14.1 Introduction

Pregnancy-related cardiovascular complications are rare clinical conditions that can lead to significant maternal morbidity and mortality. With the implementation of infertility treatment, a new selected population of woman can experience pregnancy. Women with multiple medical problems and women near or beyond menopause are now able to conceive. Despite many unanswered questions, clinicians should be prepared for the challenges and potential cardiovascular complications related to patients who are epidemiologically different than those seen in the past.

As a consequence of the combined effect of social changes and medical progress, interventions for infertility have greatly increased in number and sophistication; medical complications of infertility interventions can be direct effects of related drugs and technologies and indirect consequences of the induced pregnancy, multiple gestation, or associated medical condition.

An Italian prospective study conduct in a tertiary university maternity hospital between 2005 and 2016 [1] was done to assess whether risk of severe maternal morbidity at delivery differs for women who conceived using assisted reproductive technology (ART) compared to those with a spontaneous conception using the World Health Organization criteria for potentially life-threatening conditions and near miss maternal mortality. The incidence of near miss in the entire cohort was 3.3 cases per 1000 births (95% confidence interval 2.6–4.1). The crude prevalences of potentially life-threatening conditions and maternal near miss were higher among ART than non-ART deliveries (27.1% vs. 5.7% and 2.6% vs. 0.3%, respectively). The cardiovascular dysfunction requiring vasoactive drugs was one of the three most common causes of maternal near miss cases.

Therefore it is essential to assess whether risk of severe maternal cardiovascular morbidity differs for women who conceives using ART compared to those with a spontaneous conception in order to define qualitative and quantitative strategies to improve patient care, especially in the prevention of severe cardiovascular complications.

14.2 Advanced Maternal Age

Motherhood at or beyond the edge of reproductive age is a new aspect of what clinicians previously referred to as pregnancy in the “older gravida” [2]. In the United States alone, the 2001 rates for births to women aged 35–39, 40–44, and 45–49 years rose 30, 47, and 190% compared with 1990. Specifically, there were about 5000 births to women ≥ 45 years. Some complications may occur more frequently in older mothers as a result of accumulated prior diseases. Hypertension is the most common modifiable risk factor for cardiovascular disease, the leading cause of death in both men and women. The prevalence and severity of hypertension rise markedly with age, and blood pressure control becomes more difficult with aging in both genders, particularly in women [3]. Hypertension is a major risk factor for cardiovascular disease (CVD) in pregnant women. Hypertensive disorders in pregnancy include chronic hypertension, gestational hypertension, pre-eclampsia, and eclampsia. All of these have been associated with maternal, fetal, and neonatal morbidity and mortality. The recent European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension [4] recommend drug treatment of severe hypertension in pregnancy (>160/110 mmHg, Class I; Level of Evidence C) and consideration of drug treatment in pregnant women with persistent elevation of BP 150/95 mmHg and in those with BP 140/90 in the presence of gestational hypertension (with or without pre-existing hypertension), asymptomatic organ damage, or symptoms at any time during pregnancy (Class IIb; Level of Evidence C).

Hypertension occurs in about 8% of women of reproductive age. There are remarkable differences in the prevalence of hypertension between racial/ethnic groups. Obesity is a risk factor of particular importance in this population because it affects over 30% of young women in the USA, is associated with more than fourfold increased risk of hypertension, and is potentially modifiable [5].

Using NHANES from 1999 to 2008, in women 20–44 years old hypertension estimated to complicate up to 5% of the estimated four million pregnancies in the United States each year [6] is a major source of maternal and fetal morbidity. Between 10 and 25% of women with chronic hypertension will develop superimposed pre-eclampsia [7].

The prevalence of hypertension increased significantly with age, from 2.7% in women age 20–34 to 18.4% in women age 40–44. The increased prevalence of hypertension with advanced age may explain the increased cardiovascular risk for some pregnancy complications in women of advanced maternal age. The problem of chronic hypertension in pregnancy is likely to become more common as the number of mothers of advanced age increases, in particular for women who conceive using ART compared to those with a spontaneous conception. Approximately 5% of women of reproductive age took antihypertensive medications. Futhermore, in most epidemiologic studies of women in reproductive age, is defined the upper age limit for statistical analysis of population at 44 years old, but women older than this can become pregnant through assisted reproduction, and hypertension is likely even more prevalent in this group.

