Assisted reproductive technology: what are the cardiovascular risks for women?

The conflicting evidence for whether ART is associated with elevated risk of CVD is contributed to by multiple factors. First, the population included in many observational studies has been limited. In studies linking infertility to CV risk factors and CVD, the study population has been largely composed of women with PCOS and endometriosis, which may uniquely predispose patients to adverse CVD outcomes in a way that is not reflective of the general risk of patients with infertility. In studies directly examining the correlation of ART and CVD, it is difficult to untangle the risk posed by infertility and its associated comorbidities from the risk of ART itself. It thus remains unknown whether the elevated risk is mediated through known CVD risk factors or if ART is causally associated with elevated CVD risk. With the majority of studies analyzed through cohort and cross-sectional methods, long term CV risk is particularly difficult to interpret. Although many variables are adjusted for, there still remains a level of uncertainty whether unmeasured confounding variables are affecting statistical interpretation. Furthermore, the mechanisms used to gather information on fertility therapy, as well as CVD events, mainly relied on individual ICD codes and self-reported public data[ 38 ]. Therefore, consistency of coding, type of fertility therapy, and categorization of CVD event may be inconsistent and misclassified. Moreover, certain legislation also contributes to the difficulty of linking health data that can assist in association of fertility therapy with long term CVD events[ 96 ]. The field of study linking ART and CVD risk is in its early stages. While there is established literature on comorbidities and pregnancy-complications associated with ART that are known CVD risk factors, studies linking ART and CVD events are relatively sparse. There have been significant changes in the practice of ART in the last two decades and there is marked variability in practice patterns as well as disparities in access to ART, meaning that there are few standardized studies with representative populations investigating CVD events with long-term follow-up[ 76 ]. Given the recent rise in single embryo transfer and decrease in multifetal gestations, it will be interesting to investigate if this leads to a reduction in CVD risk. With the growing utilization of ART, as well as the increasing proportion of patients presenting at the time of conception with known CVD risk factors, it will be of utmost importance to increase the number of studies documenting the incidence of long-term CVD complications in pre- and post-menopausal patients who have undergone ART. These studies should ideally measure CVD and its various subtypes, including MI, heart failure, stroke, and CVD mortality. They should be of prospective cohort design, with a large multiethnic population gathered from multiple centers, with adequate assessment of potential confounding factors such as PCOS, endometriosis, and other CVD risk factors. Future research should also seek to elucidate the mechanism linking sex-specific CVD risk factors with long-term CVD events in order to help tailor preventive management. This research will lead to the continued growth of a robust evidence base that will allow for more definitive conclusions on the association and causality between ART and CVD risk, and help alter patients’ long-term CV health trajectory.

It has been shown in the literature that women who conceive with ART have a higher prevalence of various CVD comorbidities, suggesting shared risk factors that underlie both infertility and CVD. This section will explore the individual associations between both infertility and ART with specific CVD risk factors. Figure 1 demonstrates the interrelationships of infertility, ART, CVD risk factors, and future CVD events. Women with infertility often have a less favorable cardiovascular health profile. A recent meta-analysis comparing cardiometabolic risk factors among women of reproductive age with and without infertility found that women with infertility had statistically significant higher body mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), compared with fertile women[ 14 ]. Similarly, a cross-sectional analysis from the Framingham Heart Study found that patients with self-reported infertility had higher BMI, waist circumference, TG levels, and lower high-density cholesterol (HDL-C) levels. They were also found to have an increased odds of obesity and diabetes[ 15 ]. Notably, many studies investigating the correlation between infertility and CVD risk factors focus on PCOS. PCOS, which affects 5-13% of women in the general population is characterized by having at least 2 out of 3 of the following features: hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology[ 16 ]. PCOS is a common cause