Reproduction as a window to future health in women
2023; Elsevier BV; Volume: 120; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2023.01.005
ISSN1556-5653
AutoresAlexandra Huttler, Gayathree Murugappan, N.C. Stentz, Marcelle I. Cedars,
Tópico(s)Ovarian function and disorders
ResumoCultivating awareness for reproduction as a window to future health presents an opportunity for early identification and modification of risk factors that can affect both individual and population-level morbidity and mortality. Infertility could serve as both a window into future health as well as a pathway to future pathology. The underlying mechanisms of infertility may share common pathways with long-term risk for health and well-being. Making this identification early in the disease process may improve opportunities for intervention, and deepen our understanding of long-term risk. Additionally, fertility treatments may increase individual risk. Only by making these associations and designing studies to understand how disease and treatment risk impact health can we truly fulfill our goal of building healthy families. The aim of this review is to discuss the short-term impact of fertility challenges and treatment, long-term associations of infertility with morbidity and mortality, and the role of parity in modifying these risk associations. Cultivating awareness for reproduction as a window to future health presents an opportunity for early identification and modification of risk factors that can affect both individual and population-level morbidity and mortality. Infertility could serve as both a window into future health as well as a pathway to future pathology. The underlying mechanisms of infertility may share common pathways with long-term risk for health and well-being. Making this identification early in the disease process may improve opportunities for intervention, and deepen our understanding of long-term risk. Additionally, fertility treatments may increase individual risk. Only by making these associations and designing studies to understand how disease and treatment risk impact health can we truly fulfill our goal of building healthy families. The aim of this review is to discuss the short-term impact of fertility challenges and treatment, long-term associations of infertility with morbidity and mortality, and the role of parity in modifying these risk associations. Reproduction and health have long been recognized as intimately related, affecting each other in a reciprocal fashion. Many chronic conditions can affect a woman's ability to conceive, whereas reproductive events, including childbirth, can have lasting effects on a woman's health. In this article, we reviewed the short-term impact of fertility challenges and treatment including pregnancy-related morbidity, long-term associations of reproductive health with morbidity and mortality, and the role of parity in modifying these risk associations. Finally, we discuss the value of considering infertility as a vital sign, and the importance of incorporating reproductive history in routine health care encounters to facilitate early identification and modification of risk factors for morbidity and mortality. The relationship between infertility and short-term health can be assessed through evaluation of obstetric complications and maternal morbidity in the pregnancies resulting from treatment of infertility. It has been established that there is an increased risk of adverse obstetric outcomes in pregnancies including both antepartum and postpartum bleeding, placental complications such as abruption and previa, pregnancy-related hypertension, gestational diabetes, and preterm hospital admission (1Romundstad L.B. Romundstad P.R. Sunde A. von Düring V. Skjaerven R. Vatten L.J. Increased risk of placenta previa in pregnancies following IVF/ICSI; a comparison of ART and non-ART pregnancies in the same mother.Hum Reprod. 2006; 21: 2353-2358Crossref PubMed Scopus (230) Google Scholar, 2Stern J.E. Luke B. Tobias M. Gopal D. Hornstein M.D. Diop H. Adverse pregnancy and birth outcomes associated with underlying diagnosis with and without assisted reproductive technology treatment.Fertil Steril. 2015; 103: 1438-1445Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 3Zhu L. Zhang Y. Liu Y. Zhang R. Wu Y. Huang Y. et al.Maternal and live-birth outcomes of pregnancies following assisted reproductive technology: a retrospective cohort study.Sci Rep. 2016; 635141Google Scholar, 4Qin J. Liu X. Sheng X. Wang H. Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies.Fertil Steril. 2016; 85: 73-85.e1Abstract Full Text Full Text PDF Scopus (330) Google Scholar, 5Luke B. Gopal D. Cabral H. Stern J.E. Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.Am J Obstet Gynecol. 