Many clinical studies show that the ART singleton pregnancies had a significantly increased risk of pregnancy-induced hypertension [8].

In a meta-analysis of Qin [8], 50 cohort studies comprising 161,370 ART and 2,280,224 spontaneously conceived singleton pregnancies were identified to determine whether there are any increases in pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies after ART compared with those conceived naturally. The ART singleton pregnancies had a significantly increased risk of pregnancy-induced hypertension (relative risk [RR] 1.30, 95% confidence interval [CI] 1.04–1.62; I(2) = 79%), gestational diabetes mellitus (RR 1.31, 95% CI 1.13–1.53; I(2) = 6%), and other adverse pregnancy outcomes. These results are largely related to the increased gestational age of ART pregnancies women. A retrospective cohort study was done in 2015 to determine whether there are differences in adverse pregnancy outcomes in very advanced maternal age (vAMA) women (a total of 472 women aged ≥45 years) who conceived with ART compared with spontaneous conceptions [9]. For singleton pregnancies, vAMA women who conceived with ART were significantly older (47.0 ± 2.3 vs. 45.6 ± 0.1 years), more likely to be white (88.1% vs. 75.6%), and less parous (0.4 ± 0.9 vs. 1.2 ± 1.8) than vAMA women who conceived spontaneously. Rates of cardiovascular maternal complications were similar in the two populations.

The majority of the published studies have been unanimous about the special caution attitude required for the older mother, especially those women who experience pregnancy after ART.

14.3 Metabolic Disorders

Metabolic disorders are a major problem for overweight women seeking pregnancy (Fig. 14.1).

Women with a history of fertility problems have a higher risk of gestational diabetes mellitus (GDM) than women without a history of fertility problems (Fig. 14.2).

The association between fertility problems and risk of GDM is attenuated with increasing age and is more pronounced among primiparous women and women with polycystic ovary syndrome [10].

In the Danish National Patient Registry during 2004–2010 among women with fertility problems (n = 49,616) and women without fertility problems (n = 323,061), after adjustment for potentially confounding factors, including maternal age, prepregnancy BMI, parity, parental history of diabetes, level of education, and smoking during pregnancy, a total of 7433 (2%) pregnant women received a diagnosis of GDM. Multivariate analysis showed that the pregnant women with a history of fertility problems had a statistically significantly higher risk of GDM than pregnant women without fertility problems.

In a population retrospective cohort Australian study of 400,392 mothers between 2007 and 2009, the prevalence of GDM was compared between ART and non-ART mothers [11]. The prevalence of GDM was 7.6% for ART mothers and 5.0% for non-ART mothers (P < 0.01). Mothers who had twins had higher prevalence of GDM than those who gave births to singletons (8.8 versus 7.5%, P = 0.06 for ART mothers; and 7.3 versus 5.0%, P < 0.01 for non-ART mothers). Overall, ART mothers had a 28% increased likelihood of GDM compared with non-ART mothers (AOR 1.28, 95% CI 1.20–1.37). Of mothers who had singletons, ART mothers had higher odds of GDM than non-ART mothers (AOR 1.26, 95% CI 1.18–1.36). There was no significant difference in the likelihood of GDM among mothers who had twins between ART and non-ART (AOR 1.18, 95% CI 0.94–1.48). For mothers aged <40 years, the younger the maternal age, the higher the odds of GDM for ART singleton mothers compared with non-ART singleton mothers. It was not possible to investigate which ART procedure is associated with increased risk of GDM and how the risk could have been minimized.

Women after ART constitute a high-risk group for critical obstetric states not only in the nearest time period but also long after ART. When pregnancy terms exceeded 22 weeks after ART, the percentage of pre-eclampsia and gestation pancreatic diabetes increases, whereas bleeding is the main factor in spontaneously conceived pregnancies [12].

