Waltraut M. Merz

Pregnancy in Women With a Mechanical Heart Valve Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC)

Background— Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity. Methods and Results— Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve (P=1.000), and in 0.2% of patients without a prosthetic valve (P=0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve (P<0.001), and in 4.9% of patients without a prosthetic valve (P<0.001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve (P<0.001) and 78% of patients without a prosthetic valve (P<0.001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2%; P<0.001) and late fetal death (7.1% versus 0.7%; P=0.016). Conclusions— Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care.Background— Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity. Methods and Results— Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve ( P =1.000), and in 0.2% of patients without a prosthetic valve ( P =0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve ( P <0.001), and in 4.9% of patients without a prosthetic valve ( P <0.001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve ( P <0.001) and 78% of patients without a prosthetic valve ( P <0.001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2%; P <0.001) and late fetal death (7.1% versus 0.7%; P =0.016). Conclusions— Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care. # CLINICAL PERSPECTIVE {#article-title-24}

Circulating N-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment

Background:N-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established marker of heart failure in adult cardiology. We analyzed nt-proBNP in the circulation of fetuses with increased volume load secondary to anemia and investigated the effect of treatment on nt-proBNP concentration.Methods:Fetuses undergoing intrauterine transfusion (IUT) were examined. nt-proBNP was measured before IUT and correlated with hemoglobin concentrations, ultrasonographic findings, and Doppler measurements of the peak systolic velocity of the middle cerebral artery (MCA-PSV).Results:A total of 27 patients (7 with hydrops) and 78 controls were examined. nt-proBNP was markedly elevated in anemia (P < 0.001). Concentrations were highest in hydropic fetuses (P < 0.03); no differences were present in hemoglobin and MCA-PSV values between hydropic and nonhydropic cases. In fetuses undergoing multiple IUTs nt-proBNP normalized after the third IUT, whereas hemoglobin and MCA-PSV remained abnormal.Conclusion:Levels of circulating nt-proBNP correlate well with the degree of myocardial workload in the hyperdynamic state of fetal anemia. We hypothesize that normalization of nt-proBNP after serial transfusions is an indicator of myocardial adjustment to chronic anemia. nt-proBNP measurement may be useful in the management of fetal anemia, particularly in cases at risk of hydrops and fetuses requiring multiple transfusions.

Reference values for N-terminal pro-B-type natriuretic peptide in fetal circulation between 20 and 34 weeks of gestation.

OBJECTIVE We aimed to investigate the range of fetal NT-proBNP values in normal pregnancy between 20 and 34 weeks of gestation. METHOD NT-proBNP was measured in 56 fetal blood samples. RESULTS Mean (+ or - 2 SD) NT-proBNP concentration was 1998 (242-3754) ng/L; a significant decline occurred with advancing gestational age (p=0.012). CONCLUSIONS Gestational age has to be taken in to consideration in the assessment of NT-proBNP. Our data may be used as reference values in fetal and neonatal medicine.

High-risk pregnancy management in women with hypopituitarism

Pregnancy after complete loss of pituitary function is uncommon. However, advances in fertility treatment have led to increased pregnancy rates in hypopituitary women. We hereby present a literature review of pregnancies affected by hypopituitarism, including a comparison with published controls; further, we add one case report of severe hypopituitarism where third-trimester oxytocin supplementation was performed. As only limited information is available on management and outcome, our purpose was to determine obstetric complications associated with deficiency of pituitary hormones. The analysis of 31 pregnancies in 27 women revealed that hypopituitary women are at increased risk: postpartum hemorrhage occurred in 8.7%, transverse lie in 16%; 42.4% of the newborns were small for gestational age. These findings are supposedly the result of uterine dysfunction caused by hormone deficiency. Oxytocin supplementation was performed with the aim to establish physiologic conditions and to prevent postpartum uterine inertia. In this case substitution may have contributed to correct fetal presentation but did not prevent postpartum hemorrhage. Further investigations into both oxytocin-dependent and -independent mechanisms regulating uterine contractions and contractility are necessary to develop strategies for prevention of uterine inertia in oxytocin-deficient pregnancies.