2017; 217: 327.e1-327.e14Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 6Chih H.J. Elias F.T.S. Gaudet L. Velez M.P. Assisted reproductive technology and hypertensive disorders of pregnancy: systematic review and meta-analyses.BMC Pregnancy Childbirth. 2021; 21: 449Crossref PubMed Scopus (54) Google Scholar), which result from the use of assisted reproductive technology (ART). Further, when compared with fertile women, women diagnosed with and treated for infertility have significantly high risks of experiencing both composite and individual indicators of severe maternal morbidity (SMM) as defined by the Center for Disease Control, including development of disseminated intravascular coagulation, eclampsia, heart failure, pulmonary edema, and thrombotic embolism (7Murugappan G. Li S. Lathi R.B. Baker V.L. Luke B. Eisenberg M.L. Increased risk of severe maternal morbidity among infertile women: analysis of US claims data.Am J Obstet Gynecol. 2020; 223: 404.e1-404.e20Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The diagnosis of infertility is associated with adverse pregnancy outcomes (5Luke B. Gopal D. Cabral H. Stern J.E. Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.Am J Obstet Gynecol. 2017; 217: 327.e1-327.e14Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 8Luke B. Stern J.E. Hornstein M.D. Kotelchuck M. Diop H. Cabral H. et al.Is the wrong question being asked in infertility research?.J Assist Reprod Genet. 2016; 33: 3-8Crossref PubMed Scopus (31) Google Scholar, 9Stern J.E. Liu C.-L. Cui X. Cabral H.J. Farland L.V. Coddington C. et al.Assisted reproductive technology treatment increases obstetric and neonatal risks over that of the underlying infertility diagnosis.Fertil Steril. 2022; 117: 1223-1234Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). However, the inherent nature of infertility and its treatment makes it challenging to discern whether adverse pregnancy and future health outcomes are due to the effects of underlying infertility diagnosis itself or its treatment (8Luke B. Stern J.E. Hornstein M.D. Kotelchuck M. Diop H. Cabral H. et al.Is the wrong question being asked in infertility research?.J Assist Reprod Genet. 2016; 33: 3-8Crossref PubMed Scopus (31) Google Scholar, 10Buck Louis G.M. Schisterman E.F. Dukic V.M. Schieve L.A. Research hurdles complicating the analysis of infertility treatment and child health.Hum Reprod. 2005; 20: 12-18Crossref PubMed Scopus (62) Google Scholar). It is accepted that ART is associated with an increased risk of multiple pregnancy and birth, which is itself associated with increased perinatal complications. Therefore, studies evaluating the interactions between infertility diagnoses, ART, and perinatal outcomes must control for plurality (8Luke B. Stern J.E. Hornstein M.D. Kotelchuck M. Diop H. Cabral H. et al.Is the wrong question being asked in infertility research?.J Assist Reprod Genet. 2016; 33: 3-8Crossref PubMed Scopus (31) Google Scholar). Some analyses have attempted to evaluate these relationships through a comparison of outcomes in ART pregnancies to spontaneous conceptions within gestational carriers, effectively using each woman's previous spontaneous pregnancy as a control reference. Gestational carriers have an increased likelihood of adverse obstetric outcomes in ART pregnancies, including gestational diabetes, gestational hypertension, and placental abnormalities such as previa (11Woo I. Hindoyan R. Landay M. Ho J. Ingles S.A. McGinnis L.K. et al.Perinatal outcomes after natural conception versus in vitro fertilization (IVF) in gestational surrogates: a model to evaluate IVF treatment versus maternal effects.Fertil Steril. 2017; 108: 993-998Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12Pavlovic Z. Hammer K.C. Raff M. Patel P. Kunze K.N. Kaplan B. et al.Comparison of perinatal outcomes between spontaneous vs. commissioned cycles in gestational carriers for single and same-sex male intended parents.J Assist Reprod Genet. 2020; 37: 953-962Crossref PubMed Scopus (5) Google Scholar), suggesting a unique impact of ART on these outcomes. By design these studies could not control for potential contributing factors such as sperm source and associated immune response. An alternative approach to answering the same question compares ART pregnancies in women with infertility diagnoses to ART pregnancies with male factor infertility. In these comparisons, pregnancies resulting from assisted reproductive technique that was performed solely to mitigate male factor infertility serve as a control group in which the effects of underlying female infertility diagnoses are presumed to be absent, thus allowing for assessment of the isolated effect of female infertility itself. In such analyses, higher rates of gestational diabetes, prenatal hospital admissions, and preterm deliveries were seen within specific