of female infertility; however, even during pregnancy, PCOS is associated with increased risk of APOs such as gestational diabetes and preeclampsia, as well as CV complications such as peripartum cardiomyopathy[ 17 ]. Women with PCOS commonly present with multiple cardiometabolic risk factors[ 18 , 19 ]. In a meta-analysis, women with PCOS were found to have higher levels of LDL-C and TGs, and lower levels of HDL-C than controls[ 20 ]. Studies have also shown increased prevalence of insulin resistance, metabolic syndrome, and hypertension, which are independent of BMI but exacerbated by obesity[ 21 - 23 ]. A meta-analysis found that women with PCOS are more likely to be overweight [RR 1.73 (95% CI, 1.52-2.50)] and obese [RR 2.77 (1.88-4.10)] compared to women without PCOS[ 24 ]. Studies have also found a higher coronary artery calcium (CAC) score, a marker of subclinical atherosclerosis, in pre- and post-menopausal women with PCOS even after adjusting for age and BMI[ 25 - 27 ]. These comorbidities place women at higher risk for long-term metabolic sequelae such as type 2 diabetes (T2D) and CVD[ 19 , 28 ]. Another condition linked with infertility and CVD is endometriosis, which affects approximately 5-10% of women of reproductive age[ 29 ]. Endometriosis is defined as the presence of endometrium-like tissue outside of the uterus, primarily in the pelvis and ovaries, leading to chronic pelvic pain, dysmenorrhea, dyspareunia and reduced fertility[ 29 ]. Women with endometriosis have been shown in cross-sectional studies to have higher levels of LDL-C and lower levels of HDL-C[ 30 ]. They have also been shown to have elevated markers of chronic systemic inflammation, such as various cytokines and reactive oxygen species, which contribute to endothelial dysfunction and atherosclerotic plaque progression[ 31 , 32 ]. Mirroring the association of infertility with CVD risk, the use of ART has also been associated with a greater prevalence of cardiometabolic risk factors. A recent analysis using data from the U.S. National Inpatient Sample (NIS) found that women who conceived with ART had a significantly higher prevalence of maternal congenital heart disease, valvular disease, and obesity[ 2 ]. Another recent NIS database analysis similarly found higher prevalence of hypertension, PCOS, and dyslipidemia[ 33 ]. A 2013 Canadian cohort analysis of over 1 million patients found that among women who used fertility therapy (defined as reproductive treatment monitoring of iatrogenic ovulation) there was a statistically significant higher prevalence of older age, hypertension (3.1% vs 2.5%), hyperlipidemia (3.8% vs 2.5%), and diabetes (2.2% vs 1.5%)[ 34 ]. A 2017 U.S. study of women with twin pregnancies who were categorized as fertile, subfertile, or receiving IVF found that women in the subfertile and IVF groups were more likely to have preexisting chronic conditions, including diabetes and chronic hypertension[ 35 ]. ART may lead to increased cardiometabolic demands through multiple mechanisms, including controlled ovarian stimulation, pregnancy itself, and higher rates of multifetal gestations. ART, namely IVF, first involves controlled ovarian stimulation to develop and obtain multiple mature oocytes; there are several main ovarian stimulation protocols[ 36 , 37 ]. The long protocol utilizes gonadotropin-releasing hormone (GnRH) agonists to downregulate the pituitary gland, followed by exogenous follicle-stimulating hormone (FSH) to stimulate follicular growth and oocyte maturation, to make available multiple mature oocytes [ 36 ]. The short protocol begins with the co-administration of a GnRH agonist and FSH[ 36 ]. The most commonly used protocol currently utilizes a GnRH antagonist, rather than a GnRH agonist, to prevent premature ovulation. These ovarian stimulation protocols are concluded by administration of human chorionic gonadotropin (hCG), retrieval of mature oocytes from the follicle, and fertilization in vitro by multiple motile sperm or, more commonly, through intracytoplasmic sperm injection[ 5 ]. Studies of ovarian stimulation have found that the corresponding increases in endogenous estrogen may lead to endothelial dysfunction and a prothrombotic state[ 38 , 39 ]. This may explain the elevated incidence of pulmonary embolism during the first trimester of an IVF pregnancy compared to a spontaneous one[ 36 ]. A small mechanistic cohort study also found activation of the renin-angiotensin system during periods of elevated estradiol[ 39 ]. Additionally, an exaggerated response to controlled ovarian stimulation can lead to ovarian hyperstimulation syndrome (OHSS). OHSS is characterized by drastically increased vascular permeability leading to accumulation of fluid in third space compartments, which results in hypotension, hemoconcentration, and an estrogen-induced prothrombotic state that elevates the risk of venous thromboembolism (VTE)[ 36 , 40 ]. With