Determinants of brain-derived neurotrophic factor (BDNF) in umbilical cord and maternal serum.

OBJECTIVE Brain-derived neurotrophic factor (BDNF) plays a fundamental role in brain development; additionally, it is involved in various aspects of cerebral function, including neurodegenerative and psychiatric diseases. Involvement of BDNF in parturition has not been investigated. The aim of our study was to analyze determinants of umbilical cord BDNF (UC-BDNF) concentrations of healthy, term newborns and their respective mothers. METHODS This cross-sectional prospective study was performed at a tertiary referral center. Maternal venous blood samples were taken on admission to labor ward; newborn venous blood samples were drawn from the umbilical cord (UC), before delivery of the placenta. Analysis was performed with a commercially available immunoassay. Univariate analyses and stepwise multivariate regression models were applied. RESULTS 120 patients were recruited. UC-BDNF levels were lower than maternal serum concentrations (median 641 ng/mL, IQR 506 vs. median 780 ng/mL, IQR 602). Correlation between UC- and maternal BDNF was low (R=0.251, p=0.01). In univariate analysis, mode of delivery (MoD), gestational age (GA), body mass index at delivery, and gestational diabetes were determinants of UC-BDNF (MoD and smoking for maternal BDNF, respectively). Stepwise multivariate regression analysis revealed a model with MoD and GA as determinants for UC-BDNF (MoD for maternal BDNF). CONCLUSIONS MoD and GA at delivery are determinants of circulating BDNF in the mother and newborn. We hypothesize that BDNF, like other neuroendocrine factors, is involved in the neuroendocrine cascade of delivery. Timing and mode of delivery may exert BDNF-induced effects on the cerebral function of newborns and their mothers.

Diagnosis, treatment and application of color Doppler in conservative management of abnormally adherent placenta.

PURPOSE Placenta ac-, in-, percreta is rare, but associated with high maternal morbidity. We report the results of diagnosis and management of patients with this condition at our institution. Serial color Doppler examinations were performed to investigate the pattern and duration of perfusion to abnormally adherent placenta after conservative treatment. The influence of these results on management decisions was evaluated. MATERIALS AND METHODS Women with placenta ac-, in-, percreta delivering within a three-year interval were included. Diagnosis was established by ultrasound, color Doppler, MRI, and histology specimen. B-mode ultrasound and color Doppler were applied post-operatively. RESULTS Fifteen cases of placenta ac-, in-, percreta occurred (0.29% of deliveries). 73.3% were associated with placenta previa, 66.6% had > or = 1 previous uterine surgery. Abnormal placentation was diagnosed antenatally in 5/15 cases; in these women complication rate (0/5 vs. 8/10, p = 0.12) and blood loss was significantly lower (mean 1.140 vs. 3.080 ml, p < 0.01). 8/15 women underwent Cesarean hysterectomy, 2 after embolization of uterine arteries. 7/15 women had conservative management. In 3 of these cases complete removal of the placenta was achieved; in the remaining 4 the entire (n = 2) or parts (n = 2) of the placenta were left in place, methotrexate was administered postoperatively, and close clinical and laboratory controls were performed. Serial color Doppler examinations revealed cessation of blood flow to the adherent tissue 9 - 13 weeks postoperatively, followed by complete resorption (n = 1)/expulsion (n = 1) of placental fragments. In two cases (placenta previa percreta) curettage was performed without major complications after negative blood flow. CONCLUSION The high maternal morbidity of placenta ac-, in-, percreta can be reduced with antenatal diagnosis and elective delivery. Conservative management of placenta percreta may be considered in selected cases, with embolization and/or methotrexate as an adjuvant therapy. Serial examinations of the perfusion in the retained placental tissue allow conclusions about the degree of involution and aid in determining the appropriate timing of curettage if necessary.