female infertility diagnosis groups, supporting the role of underlying infertility rather than treatment with ART itself in the risk for adverse obstetric outcomes (13Luke B. Stern J.E. Kotelchuck M. Declercq E.R. Cohen B. Diop H. Birth outcomes by infertility diagnosis analyses of the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART).J Reprod Med. 2015; 60: 480-490PubMed Google Scholar). Recent analyses using linked health data registries have compared outcomes between subfertile women treated and not treated with ART in an attempt to identify whether an independent effect of ART treatment exists. In a 2017 analysis, obstetric complications including gestational diabetes and pregnancy hypertension increased in subfertile women compared with fertile women, but were no different when comparing women treated with in vitro fertilization (IVF) to the subfertile cohort not treated with IVF, thereby suggesting a role infertility diagnosis in the development of these complications (5Luke B. Gopal D. Cabral H. Stern J.E. Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.Am J Obstet Gynecol. 2017; 217: 327.e1-327.e14Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). In this same study, uterine bleeding, placental abnormalities, and prenatal hospitalizations were increased in women treated with IVF compared with subfertile women not treated with IVF, supporting a role of IVF in the development of these complications (5Luke B. Gopal D. Cabral H. Stern J.E. Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.Am J Obstet Gynecol. 2017; 217: 327.e1-327.e14Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Similarly, a nearly twofold increased risk of SMM has been noted in women using ART when compared with non-ART-treated subfertile women, again suggesting an association of these adverse health effects with treatment rather than underlying infertility diagnoses (2Stern J.E. Luke B. Tobias M. Gopal D. Hornstein M.D. Diop H. Adverse pregnancy and birth outcomes associated with underlying diagnosis with and without assisted reproductive technology treatment.Fertil Steril. 2015; 103: 1438-1445Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 14Belanoff C. Declercq E.R. Diop H. Gopal D. Kotelchuck M. Luke B. et al.Severe maternal morbidity and the use of assisted reproductive technology in Massachusetts.Obstet Gynecol. 2016; 127: 527-534Crossref PubMed Scopus (45) Google Scholar). A recent analysis using a more representative comparison group of women with infertility reported that infertility-related diagnoses including polycystic ovarian syndrome (PCOS), tubal factor, and ovulatory dysfunction were associated with increased risks of gestational hypertension, preeclampsia or eclampsia, gestational diabetes, and placental abnormalities compared with fertile women, and for each infertility diagnosis, the use of ART consistently increased the risk of placental problems (9Stern J.E. Liu C.-L. Cui X. Cabral H.J. Farland L.V. Coddington C. et al.Assisted reproductive technology treatment increases obstetric and neonatal risks over that of the underlying infertility diagnosis.Fertil Steril. 2022; 117: 1223-1234Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). This refined analysis supports a role of the underlying infertility diagnosis in the development of adverse outcomes as well as an additive modulating effect of ART. A limitation of such retrospective studies is that not all relevant variables can be evaluated; specifically that there is no reliable assessment of severity of infertility, which would be a useful metric to determine if the increased risk observed in IVF-treated women reflects more severe infertility or more extensive underlying pathology. There are substantial psychological implications of an infertility diagnosis, indeed 31% to 40% of women with infertility have psychiatric comorbidities, primarily depression and anxiety (15Chen T.H. Chang S.P. Tsai C.F. Juang K.D. Prevalence of depressive and anxiety disorders in an assisted reproductive technique clinic.Hum Reprod. 2004; 19: 2313-2318Crossref PubMed Scopus (267) Google Scholar, 16Volgsten H. Skoog Svanberg A. Ekselius L. Lundkvist O. Sundström Poromaa I. Prevalence of psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment.Hum Reprod. 2008; 23: 2056-2063Crossref PubMed Scopus (213) Google Scholar, 17Sejbaek C.S. Hageman I. Pinborg A. Hougaard C.O. Schmidt L. Incidence of depression and influence of depression on the number of treatment cycles and births in a national cohort of 42,880 women treated with ART.Hum Reprod. 2013; 28: 1100-1109Crossref PubMed Scopus (62) Google Scholar, 18Holley S.R. Pasch L.A. Bleil M.E. Gregorich S. Katz P.K. Adler N.E. Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners.Fertil Steril. 