GnRH antagonist protocols, a trigger with a GnRH agonist can be used instead of hCG, or with a low dose of hCG, to reduce the risk of OHSS. It is also now becoming very common to freeze all embryos (no fresh embryo transfer), with a subsequent frozen embryo transfer in a cycle that does not include controlled ovarian stimulation. With frozen embryo transfer, pregnancy does not begin when the estradiol levels are high as they may be with a fresh embryo transfer. Furthermore, the absence of the corpus luteum in a programmed cycle (rather than a natural ovulation cycle) has been implicated as being partially responsible for the reported increased risk of hypertensive disorders of pregnancy with a frozen compared to a fresh embryo transfer[ 41 ]. The corpus luteum produces not only estradiol and progesterone but also vasoactive hormones such as relaxin which may be important for cardiovascular health[ 41 ]. Additionally, pregnancy itself has often been referred to as nature’s free CV stress test due to the changes in systemic vasodilation, stroke volume, and heart rate, which lead to a cardiac output increase of around 30-50% by the third trimester[ 42 , 43 ]. ART also predisposes patients to multiple-gestation pregnancies, during which cardiac output increases by another 20% compared to single-gestation pregnancies, leading to more hyperdynamic circulation[ 44 ]. Pregnancy at advanced age (defined as pregnancy at age ≥35 years), as is often the case for women undergoing ART, is associated with increased risk for APOs such as preeclampsia, as well as higher prevalence of CVD events[ 45 , 46 ]. These physiologic demands may be intolerable, especially for patients with valvular disease or congenital heart disease. Many studies have investigated the association between ART and VTE in pregnancy ( Supplementary Table )[ 47 ]. Two recent NIS analyses women who conceived by ART had a higher risk for VTE at time of delivery, which was highest among women with preexisting CVD risk factors[ 2 , 33 ]. A 2023 systematic review and meta-analysis including fourteen studies found that the overall frequency of VTE associated with ART was 0.23% (95% CI, 0.07-0.46)[ 48 ]. In this study women undergoing ART were found to have a two- to threefold increased risk of VTE [RR 2.66 (1.60-4.43)]. This was corroborated by a 2018 systematic review that showed antepartum risk of VTE after IVF doubled [OR 2.18 (1.63-2.92)][ 49 ]. They found the risk of VTE after ART complicated by OHSS was even higher, citing an up to 100-fold increase of VTE, or an absolute risk of 1.7%. Another study found that women giving birth after fresh embryo transfer IVF had an eightfold increased risk of VTEs and pulmonary embolisms during the first trimester compared to women giving birth after natural conception, but there was no increase in the incidence of VTE in women giving birth after frozen-thawed embryo transfer[ 36 , 50 ]. Studies have also investigated the association between ART and APOs such as preeclampsia and preterm delivery ( Supplementary Table ). Among U.S. women in a NIS analysis, women who conceived by ART were older compared to their non-ART counterparts (median age 35 and 28 respectively), but ART was found to be an independent predictor of peripartum CV complications even after adjustment for demographics, comorbidities, and multiple gestations[ 33 ]. Particularly, women who used ART to assist in fertility had an increased risk of preeclampsia/eclampsia, heart failure, cardiac arrhythmias, ischemic stroke, and hemorrhagic stroke at the time of delivery. Another recent NIS analysis found that pregnancies conceived by ART were associated with higher risk of obstetric complications such as placental abruption and preterm delivery, as well as vascular complications such as acute kidney injury and arrhythmia, including in subgroups without CVD risk factors and multifetal gestations[ 2 ]. The risk for acute kidney injury, arrhythmia, and ischemic stroke was the highest in women who conceived with ART and had preexisting CVD risk factors. Women who use ART to increase their chance of pregnancy are more likely to experience multifetal gestation[ 51 ]. Multiple studies have shown that multifetal gestation is associated with three to four times increased risk of preeclampsia and in turn a higher chance of developing peripartum cardiomyopathy compared to singleton pregnancies[ 52 , 53 ]. Thus, multifetal gestations are likely a contributing factor to the increased CVD risk in these women[ 53 , 54 ]. However, in more recent years, there has been a dramatic reduction in the risk of multiple pregnancy in the U.S., due to adoption of elective single embryo transfer[ 55 ]. It should be noted that ART is a heterogenous term that encompasses a number of different procedures, and the CV risks are likely not the same. For example, a recent analysis found an increased risk of hypertensive disorders of pregnancy