Pregnancy in women with hypertrophic cardiomyopathy : data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC)

Aims We report the maternal and foetal outcomes at birth and after 6 months in a cohort of pregnant women with hypertrophic cardiomyopathy (HCM). Although most women with HCM tolerate pregnancy well, there is an increased risk of obstetric and cardiovascular complications. Methods and results All pregnant women with HCM entered into the prospective worldwide Registry of Pregnancy and Cardiac disease (ROPAC) were included in this analysis. The primary endpoint was a major adverse cardiovascular event (MACE), which included death, heart failure (HF), thrombo-embolic event, and arrhythmia. Baseline and outcome data were analysed and compared for patients with MACE vs. without MACE and for patients with obstructive HCM vs. non-obstructive HCM. Sixty pregnant women (mean age 30.4 ± 6.0 years) with HCM (41.7% obstructive) were included. No maternal mortality occurred in this cohort. In 14 (23%) patients at least one MACE occurred: 9 (15.0%) HF and 7 (12%) an arrhythmia (6 ventricular and 1 atrial fibrillation). MACE occurred most commonly during the 3rd trimester and postpartum period. In total, 3 (5.0%) women experienced foetal loss. Women with MACE had a higher rate of emergency Caesarean delivery for cardiac reasons (21.4% vs. 0%, P = 0.01). No significant differences in pregnancy outcome were found between women with obstructive and non-obstructive HCM. NYHA functional class of ≥II and signs of HF before pregnancy, were associated with MACE. Conclusion Although most women with HCM tolerated pregnancy well, cardiovascular complications were not uncommon and predicted by pre-pregnancy status facilitating pre-pregnancy counselling and targeted antenatal care.

Conception, Pregnancy, and Lactation Despite Chronic Intestinal Failure Requiring Home Parenteral Nutrition.

BACKGROUND Short-term parenteral nutrition is commonly accepted to be safe in pregnancy, but knowledge about the management of pregnancy during long-term home parenteral nutrition (HPN) is sparse. METHODS AND RESULTS A systematic literature review revealed that the published experience is limited to 15 pregnancies with parenteral nutrition from preconception to delivery and beyond. Maternal morbidity was surprisingly low, and fetal outcome was good; however, micronutrient deficiencies may have contributed to fetal anomalies. Herein, we additionally report the case of a 26-year-old Caucasian woman with long-term HPN dependence secondary to short bowel syndrome caused by recurrent thromboembolic mesenteric infarctions who delivered a healthy fetus at 37 weeks of gestation. Individual macronutrient support and adequate micronutrient supplementation ensured normal maternal weight gain and fetal development. Based on the individual maternal risk of recurrent thrombosis, anticoagulant treatment was carefully titrated throughout pregnancy. Furthermore, loss of abdominal domain with a rigid maternal abdominal wall secondary to short bowel syndrome and multiple laparotomies resulted in food intolerance during the third trimester. Still, with multidisciplinary efforts, both mother and the breast-fed infant were in good health at 12 months after delivery. CONCLUSIONS Taking the reported literature into consideration, we conclude that under the premise of optimal medical care, the risk:benefit ratio for pregnancy of HPN-dependent women seems to be justifiable. To minimize the risks, we recommend preconception counseling and early referral to a tertiary center offering both a high-risk pregnancy unit and a nutrition service. In particular, maternal micronutrient levels should be monitored.