2015; 103: 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). In a recent cohort of women presenting to fertility clinics in California, 56% reported symptoms of depression and 76% symptoms of anxiety (19Pasch L.A. Holley S.R. Bleil M.E. Shehab D. Katz P.P. Adler N.E. Addressing the needs of fertility treatment patients and their partners: are they informed of and do they receive mental health services?.Fertil Steril. 2016; 106: 209-215.e2Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). The prevalence of depression is 2 times higher in women with infertility than in controls, with increased depression scores on validated scales (20Domar A.D. Broome A. Zuttermeister P.C. Seibel M. Friedman R. The prevalence and predictability of depression in infertile women.Fertil Steril. 1992; 58: 1158-1163Abstract Full Text PDF PubMed Google Scholar, 21Williams K.E. Marsh W.K. Rasgon N.L. Mood disorders and fertility in women: a critical review of the literature and implications for future research.Hum Reprod Update. 2007; 13: 607-616Crossref PubMed Scopus (152) Google Scholar). In addition to its negative effect on overall psychological well-being, infertility negatively impacts sexual, and potentially marital, relationships (22Luk B.H.K. Loke A.Y. The impact of infertility on the psychological well-being, marital relationships, sexual relationships, and quality of life of couples: a systematic review.J Sex Marital Ther. 2015; 41: 610-625Crossref PubMed Scopus (198) Google Scholar). Fertility-related quality of life, evaluated through the use of a validated fertility-specific survey, FertiQOL (23Boivin J. Takefman J. Braverman A. The Fertility Quality of Life (FertiQoL) tool: development and general psychometric properties.Fertil Steril. 2011; 96: 409-415.e3Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar), has been found to vary based on fertility diagnosis, with lower quality of life reported in the PCOS population than among women with unexplained infertility (24Santoro N. Eisenberg E. Trussell J.C. Craig L.B. Gracia C. Huang H. et al.Reproductive Medicine Network Investigators. Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome.Hum Reprod. 2016; 31: 2268-2279Crossref PubMed Scopus (40) Google Scholar). Women with infertility present for several clinical visits in the course of their evaluation and treatment. In line with guidelines established by the American Congress of Obstetricians and Gynecologists (25American College of Obstetricians and GynecologistsProlog: patient management in the office. American College of Obstetricians and Gynecologists, Washington, DC2012Google Scholar), these preconception interactions represent an ideal opportunity for counseling regarding the unique adverse pregnancy outcomes in women with infertility and addressing modifiable risk factors. Indices for predicting maternal morbidity based on preconception comorbidities have been developed and validated, including tools uniquely designed for patients with infertility (Table 1) (26Leonard S.A. Kennedy C.J. Carmichael S.L. Lyell D.J. Main E.K. An expanded obstetric comorbidity scoring system for predicting severe maternal morbidity.Obstet Gynecol. 2020; 136: 440-449Crossref PubMed Scopus (104) Google Scholar, 27Murugappan G. Alvero R.J. Lyell D.J. Khandelwal A. Leonard S.A. Development and validation of a risk prediction index for severe maternal morbidity based on preconception comorbidities among infertile patients.Fertil Steril. 2021; 116: 1372-1380Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). Although these tools provide data that can aid in counseling and informed decision-making, their impact on reduction of SMM is yet unknown (28Bateman B.T. Robinson J.N. Getting risk prediction right.Obstet Gynecol. 2020; 136: 437-439Crossref PubMed Scopus (6) Google Scholar). Prospective studies of behavioral modifications including weight loss have shown to decrease perinatal risk (29Bogaerts A. Ameye L. Martens E. Devlieger R. Weight loss in obese pregnant women and risk for adverse perinatal outcomes.Obstet Gynecol. 2015; 125: 566-575Crossref PubMed Scopus (57) Google Scholar), but inevitably result in treatment delays. Further understanding of the amount of risk reduction in comparison to the "cost" of treatment delays is warranted to better counsel patients on optimizing preconception health.Table 1Risk prediction indices for SMM.PopulationSample sizeInput variablesNo. of input valuesPredicted outcomesLeonard et al. 2020 [26Leonard S.A. Kennedy C.J. Carmichael S.L. Lyell D.J. Main E.K. An expanded obstetric comorbidity scoring system for predicting severe maternal morbidity.Obstet Gynecol. 