Ultrasound Obstet Gynecol 2014; 44: 532–537 Published online 22 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13438
Maternal aspects of fetal cardiac intervention C. WOHLMUTH*†, G. TULZER*, W. ARZT‡, R. GITTER* and D. WERTASCHNIGG*†‡ *The Children’s Heart Center, Linz, Austria; †Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, Austria; ‡Department of Prenatal Medicine, Women’s and Children’s Hospital, Linz, Austria
K E Y W O R D S: fetal cardiac intervention; fetal surgery; intrauterine valvuloplasty; maternal–fetal surgery; maternal morbidity; percutaneous ultrasound-guided procedure
ABSTRACT Objectives Fetal cardiac interventions have the potential to alter natural disease progression and reduce morbidity and mortality in children. Although there are already encouraging data on fetal outcome, information on maternal morbidity and mortality after intervention is scarce. The aim of the present study was to assess maternal aspects, pregnancy-associated risks and adverse events in 53 intrauterine cardiac interventions. Methods Between October 2000 and December 2012, 53 fetal cardiac interventions were performed in 47 patients (43 aortic valve dilations in 39 patients, seven pulmonary valve dilations in six patients and three balloon atrioseptostomies in two patients). Median gestational age was 26 + 4 (range, 20 + 3 to 33 + 1) weeks. Interventions were performed by an ultrasound-guided percutaneous approach under general anesthesia. All medical records and patient charts were analyzed retrospectively. Results All women were considered to be healthy in the preoperative assessment; 39 (83%) patients continued pregnancy until term and eight of 47 patients had an intrauterine fetal death (IUFD) and were induced. Postoperative nausea was reported in 29.8% of patients and abdominal pain in 36.2% of patients on the day of surgery. Preterm contractions were observed in two patients; no preterm prelabor rupture of membranes occurred. One severe postpartum hemorrhage was observed in a patient with IUFD and subsequent induction; however, this was unrelated to the balloon valvuloplasty. No intensive care unit admission and no major anesthesia-associated complications (aspiration, anaphylactic reaction, cardiovascular collapse, damage to teeth, laryngeal damage, awareness or hypoxic brain damage) were observed. Maternal mortality was zero. A significant learning curve was observed in terms of duration of intervention.
Conclusion In our experience, percutaneous needleguided fetal cardiac intervention seems to be a safe procedure for the mother. In 53 procedures no major maternal complication directly related to the intervention was observed. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION As a result of the increasingly widespread offer of prenatal scanning and great technical progress in imaging facilities, a growing number of congenital anomalies are diagnosed and observed early before birth. With better understanding of the natural course and often unsatisfactory intrauterine disease progression1,2 , attempts to influence specific conditions and alter disease progression before birth have been initiated3 . In 1991, Maxwell and coworkers reported technically feasible and successful fetal balloon dilation of the aortic valve for the first time4 . Since then, several dedicated centers have repeatedly performed fetal cardiac surgery in a selected patient collective. Newer attempts allowed intervention not only in aortic stenosis, but also in right outflow tract obstruction and hypoplastic left heart syndrome (HLHS) with restrictive foramen ovale5 – 9 . Prenatal balloon valvuloplasty of stenotic or atretic semilunar valves performed in a timely manner may alter natural disease history, prevent evolution of end-stage hypoplastic left or right heart syndrome and direct treatment towards postnatal biventricular repair under optimal circumstances. In fetuses with HLHS, an intact or restrictive atrial septum is a strong risk factor for poor outcome caused by lymphangiectasia, muscularized pulmonary veins and elevated pulmonary vascular resistance, even with timely prenatal diagnosis and early postnatal intervention10 – 12 . Fetal cardiac intervention is an invasive procedure performed to treat the fetus while the anesthetized mother
¨ Correspondence to: Dr C. Wohlmuth, Department of Obstetrics and Gynecology, Paracelsus Medical University, Mullner Hauptstraße 48, 5020 Salzburg, Austria (e-mail: [email protected]) Accepted: 30 May 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Maternal aspects of fetal surgery who undergoes surgery is solely a bystander; the procedure is without direct benefit to her and thus is an altruistic act by the mother on behalf of her unborn child13 . Hence, it is especially critical to know the possible adverse effects on both mother and pregnancy to ensure appropriate pre-interventional counseling and accurate risk–benefit consideration. Whilst there are already experiences on technical success and outcome of the children following fetal cardiac interventions8,14 – 16 , there is currently still a paucity of data concerning maternal aspects. The Children’s Heart Center Linz is one of the few dedicated fetal cardiac surgery centers worldwide, with referrals from many European countries. The purpose of this study was to assess maternal aspects, maternal morbidity and mortality, as well as complications in pregnancy after fetal cardiac interventions. We provide a single-center experience on outcome of mother and pregnancy after intrauterine balloon valvuloplasties and balloon atrioseptostomies (BAS) between 2000 and 2012.