with frozen embryo transfer, but not fresh embryo transfer compared to natural conception[ 56 ]. Another study found that the protocol utilized for frozen embryo transfer may influence the risk of preeclampsia[ 57 ]. Furthermore, it is also important to note that infertility itself has also been implicated in the development of CVD[ 13 , 58 ], as further discussed below. Therefore, it remains unclear whether the increased prevalence of pregnancy-related CV complications is a direct result of the ART treatment or due to the underlying conditions and morbidities associated with infertility. Infertility has been associated with long-term CVD risk, although the mechanisms are not fully elucidated[ 13 ]. There is also some inconsistency across studies, with infertility being independently associated with incident CVD in some longitudinal cohort studies[ 59 , 60 ], but not in others[ 61 , 62 ]. In one study from a Swedish cohort of parous women, a history of subfertility (defined as an inability to conceive for at least 1 year) for 5 or more years prior to pregnancy was associated with a 19% increased risk of future CVD [adjusted HR 1.19 (1.02-1.39)] compared to parous women who had not experienced infertility[ 59 ]. In another study from the Women’s Health Initiative, women with infertility were 16% more likely to develop heart failure, particularly heart failure with preserved ejection fraction, and this was independent of traditional cardiovascular and infertility-related factors[ 60 ]. In contrast, in the Study of Women’s Health Across the Nation (SWAN), there was no association between infertility and metabolic syndrome or CVD event[ 62 ]. Women who experience infertility may have underlying conditions such as PCOS and endometriosis which may confer an increased cardiovascular risk[ 13 , 63 ]. A 2020 umbrella meta-analysis covering three meta-analyses found that PCOS was associated with an increased risk of coronary heart disease (CHD) [OR 1.44 (1.13-1.84)], stroke [1.36 (1.09-1.70)], and composite CVD [1.30 (1.09-1.56)], although conclusions across studies of the significance of this association have been mixed given the numerous confounding factors[ 64 ]. This study also found that women with premature ovarian insufficiency was associated with a 1.69- and 1.61-fold risk for CHD and composite CVD, respectively. Among women in the Nurses’ Health Study II (1989-2009), women with laparoscopically-confirmed endometriosis had a higher risk of CHD [RR 1.62 (1.39-1.89)], including myocardial infarction (MI) [1.52 (1.17-1.98)], angina [1.91 (1.59-2.29)], and coronary artery bypass graft/coronary angioplasty/stent [1.35 (1.08-1.69)], independent of demographic, anthropometric, reproductive, and lifestyle confounders[ 65 ]. More investigation is needed to explain the relationship between infertility and long-term CVD. The use of ART and its association with long term CVD has not been widely studied; studies are few and heterogenous, and results have drawn mixed conclusions[ 13 ]. A meta-analysis with six observational studies that included 41,910 women who received fertility therapy, including IVF and non-IVF options, showed that there was no increase of a cardiac event and a trend towards increased risk of stroke compared to women who did not use fertility therapies[ 38 ]. It was hypothesized that repeated ovarian hyperstimulation and hyper-estrogenic state could lead to a prothrombotic state and cause endothelial injury contributing to further CVD risk[ 36 , 38 ]. A cohort study of over 6,000 women also found no increased CV risk after ART therapy[ 13 , 34 ]. A recent 2023 registry-based cohort study using nationwide data from Denmark, Finland, Norway, and Sweden found that women who gave birth after ART were not an increased risk of CVD after median follow-up of 11 years compared to those who had not conceived through ART[ 66 ]. There was however weak evidence that frozen, but not fresh, embryo transfers were associated with an increased risk of stroke (HR 1.59 [1.11-2.26], HR 0.91 [0.80-1.05], respectively). Although some studies have showed no increased risk of CVD, ART has other associations that put women at higher chances of developing CVD in the future. For instance, women who use ART tend to be of an advanced maternal age, which could contribute to an increased risk of CVD[ 67 ]. Additionally, the use of ART, particularly frozen embryo transfer, has been implicated with hypertensive disorders of pregnancy, as well as gestational diabetes, which both have had associations with increased CVD and cardiovascular risks in the future[ 68 , 69 ]. Women with a history of pre-eclampsia have been shown to have endothelial dysfunction that can predispose these women to future vascular and cardiovascular diseases[ 70 ]. The risk extends further with women with previous hypertensive pregnancy disorders having higher glucose, insulin, TG, total cholesterol, and LDL-C levels