2020; 136: 440-449Crossref PubMed Scopus (104) Google Scholar]Pregnant women in the United States919,546Medical comorbidities, comorbidities related to the current pregnancy, previous cesarean birth, and maternal age27CDC SMM Index indicators, both including and excluding (non-transfusion SMM) blood transfusionMurugappan et al. 2021 [27Murugappan G. Alvero R.J. Lyell D.J. Khandelwal A. Leonard S.A. Development and validation of a risk prediction index for severe maternal morbidity based on preconception comorbidities among infertile patients.Fertil Steril. 2021; 116: 1372-1380Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]Women with infertility in the United States94,097Medical comorbidities, previous cesarean birth, and maternal age20CDC SMM Index indicators, excluding blood transfusion aloneCDC = Centers for Disease Control and Prevention, SMM = severe maternal morbidity. Open table in a new tab CDC = Centers for Disease Control and Prevention, SMM = severe maternal morbidity. Women with infertility are at an increased risk of developing chronic disease, notably cancer and cardiovascular disease (30Murugappan G. Li S. Lathi R.B. Baker V.L. Eisenberg M.L. Risk of cancer in infertile women: analysis of US claims data.Hum Reprod. 2019; 34: 894-902Crossref PubMed Scopus (31) Google Scholar, 31Murugappan G. Li S. Lathi R.B. Baker V.L. Eisenberg M.L. Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data.Am J Obstet Gynecol. 2019; 220: 473.e1-473.e14Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 32Murugappan G. Leonard S.A. Farland L.V. Lau E.S. Shadyab A.H. Wild R.A. et al.Association of infertility with atherosclerotic cardiovascular disease among postmenopausal participants in the Women's Health Initiative.Fertil Steril. 2022; 117: 1038-1046Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). In a large cohort using US claims data, women with infertility were more likely to develop diabetes, liver disease, cerebrovascular disease, ischemic and other heart disease, and drug abuse than the fertile controls (31Murugappan G. Li S. Lathi R.B. Baker V.L. Eisenberg M.L. Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data.Am J Obstet Gynecol. 2019; 220: 473.e1-473.e14Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). When examining the association of infertility with future cancer diagnoses, women with infertility had higher risks of developing both gynecologic and nongynecologic cancers than the fertile controls (30Murugappan G. Li S. Lathi R.B. Baker V.L. Eisenberg M.L. Risk of cancer in infertile women: analysis of US claims data.Hum Reprod. 2019; 34: 894-902Crossref PubMed Scopus (31) Google Scholar). Specifically, in another large study of US claims data, women with infertility were found to have a higher risk of developing cancer overall (adjusted hazard ratio [aHR], 1.18; confidence interval [CI], 1.12–1.24), uterine cancer (aHR, 1.78; CI, 1.39–2.28), ovarian cancer (aHR, 1.64; CI, 1.33–2.01), lung cancer (aHR, 1.38; CI, 1.01–1.88), thyroid cancer (aHR, 1.29; CI, 1.09–1.53), leukemia (aHR, 1.55; CI, 1.21–1.98) and liver and gallbladder cancer (aHR, 1.59; CI, 1.11–2.30) than non-women with infertility (30Murugappan G. Li S. Lathi R.B. Baker V.L. Eisenberg M.L. Risk of cancer in infertile women: analysis of US claims data.Hum Reprod. 2019; 34: 894-902Crossref PubMed Scopus (31) Google Scholar). In regard to cardiovascular disease, a study by Gleason et al. (33Gleason J.L. Shenassa E.D. Thoma M.E. Self-reported infertility, metabolic dysfunction, and cardiovascular events: a cross-sectional analysis among U.S. women.Fertil Steril. 2019; 111: 138-146Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar), demonstrated that women with infertility had an 80% increased likelihood of metabolic syndrome and a 71% increased likelihood of cardiovascular event compared with fertile controls. A moderate association between infertility and atherosclerotic cardiovascular disease (ASCVD) has been previously identified, with more significant risk noted in the more extreme phenotypes of infertility, manifested as nulliparous women with infertility who either had or had not experienced a pregnancy loss (32Murugappan G. Leonard S.A. Farland L.V. Lau E.S. Shadyab A.H. Wild R.A. et al.Association of infertility with atherosclerotic cardiovascular disease among postmenopausal participants in the Women's Health Initiative.Fertil Steril. 2022; 117: 1038-1046Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). In nulliparous women who eventually had a child after longer standing infertility diagnoses (≥5 years), increased risk of cardiovascular disease has also been identified compared with women with no years of infertility (34Parikh N.I. Cnattingius S. Mittleman M.A. Ludvigsson J.F. Ingelsson E. Subfertility and risk of later life maternal cardiovascular disease.Hum Reprod. 