It is uncertain if the increased risk of pregnancy cardiovascular complications related with ART is caused by ART directly or is an association of the underlying factors causing infertility. In a retrospective database analysis of 50,381 women delivering a singleton pregnancy in four public hospital obstetric units in western Sydney [13] (1727 pregnancies followed ART; 48,654 spontaneous conceptions), adjusted for age, body mass index, and smoking, ART was associated with increased risk of hypertension and diabetes. In a selected cohort of 508 women receiving ART in whom the cause of infertility was known, ovulatory dysfunction was present in 145 women and 336 had infertility despite normal ovulatory function. Ovulatory dysfunction was associated with increased risk of diabetes (OR 2.94, 95% CI 1.72–5.02) and hypertension (OR 2.40, 95% CI 1.15–5.00) compared to women with normal ovulatory function. The risk of cardiovascular complications rests predominantly when ovulatory dysfunction is the cause of infertility. Such disorders probably predispose towards diabetes and hypertension, which is then exacerbated by pregnancy. Ovulatory disorders are an independent risk factor for GDM and hypertension in women receiving assisted reproduction treatments [14]. Strong risk factors for GDM are age, body mass index, mode of ART (major in IVF/ICSI than in IUI pregnant) [15], and progesterone use during pregnancy.

The impact of ovulation induction and ovarian stimulation on the risk of GDM and hypertension requires further study. In a large French cohort to evaluate the role of ovarian stimulation procedures on the risk of pregnancy-induced hypertension and GDM, spontaneous pregnancies (group A), pregnancies achieved after mild ovarian ovulation induction without other ART procedures (group B), pregnancies after mild ovarian stimulation and ART procedures (group C), and pregnancies after multi (>2) follicular stimulation with gonadotropin therapy and ART procedures (group D) were selected [16]. The incidence rates of pregnancy-induced hypertension are 2.7, 11.6, 4.2, and 2.5% in groups A, B, C, and D, respectively (P = 0.004). The high incidence of pregnancy-induced hypertension in pregnancies following ovulation induction was driven by polycystic ovarian syndrome (PCOS) per se. In other case, a significant contribution of IVF compared to conception with ovulary induction drugs without IVF was significant only for pre-eclampsia [17].

The exogenous sex hormones, GnRH-a and gonadotropin may affect the sex hormones secretion through hypothalamic-pituitary-gonadal axis and other mechanism, so the hormone-related complications like GDM and pre-eclampsia may occur. Most reports haven’t done the systematic research and could not reveal the correlation between controlled ovarian hyperstimulation (COH), exogenous progesterone treatment, and pregnancy complications.

In a Chinese prospective population-based cohort study [18], the use of Gn was a risk factor in GDM and PE and, as shown in Table 14.1, there was a significant correlation between the dosages of Gn and the incidence of GDM and PE whether adjusted with maternal age, ethnicity, and body mass index. There was not a significant correlation between the exogenous progesterone treatment and the incidence of GDM and PE whether adjusted with maternal age, ethnicity, and body mass index.

Table 14.1

Correlations between the dosages of Gn and pregnancy complications

GDM gestational diabetes mellitus, PE pre-eclampsia

14.4 Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a type of dilated cardiomyopathy of unknown origin that occurs in previously healthy women in the final month of pregnancy and up to 5 months after delivery. The reported incidence of PPCM varies because the diagnosis is not always consistent and a comparison with age-matched nonpregnant women does not exist. Although the incidence is low—less than 0.1% of pregnancies—morbidity and mortality rates are high at 5–30% [19–21].

Several risk factors predispose a woman to PPCM, including increased maternal age, multiparity, multiple pregnancies, and pregnancies complicated by pre-eclampsia and gestational hypertension [22]. Precise mechanisms that lead to PPCM remain poorly defined. During pregnancy, blood volume and cardiac output increase, increase metabolic demands, and afterload decreases because of relaxation of vascular smooth muscle. These changes cause a brief, and reversible, hypertrophy of the left ventricle to meet the needs of the mother and fetus (Figs. 14.3 and 14.4). This transient left ventricular dysfunction during the third trimester and early postpartum period resolves shortly after birth in a normal pregnancy. PPCM might be due, in part, to an exaggerated decrease in left ventricular function when these hemodynamic changes of pregnancy occur. Thus, the onset of PPCM can easily be masked and missed because the manifestations can mimic those of mild heart failure. Women with PPCM most commonly have dyspnea, dizziness, chest pain, cough, neck vein distension, fatigue, and peripheral edema. Women can also have arrhythmias, embolic events due to the dilated dysfunctional left ventricle. They can also have other indications typical of heart failure: hypoxia, jugular venous distention, gallop, rales, and hepatomegaly.

