Progressive calcification of bioprosthetic mitral valve observed during pregnancy resulting from in vitro fertilization: a case report

Abstract

Background

Women with pre-existing cardiac conditions who undergo assisted reproductive technologies (ART) are believed to be at a heightened risk of cardiovascular events during both the treatment and pregnancy phases. An unresolved question within this context pertains to whether the ART procedure itself constitutes a risk factor for individuals with bioprosthetic heart valves (BHV). Additionally, there is ongoing controversy regarding whether pregnancies expedite the process of structural valve degeneration (SVD) in BHV. The purpose of this study is to present the developmental process of BHV calcification, which is considered the primary cause of SVD, during a pregnancy resulting from in vitro fertilization and embryo transfer (IVF-ET), an ART modality, and to elucidate the underlying mechanisms.

Case presentation

At 7 + 3 weeks of gestation in a twin pregnancy resulting from IVF-ET, a 27-year-old woman with a bioprosthetic mitral valve manifesting severe mitral stenosis and moderate pulmonary arterial hypertension, was suspected of SVD. Despite undergoing fetal reduction, she experienced progressive calcification of the bioprosthetic valve, increasing pulmonary arterial pressure and ultimately deteriorated into heart failure. An elective cesarean section and redo valve replacement was subsequently administered to improve her cardiovascular condition. As a result, a healthy young boy was delivered and the dysfunctional BHV was replaced with a mechanical valve. She did not report any discomfort during the 3-month follow-up.

Conclusion

The progressive calcification of the BHV was observed during IVF pregnancy, indicating a potential connection between fertility therapy, pregnancy and calcification of BHV. Pregnant women with pre-implanted BHV should be treated with caution, as any medical interventions during ART and pregnancy can have a significant impact on both maternal and fetal outcomes. Thus, involving a multidisciplinary team in decision-making early on, starting from the treatment of the original heart disease, throughout the entire process of ART and pregnancy, is crucial.

Introduction

Against the backdrop of the increasing usage of fertility therapy, there is a growing body of research that reports on the impact of assisted reproductive technologies (ART) in patients with heart disease recently [1,2,3]. However, it is worth noting that most of these studies are small-scale and predominantly focus on congenital heart disease, with little mention of patients with mechanical prosthetic heart valves (MHV), let alone bioprosthetic heart valves (BHV) [4,5,6]. Moreover, the contentious issue of whether gestation accelerates BHV failure remains unresolved. In light of these circumstances, we present a case study of a woman who became pregnant after ART and subsequently experienced progressive calcification of her mitral BHV. This case serves as an illustrative example highlighting the relationship between fertility treatment, pregnancy, and the calcification of BHV, shedding light on the potential mechanisms involved. Consequently, it underscores the importance of exercising caution and providing prudent care for women in similar situations.

Case presentation

A 27-year-old primigravida was referred to our tertiary hospital (10-17-2022) in the 7 + 3 week’s gemellary pregnancy with New York Heart Association (NYHA) functional class I seeking evaluation and management for her heart condition. Four years ago, she underwent mitral bioprosthesis replacement (Carpentier-Edwards -27) in a local hospital after being diagnosed with asymptomatic mitral valve prolapse through cardiac ultrasound during a routine medical check-up. She did not receive any anticoagulation medication following the surgery. Subsequently, she was diagnosed with infertility due to endometriosis, while her pre-pregnancy check-up showed mild mitral valve lesion on cardiac color Doppler ultrasound. To avoid another two-year period of attempting to conceive, she underwent in vitro fertilization (IVF). And to increase the chances of conception, the two remaining fresh embryos were transferred at a women and children’s hospital on September 16th. Enoxaparin 40 mg/day was administered for three months since then. Transthoracic echocardiography performed at our hospital revealed normal left ventricular size (ejection fraction 67%), but with enlargement of the left atria, right ventricle, and atria, as well as calcification of the bioprosthetic mitral valve (Fig. 1A), severe mitral stenosis (mean gradient 24 mmHg) and severe mitral regurgitation, along with moderate tricuspid regurgitation and moderate pulmonary arterial hypertension (PAH) with an estimated systolic pulmonary arterial pressure (PAP) of 56 mmHg. Additionally, the patient was diagnosed with moderate ovarian hyperstimulation syndrome (OHSS), which was based on the presence of ascites and enlarged ovaries, as confirmed by ultrasound. She also had a lower hematocrit value of 0.298, which further supported the diagnosis. The multidisciplinary team recommended either pregnancy termination or fetal reduction, and the patient opted for the latter. Subsequently, she underwent transvaginal ultrasound-guided fetal reduction at 10 + 6 weeks of gestation (11-9-2022). Five days after the procedure (11-14-2022), transthoracic echocardiography demonstrated slight improvement in her cardiac condition, with a mean mitral gradient of 20 mmHg and an estimated PAP of 52 mmHg. Ascites was aspirated, with the volume over four consecutive days being 3000 mL, 3000 mL, 1000 mL, and 1000 mL, respectively, The left ovary returned to its normal size, while the right ovary decreased in size, and the hematocrit value normalized. The follow-up transthoracic echocardiography revealed progressive aggravation stiffness and calcification of the bioprosthetic mitral valve (Fig. 1B–D), along with a gradual but slight deterioration of mitral stenosis, as well as an increase in PAP (12-19-2022: mean gradient 23 mmHg, estimated PAP 52mmHg; 2-23-2023: mean gradient 28 mmHg, estimated PAP 65 mmHg; 3-20-2023: mean gradient 24 mmHg, estimated PAP 75 mmHg). Moreover, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels gradually increased since then (12-19-2022: NT-proBNP 662.95 pg/mL; 1-6-2023: NT-proBNP 744.22 pg/mL, reference range for the second trimester: 0–200 pg/mL; 2-23-2023: NT-proBNP 934.37 pg/mL, reference range for the third trimester: 0–150 pg/mL). Despite the recommendations from the multidisciplinary team to terminate the pregnancy, the patient expressed a strong desire to continue until 32 weeks.

