parity on cause-specific mor-
tality among married men and women. Matern Child Health J 2011;15:
376–85.
10. Jacobsen BK, Knutsen SF, Oda K, Fraser GE. Parity and total, ischemic heart
disease and stroke mortality. The Adventist Health Study, 1976-1988. Eur J
Epidemiol 2011;26:711–8.
11. Cooper GS, Baird DD, Weinberg CR, Ephross SA, Sandler DP. Age at meno-
pause and childbearing patterns in relation to mortality. Am J Epidemiol
2000;151:620–3.
12. Simons LA, Simons J, Friedlander Y, McCallum J. Childbearing history and
late-life mortality: the Dubbo study of Australian elderly. Age Ageing
2012;41:523–8.
13. Jaffe DH, Neumark YD, Eisenbach Z, Manor O. Parity-related mortality:
shape of association among middle-aged and elderly men and women.
Eur J Epidemiol 2009;24:9–16.
14. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C,
Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results From the Women's Health Initia-
tive randomized controlled trial. JAMA 2002;288:321–33.
15. Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids 2013;78:782–5.
16. Kim HS, Kim TH, Chung HH, Song YS. Risk and prognosis of ovarian cancer
in women with endometriosis: a meta-analysis. Br J Cancer 2014;110:
1878–90.
17. Kim JJ, Kurita T, Bulun S. progesterone action in endometrial cancer, endo-
metriosis, uterine fibroids, and breast cancer. Endocr Rev 2013;34:130–62.
18. Yue W, Wang J, Li Y, Fan P, Liu G, Zhang N, et al. Effects of estrogen on
breast cancer development: role of estrogen receptor independent mecha-
nisms. Int J Cancer 2010;127:1748–57.
19. Read S, Grundy E, Wolf DA. Fertility history, health, and health changes in
later life: a panel study of British women and men born 1923-49. Popul
Stud 2011;65:201–15.
20. Perls TT, Alpert L, Fretts RC. Middle-aged mothers live longer. Nature 1997;
389:133.
VOL. 110 NO. 5 / OCTOBER 2018
Fertility and Sterility®
21. Sun F, Sebastiani P, Schupf N, Bae H, Andersen SL, McIntosh A, et al.
Extended maternal age at birth of last child and women's longevity in the
Long Life Family Study. Menopause 2015;22:26–31.
22. Shadyab AH, Gass ML, Stefanick ML, Waring ME, Macera CA, Gallo LC,
et al. Maternal age at childbirth and parity as predictors of longevity among
women in the United States: The Women's Health Initiative. Am J Public
Health 2017;107:113–9.
23. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS.
Scientific statement on the diagnostic criteria, epidemiology, pathophysi-
ology, and molecular genetics of polycystic ovary syndrome. Endocr Rev
2015;36:487–525.
24. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, et al. Cardi-
ometabolic aspects of the polycystic ovary syndrome. Endocr Rev 2012;33:
812–41.
25. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of
women with polycystic ovary syndrome at long-term follow-up. J Clin Epide-
miol 1998;51:581–6.
26. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De
Bie B, et al. ESHRE guideline: management of women with endometriosis.
Hum Reprod 2014;29:400–12.
27. Practice Committee of the American Society for Reproductive M.
Endometriosis and infertility: a committee opinion. Fertil Steril 2012;98:
591–8.
28. Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L, et al. Endome-
triosis: a high-risk population for major chronic diseases? Hum Reprod Up-
date 2015;21:500–16.
29. Santoro L, D'Onofrio F, Campo S, Ferraro PM, Tondi P, Campo V, et al. Endo-
thelial dysfunction but not increased carotid intima-media thickness in
young European women with endometriosis. Hum Reprod 2012;27:
1320–6.
30. Santoro L, D'Onofrio F, Flore R, Gasbarrini A, Santoliquido A. Endometriosis
and atherosclerosis: what we already know and what we have yet to
discover. Am J Obstet Gynecol 2015;213:326–31.