measured after pregnancy compared with women with previous normotensive pregnancies[ 71 ]. Thus, women who have used ART may have increased CV risk due to the higher chances of developing CV complications during pregnancy that are themselves also linked to CVD in the future. However, overall, the data remain unclear as to whether ART is casually associated with incident CVD, independent of established CVD risk factors. While it remains uncertain if ART itself is associated with a higher risk of CVD, independent of established CVD risk factors, the associated comorbidities and pregnancy complications indicate that a patient using ART is more likely to have an elevated CVD risk factor profile. Thus, ideally patients should be screened for CVD risk factors prior to initiating ART (pre-conception counseling), closely monitored for APOs and CV complications during delivery, and then after delivery, the appropriate transition of care postpartum to longitudinal CVD risk management[ 13 , 72 ]. This involves collaboration of a multidisciplinary care team that includes primary care, reproductive endocrinology, obstetrics/gynecology (OBGYN), maternal fetal medicine, and often cardiology ( Figure 2 ). Most women do not receive adequate counseling on pre-conception risk prior to pregnancy[ 73 , 74 ]. Pre-conception counseling is even more important for the population of women who undergo ART, given the elevated CV risk of OHSS and pregnancy itself, particularly with multifetal gestations[ 6 ]. This counseling should be provided by both primary and specialist care clinicians to estimate CVD risk and engage in shared decision-making regarding the best course of action. Following successful ART, patients should be screened based on their specific comorbidities and history of infertility. For example, women with PCOS should be screened for glucose intolerance, dyslipidemia, hypertension, and elevated BMI[ 16 , 75 ]. Additionally, all women could benefit from the opportunity to address CVD risk factors, such as smoking cessation. It is also important to raise awareness among clinicians of the increased prevalence of APOs among this population, including hypertensive disorders of pregnancy, as well as obstetric and vascular complications, in order to provide close monitoring and management. APOs are now considered “risk-enhancing” factors in atherosclerotic CVD (ASCVD) risk assessment. Thus, consensus statements recommend close monitoring for CVD risk factors in these patients during the first year postpartum, with a postpartum follow-up visit with a primary care clinician or cardiologist within 7-14 days of delivery for patients with APOs[ 76 , 77 ]. Postpartum transitional clinics for patients with APOs are a promising strategy to facilitate the transition to longitudinal primary care[ 72 , 78 ]. Ascertainment of a comprehensive reproductive history, including history of infertility and ART use, should be part of standard CV risk assessment in clinical practice. The American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for the primary prevention of CVD did highlight a history of APOs, such as preeclampsia, as a “risk-enhancing” factor, although there was no specific mention of infertility or ART[ 79 ]. The presence of a “risk-enhancing” factor would favor the initiation of statins among women aged 40 to 75 years for CVD prevention who are otherwise at borderline (5-7.4%) or intermediate (7.5%-40 years, for which their CVD risk is uncertain (borderline/intermediate), a CAC score may be useful to evaluate for the presence of subclinical coronary atherosclerosis to help refine CVD risk assessment and identify those who may benefit from preventive pharmacotherapy such as statins[ 79 - 81 ]. While many of these initial CVD risk screening and management would largely be carried out by primary care clinicians or OBGYNs, women with significant CVD risk factors or decision-making uncertainty can be referred to a cardiologist who specializes in CVD prevention or women’s health[ 82 ]. Furthermore, reproductive history should be incorporated into routine clinical practice, such as through screening algorithms, standardized patient questionnaires, and note templates, through collaboration between cardiologists and OBGYNs[ 83 ]. The identification of sex-specific and reproductive factors thus offers an opportunity for primordial and primary prevention of long-term CVD outcomes. Although the mechanism behind CVD and ART is still largely unknown, data have shown an increased risk of CVD and pregnancy complications among women who use ART[ 13 ], as discussed above. Therefore, increased surveillance to monitor for CV complications during pregnancy is imperative. As women who use ART are more likely to develop hypertensive disorders of pregnancy, close monitoring of blood pressure is necessary to prevent future CV complications[ 84 ], as well as treatment of chronic hypertension during