PPCM is a diagnosis of exclusion, and the definitive diagnosis of PPCM depends on echocardiographic identification of new-onset heart failure during a limited period around parturition. A diagnosis of PPCM requires the exclusion of other causes of heart failure: myocardial infarction, sepsis, severe pre-eclampsia, pulmonary embolism, valvular diseases, and other forms of cardiomyopathy.

In PPCM, the electrocardiogram may be normal or may show left ventricular hypertrophy, ST-T wave abnormalities, dysrhythmias, Q-waves in the anteroseptal precordial leads, and prolonged PR and QRS intervals.

Data on clinical outcomes and natural history of PPCM are variable. Most of the women recover completely, but a few develop progressively worsening HF and, ultimately, death.

The prognosis is best when PPCM is diagnosed and treated early. Recommended echocardiographic criteria for diagnosis of PPCM include an ejection fraction (EF) <45% and fractional shortening <30% with a left ventricular end-diastolic measurement of 4.8 cm/m² of body surface area [23].

Functional atrioventricular regurgitation may also be present secondary to ventricular dilatation. Women who recovered early have significantly higher ejection fractions on last follow-up compared with women who has late or partial recovery.

The role of hypertension in PPCM has been unclear; some consider it a risk factor for development of PPC. Pre-eclampsia is often cited as a risk factor for the development of PPCM and recent research suggests that PE and PPCM share mechanisms that contribute to their pathobiology [24].

In a systematic review to identify prevalence rates of PE, hypertension, and multiple gestations in women diagnosed with PPCM, the pooled prevalence of 22% was more than quadruple the 5% average worldwide background rate of PE in pregnancy (P < 0.001). The rates of hypertension during pregnancy (37% [95% CI: 29–45%]) and multiple gestations (9% [95% CI: 7–11%]) were also elevated. In another 2015 retrospective study [25], women diagnosed with PPCM were older than controls. A significantly higher proportion were primiparous (63.9%), carried multifetal pregnancies (33.3%) and had hypertensive pregnancy complications (38.9%). Even if there are no data on direct association between PPCM and ART, 36% of PPCM patients of this population conceived with in vitro fertilization, and six of them received ovum donation. Thus risk factors for peripartum cardiomyopathy include primiparity, hypertension, and multifetal pregnancies; ART are not independently associated with PPCM but rather through other risk factors for PPCM.

Controlled ovarian stimulation by exogenous gonadotropins is a key procedure during the in vitro fertilization cycle to obtain a sufficient number of oocytes in humans. Although generally safe, more studies demonstrated that repeated superovulation had deleterious effects on the ovaries. However, whether repeated superovulation adversely affects on heart function remains unclear. In a 2018 study by Zhang et al., the role of long-term repeated superovulation in ovarian aging and especially in associated disorders such as cardiovascular diseases was investigated [26]. This study used mice as the study model to evaluate the structure and function of ovaries that have previously received ten cycles of repeated superovulation treatments. Heart function was detected by ultrasonography, and heart ejection fraction significantly decreased in the repeated superovulation group mice. These results suggest that repeated superovulation may increase the risk of cardiovascular diseases by accelerating ovarian aging.

OHSS may involve, according to its grade of severity, elevated or decreased levels of growth factors, cytokines, mediators, changes in hormones, renin-angiotensin and kinin-kallikrein system [27]. Reports of high concentration of tumor necrosis factor-α (TNF-α), interferon-γ, interleukin-6, C-reactive protein (CRP), and Fas/apoptosis antigen 1 (Apo-1) in peripartum cardiomyopathy [28] suggest an underlying inflammatory process for the pathophysiologic development of PPCM.