31. Wang C, Liang Z, Liu X, Zhang Q, Li S. The association between endometri-
osis, tubal ligation, hysterectomy and epithelial ovarian cancer: meta-ana-
lyses. Int J Environ Res Public Health 2016;13.
32. Bulun SE. Uterine fibroids. N Eng J Med 2013;369:1344–55.
33. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic
burden of uterine fibroids among women in the United States: findings
from a cross-sectional survey analysis. Int J Womens Health 2017;9:
403–11.
34. Lawler PR, Filion KB, Dourian T, Atallah R, Garfinkle M, Eisenberg MJ. Ane-
mia and mortality in acute coronary syndromes: a systematic review and
meta-analysis. Am Heart J 2013;165:143–53.e145.
35. Lee G, Choi S, Kim K, Yun JM, Son JS, Jeong SM, et al. Association of hemo-
globin concentration and its change with cardiovascular and all-cause mor-
tality. J Am Heart Assoc 2018;7(3):1–9.
36. Barlas RS, Honney K, Loke YK, McCall SJ, Bettencourt-Silva JH, Clark AB,
et al. Impact of hemoglobin levels and anemia on mortality in acute stroke:
analysis of UK Regional Registry Data, Systematic Review, and Meta-Anal-
ysis. J Am Heart Assoc 2016;5:1–16.
37. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L,
et al. ESHRE consensus on the definition of 'poor response' to ovarian stim-
ulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011;26:
1616–24.
38. Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian reserve, premature
ovarian failure, poor ovarian responder–a plea for universal definitions. J
Assist Reprod Genet 2015;32:1709–12.
39. Verit FF, Yildiz Zeyrek F, Zebitay AG, Akyol H. Cardiovascular risk may be
increased in women with unexplained infertility. Clin Exp Reprod Med
2017;44:28–32.
40. Tani A, Yamamoto S, Maegawa M, Kunimi K, Matsui S, Keyama K, et al.
Arterial stiffness is increased in young women with endometriosis. J Obstet
Gynaecol Journal Inst Obstetrics Gynaecol 2015;35:711–5.
41. Miro F, Parker SW, Aspinall LJ, Coley J, Perry PW, Ellis JE. Sequential classifi-
cation of endocrine stages during reproductive aging in women: the
FREEDOM study. Menopause 2005;12:281–90.
787
VIEWS AND REVIEWS
42. Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature meno-
pause in a multi-ethnic population study of the menopause transition.
Hum Reprod 2003;18:199–206.
43. Vega EM, Egea MA, Mautalen CA. Influence of the menopausal age on the
severity of osteoporosis in women with vertebral fractures. Maturitas 1994;
19:117–24.
44. van der Klift M, de Laet CE, McCloskey EV, Johnell O, Kanis JA, Hofman A,
et al. Risk factors for incident vertebral fractures in men and women: the Rot-
terdam Study. J Bone Miner Res Official Journal Am Soc Bone Mineral Res
2004;19:1172–80.
45. Gardsell P, Johnell O, Nilsson BE. The predictive value of bone loss for
fragility fractures in women: a longitudinal study over 15 years. Calcif Tissue
Int 1991;49:90–4.
46. van Der Voort DJ, van Der Weijer PH, Barentsen R. Early menopause:
increased fracture risk at older age. Osteoporos Int 2003;14:525–30.
47. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk
of cardiovascular disease: the Framingham study. Ann Intern Med 1976;85:
447–52.
48. Parashar S, Reid KJ, Spertus JA, Shaw LJ, Vaccarino V. Early menopause pre-
dicts angina after myocardial infarction. Menopause 2010;17:938–45.
49. Ebong IA, Watson KE, Goff DC Jr, Bluemke DA, Srikanthan P, Horwich T,
et al. Age at menopause and incident heart failure: the Multi-Ethnic Study
of Atherosclerosis. Menopause 2014;21:585–91.
50. Parker WH, Feskanich D, Broder MS, Chang E, Shoupe D, Farquhar CM,
et al. Long-term mortality associated with oophorectomy compared with
ovarian conservation in the nurses' health study. Obstet Gynecol 2013;
121:709–16.
51. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature
menopause or early menopause: long-term health consequences. Maturitas
2010;65:161–6.
52. Cartwright B, Robinson J, Seed PT, Fogelman I, Rymer J. Hormone replace-
ment therapy versus the combined oral contraceptive pill in premature
ovarian failure: a randomized controlled trial of the effects on bone mineral
density. J Clin Endocrinol Metab 2016;101:3497–505.
53. Kalantaridou SN, Naka KK, Papanikolaou E, Kazakos N, Kravariti M,
Calis KA, et al. Impaired endothelial function in young women with prema-
ture ovarian failure: normalization with hormone therapy. J Clin Endocrinol
Metab 2004;89:3907–13.
54. Chu MC, Rath KM, Huie J, Taylor HS. Elevated basal FSH in normal cycling
women is associated with unfavourable lipid levels and increased cardiovas-
cular risk. Hum Reprod 2003;18:1570–3.
55. Pal L, Bevilacqua K, Zeitlian G, Shu J, Santoro N. Implications of diminished
ovarian reserve (DOR) extend well beyond reproductive concerns. Meno-
pause 2008;15:1086–94.
56. Tarin JJ, Garcia-Perez MA, Hamatani T, Cano A. Infertility etiologies are
genetically and clinically linked with other diseases in single meta-diseases.
Reprod Biol Endocrinol 2015;13:31.
57. Hamilton BEMJ, Martin JA, Osterman MJK, Driscoll AK, Rossen LM. Births:
Provisional data for 2016. Vital statistics rapid release, No. 2. Hyattsville,
MD: National Center for Health Statistics; 2017. Available at: https://
www.cdc.gov/nchs/data/vsrr/report002.pdf.
58. Chandra A, Copen CE, Stephen EH. Infertility service use in the United
States: data from the National Survey of Family Growth, 1982-2010. Natl
Health Stat Rep 2014:1–21.
59. Harris JA, Menke MN, Haefner JK, Moniz MH, Perumalswami CR.
Geographic access to assisted reproductive technology health care in the
United States: a population-based cross-sectional study. Fertil Steril 2017;
107:1023–7.
60. Adamson GD, Tabangin M, Macaluso M, deMouzon J. The number of ba-
bies born globally after treatment with assisted reproductive technologies
(ART). Fertil Steril 2013;100:S42.
61. Cain MA, Salemi JL, Tanner JP, Kirby RS, Salihu HM, Louis JM. Pregnancy as a
window to future health: maternal placental syndromes and short-term car-
diovascular outcomes. Am J obstetrics Gynecol 2016;215:484.e1–14.
62. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and
fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:
1213–7.
788
63. Rich-Edwards JW, Fraser A, Lawlor DA, Catov JM. Pregnancy charac-
teristics and women's future cardiovascular health: an underused
opportunity to improve women's health? Epidemiol Rev 2014;36:
57–70.
64. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of
ischaemic heart disease: a retrospective cohort study of 129,290 births. Lan-
cet 2001;357:2002–6.
65. White WM, Mielke MM, Araoz PA, Lahr BD, Bailey KR,
Jayachandran M, et al. A history of preeclampsia is associated with a
risk for coronary artery calcification 3 decades later. Am J Obstet Gy-
necol 2016;214:e511–8.
66. Practice Committee of the American Society for Reproductive Medicine.
Electronic address Aao, Practice Committee of the American Society for
Reproductive Medicine. Prevention and treatment of moderate and severe
ovarian hyperstimulation syndrome: a guideline. Fertil Steril 2016;106:
1634–47.
67. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a
cohort of infertile women. N Eng J Med 1994;331:771–6.
68. Whittemore AS, Harris R, Itnyre J, Halpern J. Characteristics relating to
ovarian cancer risk: collaborative analysis of 12 US case-control studies. I.
Methods. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:
1175–83.