pregnancy targeting a blood pressure (BP) <140/90[ 85 ]. Aspirin prophylaxis to reduce risk of preeclampsia has been recommended by the U.S. Preventive Services Task Force for pregnant women who are at high risk[ 86 ]. Specific risk factors include high-risk factors such as history of preeclampsia, chronic hypertension, and pre-gestational diabetes, as well as combinations of moderate-risk factors such as obesity and IVF conception. Although there is an increased risk of VTE in women who use ART, anticoagulation is not usually recommended and there are methods to mitigate these risks, such as delaying embryo transfer[ 36 , 87 ]. Evaluation for genetic or acquired factors that can contribute to the risk of thrombosis should occur before pregnancy[ 87 ]. The time a women comes in for her ART cycles also provides an important moment to evaluate for CVD and discuss primary prevention tools based on individual risk[ 80 ]. Elective single embryo transfer to reduce multiple gestation is important to reduce the risk of obstetric complications including hypertensive disorders of pregnancy. Reducing CVD risk is critically important given the association with high morbidity and mortality. Thus, it is imperative that patients who have utilized ART are screened and monitored for these risks and then carefully managed. There are no guideline recommendations for CVD prevention specifically for ART; thus, general approaches to CVD prevention as described below can be applied, with the understanding that a history of ART may indicate a higher CVD risk status that may warrant more intensified CV prevention screening and treatment ( Figure 3 ). One key component in lowering CVD risk is lifestyle, which involves physical activity, nutrition and tobacco cessation[ 79 ]. There is a significant inverse dose response relationship between the amount of moderate to vigorous physical activity and CVD events and mortality. It is recommended that adults partake in a minimum of 150 minutes/week of moderate intensity or 75 minutes per week of vigorous intensity physical activity including resistance exercise. Regarding nutrition, the optimal diet to reduce CVD risk and all-cause mortality includes a healthy plant based, DASH, or Mediterranean like diet high in vegetables, fruits, nuts, whole grains and lean animal protein[ 79 ]. Poor nutrition and a lack of physical activity can lead to obesity, hypertension and T2D which further elevate CVD risk. Moreover, tobacco use can result in CVD. All patients should be supported in smoking cessation efforts. Pharmaceutical supports include a variety of nicotine replacement options, varenicline and bupropion. Another major CVD risk is hyperlipidemia. LDL-C is associated with increased risk of CVD in a dose-dependent fashion[ 88 ]. Conversely, for every 39mg/dl decrease in LDL-C, there is a >20% reduction in ASCVD events and 10% reduction in all-cause mortality[ 89 ]. Although not typically used during pregnancy and lactation, statin therapy remains the first line treatment for managing hyperlipidemia for long-term CVD prevention. Statins are recommended for secondary prevention or for primary prevention in the setting of T2D, severe primary hyperlipidemia, high 10-year ASCVD risk ≥20%, borderline/intermediate ASCVD risk with a “risk-enhancing” factor, or in the presence of significant subclinical atherosclerosis (i.e., CAC). If a person develops adverse effects to statins or is treatment resistant, alternative non-statin therapies can be used[ 90 ]. Hypertension must also be meticulously screened for and managed as it carries a significantly increased risk of ASCVD. Antihypertensives are recommended in adults with stage 1 hypertension (BP 130-139/80-89 mmHg) with 10% or higher 10-year ASCVD risk, chronic kidney disease, or diabetes or stage 2 hypertension (≥140/90)[ 79 ]. The blood pressure target (outside of pregnancy) is <130/80 mm Hg with nonpharmacological strategies and anti-hypertensive medications, Regarding diabetes, historically the first line therapy to improve glycemic control and decrease CVD risk was metformin. Increasingly, guidelines have recommended prioritizing sodium glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) in persons with T2D at high CV risk[ 91 , 92 ], as these agents have been shown to be effective in reducing the risk of major adverse cardiovascular events in this population[ 93 , 94 ]. However, these agents are not be used during pregnancy itself. The GLP1-RA agents of liraglutide and semaglutide are also approved by the U.S. Food Drug Administration (FDA) for weight management in persons with BMI ≥30 or BMI ≥27 kg/m2 in the setting of at least one weight related comorbidity, after lifestyle changes have been attempted for at least 6 months. For persons with PCOS with elevated BMI and insulin resistance, GLP1-RA might be a particularly attractive choice in addressing these cardiometabolic complications[ 95 ].