Fig. 1

Transthoracic echocardiography and cardiac computed tomography examination results. The parasternal long-axis views of two-dimensional echocardiography throughout the pregnancy procedure illustrated the progressive calcification of her bioprosthetic mitral valve (arrow) (A–E). This progression can be inferred from the gradual thickening of the leaflets, narrowing of the orifice diameters (decreasing from 0.871 cm to 0.547 cm), and the enhancement of echoes observed during the examinations conducted on 10-17-2022 (A), 12-19-2022 (B), 2-23-2023 (C), 3-20-2023 (D), and 4-3-2023 (E). Cardiac computed tomography revealed the enlarged pulmonary trunk with a diameter of 44 mm (reference level : < 29 mm), and a higher pulmonary trunk to ascending aorta ratio of 1.632 (reference level: <1.0), both indicating the pulmonary arterial hypertension (F)

To improve cardiac function, restore electrolyte balance, and promote fetal lung maturation, she was prescribed furosemide, potassium magnesium aspartate, and dexamethasone, respectively. Transthoracic echocardiography performed at 31 + 3 weeks of gestation (4-3-2023) revealed an even more rigid BHV (Fig. 1E), worsening mitral stenosis (mean gradient 29 mmHg), an estimated PAP of 85 mmHg, and a small amount of pericardial effusion. The NT-proBNP level elevated to 2047.39 pg/mL, and the patient developed bilateral lower extremity edema, with cardiac function deteriorating to NYHA class III. Following a face-to-face discussion among the multidisciplinary team members, it was determined that a preterm cesarean section was the appropriate course of action considering the severity of the PAH and heart failure.

On 7th April, she underwent delivery with the administration of small-dose combined spinal-epidural anesthesia in the cardiac operating room, with cardiopulmonary bypass standby available. The delivery process was uneventful. A male infant with a small for gestational age was born, weighing 1490 g, and achieved Apgar scores of ten at two, five, and ten minutes. She was subsequently transferred to the cardiac care unit for postoperative monitoring. On the following day after the cesarean section, a bedside echocardiography revealed an improvement in pulmonary arterial pressure (PAP), although it remained elevated at 68 mmHg. Despite the improvement in her medical condition, she displayed low spirits. Consequently, in order to mitigate the risk of postpartum depression, she was promptly transferred to a general cardiology ward once her condition had stabilized. The infant was found to be free of congenital heart disease, and both mother and child were discharged on postpartum day ten.

Following the delivery, despite an improvement in mitral stenosis (as evidenced by a gradual decrease in mean gradient to 18 mmHg), PAH persisted (Fig. 1F). On 31st July, the cardiac surgeon employed an Abbott Master 29 mm mechanical heart valve to replace the original intensively calcified mitral bioprosthesis (Fig. 2). Additionally, the patient underwent tricuspid valve repair using a Carpentier-Edwards MC3 30 mm annuloplasty ring. Postoperative echocardiography demonstrated the absence of both mitral stenosis and PAH, and she did not report any discomfort during the 3-month follow-up.