69. Siristatidis C, Sergentanis TN, Kanavidis P, Trivella M, Sotiraki M,
Mavromatis I, et al. Controlled ovarian hyperstimulation for IVF: impact on
ovarian, endometrial and cervical cancer–a systematic review and meta-
analysis. Hum Reprod Update 2013;19:105–23.
70. van Leeuwen FE, Klip H, Mooij TM, van de Swaluw AM, Lambalk CB,
Kortman M, et al. Risk of borderline and invasive ovarian tumours after
ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Re-
prod 2011;26:3456–65.
71. Stewart LM, Holman CD, Finn JC, Preen DB, Hart R. In vitro fertilization is
associated with an increased risk of borderline ovarian tumours. Gynecol
Oncol 2013;129:372–6.
72. Bjornholt SM, Kjaer SK, Nielsen TS, Jensen A. Risk for borderline ovarian tu-
mours after exposure to fertility drugs: results of a population-based cohort
study. Hum Reprod 2015;30:222–31.
73. Asante A, Leonard PH, Weaver AL, Goode EL, Jensen JR, Stewart EA, et al.
Fertility drug use and the risk of ovarian tumors in infertile women: a case-
control study. Fertil Steril 2013;99:2031–6.
74. Ericson A, Kallen B. Congenital malformations in infants born after IVF: a
population-based study. Hum Reprod 2001;16:504–9.
75. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects
after intracytoplasmic sperm injection and in vitro fertilization. N Eng J
Med 2002;346:725–30.
76. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in sin-
gletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;
103:551–63.
77. Klemetti R, Gissler M, Hemminki E. Comparison of perinatal health of chil-
dren born from IVF in Finland in the early and late 1990s. Hum Reprod
2002;17:2192–8.
78. Schieve LA, Ferre C, Peterson HB, Macaluso M, Reynolds MA, Wright VC.
Perinatal outcome among singleton infants conceived through assisted
reproductive technology in the United States. Obstet Gynecol 2004;103:
1144–53.
79. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very
low birth weight in infants conceived with use of assisted reproductive tech-
nology. N Eng J Med 2002;346:731–7.
80. Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, et al.
Assisted reproductive technology and pregnancy outcome. Obstet Gynecol
2005;106:1039–45.
81. Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al.
Peak serum estradiol level during controlled ovarian hyperstimulation is
associated with increased risk of small for gestational age and preeclampsia
in singleton pregnancies after in vitro fertilization. Fertil Steril 2012;97:
1374–9.
82. Imudia AN, Awonuga AO, Kaimal AJ, Wright DL, Styer AK, Toth TL. Elec-
tive cryopreservation of all embryos with subsequent cryothaw embryo
VOL. 110 NO. 5 / OCTOBER 2018

transfer in patients at risk for ovarian hyperstimulation syndrome reduces
the risk of adverse obstetric outcomes: a preliminary study. Fertil Steril
2013;99:168–73.
83. Zhang B, Wei D, Legro RS, Shi Y, Li J, Zhang L, et al. Obstetric complica-
tions after frozen versus fresh embryo transfer in women with polycystic
ovary syndrome: results from a randomized trial. Fertil Steril 2018;109:
324–9.
84. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of
cardiovascular disease and cancer in later life: systematic review and
meta-analysis. BMJ 2007;335:974.
VOL. 110 NO. 5 / OCTOBER 2018
Fertility and Sterility®
85. Grundy E, Tomassini C. Fertility history and health in later life: a record link-
age study in England and Wales. Soc Sci Med 2005;61:217–28.
86. Sivaraman L, Conneely OM, Medina D, O'Malley BW. p53 is a potential
mediator of pregnancy and hormone-induced resistance to mammary carci-
nogenesis. Proc Natl Acad Sci U S A 2001;98:12379–84.
87. Russo J, Hu YF, Silva ID, Russo IH. Cancer risk related to mammary gland
structure and development. Microsc Res Tech 2001;52:204–23.
88. Russo J, Lynch H, Russo IH. Mammary gland architecture as a determining
factor in the susceptibility of the human breast to cancer. Breast J 2001;7:
278–91.
789