While consistent results have shown that individuals who are pregnant with the help of ART have more CVD risk factors and are at greater risk of experiencing pregnancy complications such as preeclampsia and preterm birth, and that these pregnancy conditions are sex-specific risk factors for CVD, the data are unclear regarding whether use of ART independently elevates the risk of CVD. Risks may differ by ART modality (i.e., frozen vs fresh embryo transfer). Future prospective studies evaluating ART with long-term follow-up for development of CVD may help determine association and causality. Nevertheless, CVD screening is of utmost importance in this population, as well as monitoring for APOs during pregnancy. Management of CVD risk factors through lifestyle and pharmacotherapy has the potential to prevent and improve future CVD outcomes.

Infertility, typically defined as the inability to conceive naturally after one year of regular unprotected intercourse, affects 15% of women of reproductive age in the United States (U.S.)[ 1 , 2 ]. The most common causes of female infertility include ovulatory factor and utero-tubal peritoneal factor[ 3 , 4 ]. Ovulatory factors include endocrine disorders (such as polycystic ovary syndrome (PCOS), hyperprolactinemia, functional hypothalamic amenorrhea, and thyroid dysfunction), severe diminished ovarian reserve (premature ovarian insufficiency), and physical disorders such as obesity[ 4 ]. Utero-tubal peritoneal factors include endometriosis, uterine fibroids, structural uterine anomalies, tubal disease, and pelvic adhesions[ 4 ]. There has been a rise in the use of fertility treatments to aid in the conception of pregnancy, likely due in part to delayed age at childbearing, as well as demand among same-sex couples and single persons[ 5 ]. Fertility treatments can include pharmacologic ovulation induction, intrauterine insemination, and in vitro fertilization or IVF[ 6 ]. Assisted Reproductive Technology (ART) is an umbrella term that refers to any medical or procedural interventions for assisting reproduction in which gametes are handled outside of the body, including IVF with transfer of either fresh or frozen embryos. Techniques sometimes used during the process of IVF include intracytoplasmic sperm injection and pre-implantation genetic testing[ 7 ]. The use of ART has increased dramatically globally[ 8 ]. As per the 2019 data from the Centers for Disease Control and Prevention, 2.1% of infants born in the U.S. were conceived with ART[ 9 ]. While there has been extensive research documenting the impact of infertility and ART on pregnancy outcomes and neonatal health, much less is known about the comorbidities and long-term cardiovascular (CV) health outcomes of these patients. Cardiovascular disease (CVD) is a significant contributor to maternal mortality and the leading cause of death for women in the U.S.[ 10 ]. In recent years there has been increasing attention paid to the sex-specific and reproductive factors that increase both cardiometabolic complications and risk for future CVD events[ 11 , 12 ]. While adverse pregnancy outcomes (APOs), such as gestational diabetes, preeclampsia and preterm delivery, are now recognized as sex-specific risk factors for CVD[ 13 ], infertility and the corresponding usage of ART in relation to long-term CVD risk is less well established. This review seeks to investigate whether pregnancies conceived by ART are associated with established CVD risk factors, as well as short- and long-term CVD outcomes. Furthermore, we will discuss the potential mechanisms behind these associations, as well as recommendations for screening and management to improve long-term cardiometabolic outcomes.