Fig. 2

Photo of the removed mitral valve. The removed implanted bioprosthetic mitral valve showed significant calcification

Discussion

As indicated by the prevailing trend across all age groups, there has been a notable shift from the usage of MHV to BHV [7]. A recent comprehensive study on a national scale has set out to explore the escalating phenomenon of employing BHV implantation as a substitution for dysfunctional native aortic or mitral valves in women of childbearing age [8]. In contrast to BHV, MHV expose recipients to a heightened risk of thromboembolism, subsequently mandating the lifelong use of anticoagulation medications. Administering anticoagulants to pregnant women further adds complexity, as it involves striking a delicate balance between the risks of teratogenicity, fetotoxicity, and hemorrhage [9]. Remarkably, only 58% of women with MHV manage to attain an event-free pregnancy resulting in a live birth, whereas the figure rises to 79% for those with BHV—figures that are on par with their counterparts devoid of artificial valves [10]. Additionally, the European guidelines advocate the consideration of BHV for young women who aspire to conceive [11]. However, an up-to-date investigation encompassing 5026 pregnant patients, who previously underwent a prosthetic heart valve procedure, derived from the American National Inpatient Samples database spanning the years 2008 to 2019, reveals that BHV and MHV entail comparable risks in terms of maternal and fetal events [12]. This noteworthy outcome not only challenges the established guidelines but also calls into question the Modified World Health Organization (mWHO) classification, which designates patients with MHV as mWHO III—attributing a significantly elevated risk (19–27%) of maternal cardiovascular events— while regarding BHV recipients as being at low risk. This conundrum further underscores a long-neglected paradox: why is BHV deemed hazardous for younger recipients and yet considered safe for younger women of reproductive age?

Nonstructural and structural valve degeneration are major contributing factors to the reduced durability BHV, with SVD being the primary cause of reoperation in BHV patients [13]. The most prevalent pathology associated with SVD is calcification [14], which leads to stenosis and regurgitation, ultimately resulting in BHV failure [15]. Interestingly, women who undergo aortic or mitral valve replacement have a lower likelihood of achieving pregnancy compared to individuals without heart disease [16]. In the case of women seeking conception through ART, such as in the scenario of our patient, it is important to investigate the association between ART, SVD and calcification. By doing this, we aim to identify factors that promote calcification formation in our patient before and during pregnancy, which is the pathologic foundation of subsequent mitral valve stenosis, PAH, and heart failure. Additionally, this investigation may shed light on understanding the aforementioned paradox to some extent.

During the process of IVF, ovarian stimulation involves the administration of follicle-stimulating hormone, resulting in the attainment of supraphysiological levels of circulating estrogen. These levels typically range from a minimum of 5,000 to 6,000 pmol/L, with a tightly regulated peak of 20,000 pmol/L [17]. The escalation of preovulatory estradiol concentrations is increasingly acknowledged as a predisposing factor for the initiation of OHSS subsequent to the administration of human chorionic gonadotropin, which is employed to trigger final oocyte maturation [18, 19]. Following the implantation of the embryo and the establishment of pregnancy, estrogen levels exhibit a further ascent throughout the successive trimesters, ultimately culminating in a peak of approximately 75,000 pmol/L. Estrogen and progesterone have long been postulated to possess substantive cardioprotective properties attributable to their vasodilatory and antihypertensive effects [20, 21]. Furthermore, the decline in estrogen levels has been hypothesized to boost the degeneration and calcification processes affecting the aortic and/or mitral valve among menopausal women [22]. Nonetheless, an early investigation suggested that the aforementioned hormones—namely, estrone, progesterone, and estradiol—can promote calcification of glutaraldehyde-pretreated bovine pericardium, which constitutes the same material employed in the BHV implanted in our patient prior to and during the course of her pregnancy [23]. Moreover, pregnant women exhibit augmented levels of circulating osteopontin relative to non-pregnant women [24], a biomolecule that plays a significant role in the establishment and maintenance of pregnancy [25]. The notable presence of osteopontin within the calcified regions of the BHV, in conjunction with its absence in non-calcified areas, intimates its potential involvement in the calcification process [26].