2012; 27: 568-575Crossref PubMed Scopus (76) Google Scholar). The potential impact of ovarian stimulation on short-term health includes venous thromboembolism, ovarian hyperstimulation syndrome, and surgical complications of oocyte retrieval including hemorrhage; however, the occurrence of these adverse events are uncommon (<1%) (35Senapati S. Infertility: a marker of future health risk in women?.Fertil Steril. 2018; 110: 783-789Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Analysis of long-term health effects has focused on subsequent risk of ovarian cancer in women receiving fertility treatment, with studies reporting increased risk in women receiving fertility treatment compared with the general population, but similar to an infertile reference group, suggesting that the underlying infertility or cause thereof may be the driver of these increased risks (36Siristatidis C. Sergentanis T.N. 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: 105-123Crossref PubMed Scopus (129) Google Scholar). There has also been investigation into the effects of infertility treatment on psychological factors including anxiety and depressive symptoms. The psychopharmacological effects of fertility medication may be an independent risk factor for mood changes, given intended modulation of hormones within the hypothalamic–pituitary axis that are known to influence mood. Clomiphene citrate, for example, has been reportedly associated with short-term mood changes and fatigue (21Williams K.E. Marsh W.K. Rasgon N.L. Mood disorders and fertility in women: a critical review of the literature and implications for future research.Hum Reprod Update. 2007; 13: 607-616Crossref PubMed Scopus (152) Google Scholar). However, studies analyzing the impact of infertility treatment on psychological outcomes do not often control for these factors. Some studies have noted a decrease in anxiety and generalized distress levels as well as an increased self-reported quality of life during infertility treatment compared with before its initiation, suggested to be because of a calming effect of actively addressing the identified problem (37Massarotti C. Gentile G. Ferreccio C. Scaruffi P. Remorgida V. Anserini P. Impact of infertility and infertility treatments on quality of life and levels of anxiety and depression in women undergoing in vitro fertilization.Gynecol Endocrinol. 2019; 35: 485-489Crossref PubMed Scopus (99) Google Scholar). Nulliparity has been associated with increased risk of all-cause mortality in women (38Coleman P.K. Reardon D.C. Calhoun B.C. Reproductive history patterns and long-term mortality rates: a Danish, population-based record linkage study.Eur J Public Health. 2013; 23: 569-574Crossref PubMed Scopus (24) Google Scholar, 39Barclay K. Keenan K. Grundy E. Kolk M. Myrskylä M. Reproductive history and post-reproductive mortality: a sibling comparison analysis using Swedish register data.Soc Sci Med. 2016; 155: 82-92Crossref PubMed Scopus (62) Google Scholar, 40Zeng Y. Ni Z.-M. Liu S.-Y. Gu X. Huang Q. Liu J.-A. et al.Parity and all-cause mortality in women and men: a dose-response meta-analysis of cohort studies.Sci Rep. 2016; 619351Google Scholar). Although related, nulliparity and infertility are distinct constructs and may reflect differing disease processes and/or social factors. Therefore, more recent studies have evaluated the relationship between infertility and mortality. In a secondary analysis of a multicenter randomized clinical trial, women with infertility between 1992 and 2001 were found to have a 10% increased risk of death from any cause (41Stentz N.C. Koelper N. Barnhart K.T. Sammel M.D. Senapati S. Infertility and mortality.Am J Obstet Gynecol. 2020; 222: 251.e1-251.e10Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Notably, this effect was predominantly observed in women at an otherwise low risk of mortality (26% increased risk of death), as well as no differences were observed in cardiovascular or diabetes-related mortality (41Stentz N.C. Koelper N. Barnhart K.T. Sammel M.D. Senapati S. Infertility and mortality.Am J Obstet Gynecol. 2020; 222: 251.e1-251.e10Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Interestingly, women with infertility were found to have a 23% increased risk of death related to cancer, with no difference in the risk of death from endometrial or ovarian cancer, but more than doubled risk of death from breast cancer (41Stentz N.C. Koelper N. Barnhart K.T. Sammel M.D. Senapati S. Infertility and mortality.Am J Obstet Gynecol. 2020; 222: 251.e1-251.e10Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). In an analysis of a contemporary cohort of women within a US claims-based data set from 2003 to 2019, women with infertility were found to have a 32% higher risk of all-cause mortality than fertile women across all age, race and ethnicity groups, morbidities, and delivery strata (42Murugappan G. Li S. Alvero R.J. Luke B. E
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