14.5 Management of PPCM: Compensated Heart Failure

No randomized clinical trials have been done to evaluate therapies specifically in PPCM. So management of PPCM is similar to standard treatment for heart failure; careful attention should be paid to fetal safety and to excretion of drug during breastfeeding after delivery. The first aim is to improve symptoms through conventional pharmacologic therapies and, if necessary, nonpharmacologic therapies. The second aim is to effect a cure through the administration of targeted therapies. Treatment focuses on reducing preload and afterload and increasing cardiac inotropy [29]. Polypharmacy may be required for optimal management [30]. Medications should be continued until evidence indicates improved and/or resolved left ventricular dysfunction. Preload reduction is accomplished by administration of vasodilators, such as nitrates, most of which are safe during pregnancy and breastfeeding.

Diuretics are important for management of signs and symptoms; diuretics reduce preload and treat pulmonary congestion or peripheral edema. Both hydrochlorothiazide and furosemide are safe during pregnancy and lactation. However, diuretic-induced dehydration can cause uterine hypoperfusion and maternal metabolic acidosis, so bicarbonate monitoring and management with acetazolamide are needed. Potassium-sparing diuretic spironolactone has been used successfully to treat heart failure [31], but the insufficiency of data regarding its use in pregnancy means that cautious administration is warranted for preload reduction, although caution is warranted in antepartum women because rapid changes in intravascular volume can lead to a decrease in blood supply to the uterus and therefore the fetus [32]. Restriction of dietary sodium is also helpful in preload reduction. Bed rest was once standard care but is no longer recommended because of the increased risk of thromboembolism [33].

Angiotensin-modulating agents are considered first-line drugs for heart-failure management. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve survival but are contraindicated in pregnancy because of their teratogenicity [34, 35]. Also, since they are secreted in breast milk, breastfeeding must be stopped before commencing therapy. Safe alternatives during pregnancy include hydralazine and nitrates [36]. Hydralazine is safe during pregnancy and is the primary vasodilator drug antepartum. More severe cases warrant the use of intravenous nitroglycerin starting at 10–20 μg/min and continuing up to 200 μg/min. Nitroprusside is not recommended because of the potential for cyanide toxicity [37].

β-Blockers are crucial for long-term management of systolic dysfunction. Although safe during pregnancy, β1-selective blockers are preferred over nonselective β-blockers to avoid anti-tocolytic action induced by β2-receptor blockade [38]. Carvedilol combined with a blockade to restrict peripheral vasoconstriction has been shown to be effective in peripartum cardiomyopathy. However, β-blockers should not be given in the early stages of PPCM because they can decrease perfusion in the acute decompensated phase of the disease.

Digoxin, an inotropic and dromotropic agent, is safe to use during pregnancy and calcium channel blockers (dihydropyridines, such as amlodipine) have been shown to successfully reduce interleukin-6 levels in heart-failure patients [39, 40], but concomitant uterine hypoperfusion requires cautious use of these agents.

14.6 ART in Patients with Heart Disease

The incidence of pregnancy in women with cardiovascular disease is rising, primarily due to the increased number of women with congenital heart disease reaching reproductive age and the changing demographics associated with advancing maternal age related to ART treatment. Furthermore, many of these women are delaying pregnancy until later in life when they may be exposed to a greater number of complications from their heart disease. A relatively high proportion of these women will pursue fertility treatment to achieve a pregnancy; consequently, the management of subfertile woman with heart disease is of growing importance. It is also important to consider that fertility therapy failure is anyway associated with an increased risk of long-term adverse cardiovascular events [45]. Women with heart disease have an increased baseline risk of these obstetric and perinatal complications [46, 47]. They may not tolerate additional risks imposed by ART. Although most cardiac conditions are well tolerated during pregnancy and women can deliver safely with favorable outcomes, there are some cardiac conditions that have significant maternal and fetal morbidity and mortality.