Different implanted positions are subject to varying risks of BHV calcification, which may be associated with mechanical stress. In general, BHV implanted on the left side of the heart tolerate higher mechanical stress compared to those on the right side. This disparity arises from the fact that aortic and mitral valves are exposed to pressures ranging from approximately 100 to 150 mmHg while valves in the right side bear pressure no more than 30 mmHg [27]. Studies have shown a seven-fold higher risk of SVD in the mitral position compared to the tricuspid position [9]. For BHV in the left heart, the inflow valves of the HeartMate XVE left ventricular assist device are particularly susceptible to calcification compared to the outflow valves [28]. In addition, mitral BHV demonstrate inferior durability relatively to aortic BHV [29, 30], probably due to the greater mechanical stress endured by the mitral valves, including closure pressure and pressure gradient. It has been confirmed that mechanical stress and calcification can mutually reinforce each other. On one hand, stress-driven degeneration of the extracellular matrix integrity possibly promote the deposition of Ca²⁺ on impaired BHV component [31]. On the other hand, increased leaflet stiffness restricts mobility and alters the hydrodynamic characteristics of BHV, causing additional damage and promoting calcification [31]. Therefore, it is evident that mitral BHV, as was the case in our patient, are subjected to the highest mechanical stress among the four heart valves, thereby increasing the likelihood of calcification.

Mechanical stress encompasses flexural, shear, and tensile forces that are systematically and cyclically applied to the heart valves during phases of opening (flexure), blood flow passage (shear stress), closure (flexure), and prevention of retrograde blood flow (tension) [32]. During pregnancy, it is well-established that stroke volume and heart rate increase to accommodate higher blood volume and cardiac output needed for maternal and fetal oxygenation and nutrient supply. The stroke volume, which has a positive correlation with shear stress [33]. increases by 30% during singleton pregnancy [34], and by an additional 15% during twin pregnancy [35]. Heart dimensions increase proportionally with cardiac volume, resulting in orifice area enlargement of aortic, pulmonary, and mitral valves [36]. Annular dilation poses a challenge for leaflets coaptation, leading to increased curvature radius and tensile stress [37]. This tensile stress has been identified as the primary stress on the valves [38]. In an annular dilatation model resembling pregnancy, researchers confirmed that mitral leaflets experience twice the stress compared to normal conditions [39]. Furthermore, during the cardiac cycle, the stress imposed on the mitral valve rapidly increases during the isovolumetric contraction phase due to the prompt buildup of left ventricular pressure [40]. This phase tends to be prolonged as a result of left ventricular systolic dysfunction in pregnant women [41]. Considering the interrelated relationship between calcification and mechanical stress, one might anticipate a progressive calcification process, subsequent SVD, mitral valve stenosis, PAH, and heart failure during pregnancy, as observed in our patient and reported in a systematic review and meta-analysis of 722 pregnancies with mechanical or tissue valves [42]. However, the impact of pregnancy on the accelerated SVD of BHV remains controversial, as some researchers have found evidence contradicting this theory [43, 44], while others consider it a significant factor or establish it as background knowledge [45, 46].

Moreover, it is imperative to acknowledge the distinct effects of each treatment choice on cardiac patients prior to, during, and after pregnancy. Evidently, the decisions made for this specific patient prior to her presentation at our medical facility were lacking in terms of collaboration and shared decision-making involving a multidisciplinary team, which should consist of gynecologists, obstetricians, cardiologists, cardiac surgeons, anesthesiologists, fertility specialists, cardiopulmonary bypass surgeons, surgical intensive care unit specialists, and psychologists. In actuality, several aspects of decision-making could have been optimized. In comparison to the delayed freeze-all strategy, the patient opted for fresh embryo transfer, thereby introducing a higher susceptibility to OHSS and cardiovascular events during pregnancy [17, 47]. Furthermore, it is widely recognized that pregnancies involving multiple gestations pose elevated risks as compared to singleton pregnancies, dispelling the notion that twin pregnancies are a “two for the price of one” scenario [2]. Caring for women of childbearing age with cardiac conditions is a laborious and resource-intensive endeavor, particularly in developing nations. However, this comprehensive approach undeniably minimizes patient suffering and has the potential to reduce the necessity or, at the very least, delay the need for reoperations and subsequent therapeutic expenditures.

Conclusion

Against the backdrop of the shifting trend from MHV to BHV, we enumerate the hormone- and stress-related factors regarding assisted reproductive technologies, implantation position, and pregnancy, deliberating their potential significance in promoting BHV calcification procedure prior and during gestation by presenting a vivid practical example, seeking to alert that patients with BHV should not be treated lightly. Meanwhile, it is worthwhile to reemphasize the importance of multidisciplinary collaboration not merely during the course of pregnancy but, in fact, commencing from the moment of cardiac diseases diagnosis.

Data availability

No datasets were generated or analysed during the current study.