Old tool – new application: NT‐proBNP in fetal medicine

Cardiovascular dysfunction may develop in fetuses with structural cardiac defects; congestive cardiac failure, however, occurs rarely during fetal life, because the parallel arrangement of the circulation allows redistribution of blood flow between the left and right cardiac chambers and great arteries. More frequently, myocardial compromise and failure arise in fetuses with primary myocardial diseases and cardiomyopathies and in conditions which are associated with increased cardiac output (e.g. arteriovenous malformations, sacrococcygeal teratoma, anemia) or altered intrathoracic volume relations (e.g. cystic-adenomatoid pulmonary malformation); twin–twin transfusion syndrome (TTTS) in monochorionic pregnancies and fetal growth restriction (FGR) are also complicated by various degrees of myocardial dysfunction. A number of these disorders are amenable to intrauterine treatment; for others, close surveillance and timely delivery result in improved fetal–neonatal outcomes1–6. Despite recent progress, various aspects of intrauterine surveillance and therapy are still unresolved. For intrauterine treatment, these pertain to case selection, timing of intervention, establishment of prognosis with and without intervention, and evaluation of treatment. For disorders without prenatal treatment options, the timing of delivery, particularly in early-onset cases, in which the benefit of fetal maturation needs to be gauged against the danger of irreversible damage or intrauterine demise, is critical7–15. Image-based investigations, including two-dimensional and M-mode echocardiography and Doppler studies of the fetal and placental circulation, allow functional assessment of the cardiovascular system. New techniques, such as threeand four-dimensional (3D/4D) ultrasound, tissue Doppler and speckle tracking complement the diagnostic armamentarium, allowing quantitative analysis of fetal cardiac function. Limitations include the large interand intraobserver variability and the strong influence of cardiac loading conditions16–20. Problems with non-invasive electrocardiography (ECG)-gating and motion artifacts restrict utilization of magnetic resonance imaging (MRI) in fetal cardiac imaging at present21–23. In adult cardiology, various classes of biomarker are available for diagnosis, differential diagnosis, case selection, intervention, determination of prognosis and follow-up in patients with cardiovascular diseases; N-terminal pro-B-type natriuretic peptide (NT-proBNP), the inactive cleavage product of brain natriuretic peptide (BNP), is one of these24–27. Its concentration in heart failure reflects various aspects of myocardial pathophysiology; several clinical trials have tested the utility of NT-proBNP-guided heart-failure therapy28,29. The purpose of this Editorial is to present an update on the application of NT-proBNP as a biomarker of myocardial dysfunction during fetal life. Physiology and metabolism are discussed first, particularly within the context of intrauterine development, followed by a survey of the current state of research, including present and possible future clinical applications.

Cardiorenal Syndrome is Present in Human Fetuses with Severe, Isolated Urinary Tract Malformations

Objective We analyzed the association between renal and cardiovascular parameters in fetuses with isolated severe urinary tract malformations. Methods 39 fetuses at a mean gestational age of 23.6 weeks with nephropathies or urinary tract malformations and markedly impaired or absent renal function were prospectively examined. Fetal echocardiography was performed, and thicknesses of the interventricular septum, and left and right ventricular wall were measured. Blood flow velocity waveforms of the umbilical artery, middle cerebral artery, and ductus venosus were obtained by color Doppler ultrasound. Concentrations of circulating n-terminal pro-B-type natriuretic peptide (nt-proBNP), cystatin C, ß2-microglobulin, and hemoglobin were determined from fetal blood samples. Results Malformations included 21 cases of obstructive uropathy, 10 fetuses with bilateral nephropathy, and 8 cases of bilateral renal agenesis. Marked biventricular myocardial hypertrophy was present in all cases. The ratio between measured and gestational age-adjusted normal values was 2.01 (interventricular septum), 1.85, and 1.78 (right and left ventricular wall, respectively). Compared to controls, levels of circulating nt-proBNP were significantly increased (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L); p<0.001). Cystatin C and ß2-microglobulin concentrations were elevated as follows (mean ± SD) 1.85±0.391 mg/L and 8.44±2.423 mg/L, respectively (normal range 1.66±0.202 mg/L and 4.25±0.734 mg/L, respectively). No correlation was detected between cardiovascular parameters and urinary tract morphology and function. Despite increased levels of nt-proBNP cardiovascular function was preserved, with normal fetal Doppler indices in 90.2% of cases. Conclusion Urinary tract malformations resulting in severe renal impairment are associated with biventricular myocardial hypertrophy and elevated concentrations of circulating nt-proBNP during fetal life. Cardiovascular findings do not correlate with kidney function or morphology.