Cardiac disease affects approximately 2% of pregnancies in the Western world [48]. Anemia occurs because plasma volume increases more rapidly than does red blood cell mass. Enlargement of left ventricular mass and volume manifests itself as cardiomegaly on chest radiography and as left-axis deviation on electrocardiography. Higher cardiac output is caused early (during the first trimester) by increased stroke volume, and late (after week 20 of gestation) by a rise in heart rate. Fetal compression of the inferior vena cava (when the mother is in the supine position) can diminish cardiac output and thereby contribute to a hypercoagulable state. During labor, cardiac output can increase by 80% (compared with 25% during caesarian section), which leads to fluctuations of blood pressure and venous return. In the Western world, congenital heart disease (such as left to right shunts, left ventricular outflow tract obstruction, Marfan syndrome, hypertrophic cardiomyopathy, unrepaired and repaired cyanotic heart disease) accounts for approximately 80% of cardiac disease during pregnancy. In developing countries, rheumatic heart disease remains the most common cardiac disease during pregnancy (75%), whereas congenital heart disease is much less common (15%). In the United States, hypertensive disorders are the most frequent cardiovascular events, complicating approximately 7% of pregnancies [47]. Acute coronary syndrome [49] is rare (1–2/35,000 pregnancies) but carries a mortality rate of up to 10%. Spontaneous coronary artery dissection, thought to be related to the effects of progesterone, is one manifestation.

Because of thromboembolism, mechanical heart valves are a significant cause of morbidity and—in up to 15% of affected patients—of death. Anticoagulation options include unfractionated heparin or low-molecular-weight heparin as a bridge to warfarin, which has a dose-dependent embryopathy rate of <10%.

Contraindications to pregnancy include pulmonary hypertension, severe systemic ventricular dysfunction (or residual dysfunction from peripartum cardiomyopathy), severe left-sided obstructive lesions, or a dilated aortic root (45 mm with Marfan syndrome or 50 mm with bicuspid aortic valve). Cyanosis with a baseline oxygen saturation level of <85% carries a >85% chance that pregnancy will not result in a live birth. Conversely, a baseline oxygen saturation level of >90% enables a >90% chance of a live birth.

The important question in these patients is does fertility treatment increase the risk of cardiovascular events? However, complications in pregnant women with heart disease treated with ART have not been described, despite parallel trends of delayed childbearing and increasing prevalence of heart disease among reproductive-aged women.

In medical records of women followed in the Pregnancy and Heart Disease Program, the first report of pregnancy outcomes in women with heart disease conceiving by ART [50], the 68% of pregnancies were in women with a congenital heart defect, and 32% in women with acquired heart disease. Most pregnancies were first births (nulliparity, 64%), and 9% were multiples.

All pregnancies resulted in live births, except 1 that was electively terminated at 17 weeks due to fetal omphalocele. Overall, 73% of pregnancies were associated with at least 1 complication. Adverse cardiac maternal outcomes (27% vs. 13%) and fetal or neonatal outcomes (45% vs. 20%) were more common in pregnant women with heart disease conceiving with ART series compared with pregnant women with heart disease not conceiving with ART [46]. Pre-maturity also was more common among infants in this series compared with infants in a reference ART population (32% vs. 13%) [51]. This report highlights the complex medical issues facing modern maternal demographics. ART-treated women with vulnerable heart lesions are at risk of OHSS and thromboembolism. OHSS is a potentially serious complication of ART that may result in fluid shifts, maternal hypotension, thromboembolism, and death. Even mild forms of OHSS may be poorly tolerated in women with ventricular dysfunction, left ventricular outflow tract obstruction, Fontan circulation, or pulmonary arterial hypertension.

Multiple gestations, a further important aspect in ART, remain a significant risk of gonadotropin treatment. Multiple gestations in ART pregnancies are associated with a higher cardiac output compared with single pregnancies. This increased hemodynamic burden can be problematic in women with significant left-sided obstructive valve lesions (such as aortic stenosis) or left ventricular systolic dysfunction. Multiple pregnancies have higher rates of pre-eclampsia and other morbidities that are poorly tolerated in the setting of pre-existing heart disease.

To reduce the risk of multiple pregnancies associated with ART, the number of embryos replaced should be carefully evaluated, according to characteristic such as patient’s heart defect, maternal age, and grade of embryos.

The management of women with heart disease conceiving with ART needs a risk stratification with a thorough cardiovascular history and examination, 12-lead ECG, and accurate echocardiographic evaluation (Fig. 14.5) [52].

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