METHODS Between October 2000 (the first procedure) and December 2012, 53 percutaneous ultrasound-guided fetal cardiac interventions were carried out. All patients undergoing fetal cardiac intervention in our department were included in this study. Medical records and patient charts were analyzed retrospectively. All potential candidates underwent fetal echocardiography at our department at their first visit. They were evaluated carefully, by both a pediatric cardiologist and a maternal–fetal medicine specialist, to establish whether they met the inclusion criteria for intervention. The criteria for patient selection and intervention were as previously published17 . Maternal exclusion criteria were any disease that significantly increases the risk of undergoing general anesthesia (defined as American Society of Anesthesiologists (ASA) physical status > 2) or impaired psychological state. No patients were excluded for a maternal reason. Our local Ethics Committee endorsed the study protocol before data acquisition, and informed consent was obtained after careful discussion before intervention. In a detailed counseling session, parents were offered three possibilities: (1) close prenatal follow up and optimal timing of delivery; (2) fetal cardiac intervention; and (3) termination of pregnancy. The following data were collected: maternal age, gestational age at intervention and delivery, body mass index (BMI), mode of delivery, ASA physical status classification, duration of intervention (defined as anesthesia time), postoperative nausea and vomiting (PONV; assessed by anti-emetic requirement on the day of intervention), postoperative pain (assessed by analgesia requirement on the day of intervention), aspiration, death, need for blood transfusions within 1 week of intervention, intensive care unit admission, mode of anesthesia, anesthesia-associated complications, preterm labor, administered tocolytics, preterm prelabor rupture of membranes (PPROM),
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chorioamnionitis (defined as the presence of typical clinical findings: fever, uterine fundal tenderness, maternal tachycardia (>100/min), fetal tachycardia (>160/min)18 ), length of hospital stay and administration of digitalis. Patients were divided into three groups according to the type of fetal cardiac surgery: aortic valvuloplasty; pulmonary valvuloplasty; and BAS. Fetal lie and anatomy were assessed by ultrasound (Voluson E8; GE Healthcare GmbH, Solingen, Germany). When the fetus was considered to be in a suitable position, general anesthesia of the mother (and transplacentally of the fetus) was induced with either propofol or thiopental, depending on the anesthesiologist’s preference. Continuous anesthesia and uterine relaxation were achieved by volatile anesthetics (Sevoflurane®), and analgesia of the fetus was accomplished by remifentanil-perfusor 0.1 μg/kg/h via the mother. No additional premedication was applied to the fetus. Before 24 weeks of gestation, a 19-gauge needle was used; in all other patients an 18-gauge needle (Cook Medical® Trocar Needle; Cook Medical Inc., Bloomington, IN, USA) was introduced under ultrasound guidance through the maternal abdomen and then through an intercostal space or through the fetal abdomen, as soon as fetal movement stopped following anesthesia induction. Depending on the type of fetal cardiac intervention, the tip of the needle was placed in the left ventricle, directly in front of the stenotic aortic valve (critical aortic stenosis), in the right ventricle through the pulmonary valve into the right ventricular outflow tract (pulmonary atresia) or through the right atrium across the atrial septum into the left atrium (BAS). A balloon catheter with a diameter of 3.00–4.48 mm was introduced through the needle, manipulated across the point of constriction and dilated three to five times. After a successful procedure, the whole ensemble was withdrawn from the heart. Postoperative care included close maternal and fetal monitoring. Before discharge, in all fetuses positive inotropic treatment with digoxin was initiated via the mother after obtaining a maternal electrocardiogram and exclusion of contraindications. Digoxin 0.2 mg was administered intravenously three times a day for 2 days and then digoxin 0.1 mg was given orally four times a day until delivery. Mothers were followed up by the instructed general practitioner or the referral hospital with a weekly routine check of the digoxin serum level on a regular appointment basis.
Statistical analysis Continuous data are expressed as mean ± SD or median with range, as appropriate. Differences between two groups were compared using the unpaired Student’s t-test. Differences between more than two groups were analyzed by ANOVA. If a significant difference was evident, Tukey- or Games–Howell post-hoc tests were carried out, as appropriate. Correlation was determined using the Pearson correlation coefficient. All calculations were carried out with SPSS 21.0 (IBM, Armonk, NY,
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USA). P < 0.05 was considered to indicate a statistically significant difference, as generally accepted; a trend was defined as P = 0.10–0.05.
RESULTS Between October 2000 and December 2012, 53 fetal cardiac interventions were carried out in 47 patients (six patients underwent a repeat procedure because of either technical failure during the first procedure or disease progression), as follows: 43 aortic valve dilations in 39 patients; seven pulmonary valve dilations in six patients; and three BAS in two patients. The number of interventions per year in our department is shown in Figure 1. We performed percutaneous needle-guided surgery in all cases, in contrast to the Boston group15,16,19 , in which minilaparotomy was carried out in some cases to improve position and imaging. Twenty-one (44.7%) patients were Austrian citizens; the remaining 26 were referred from other European countries and all were Caucasian. Median maternal age at intervention was 28 (range, 19–38) years; and 53% of
women were nulliparous, 32% were para 1, 13% para 2 and 2% para 3. Patient characteristics are given in Table 1. In the preoperative anesthesiology assessment, all women were considered to be in good health. Placental location was described as mainly anterior in 45% and mainly posterior in 55%, respectively. There was no difference in maternal age among the three groups. BMI was lower in the pulmonary valvuloplasty compared with the aortic stenosis group (20.6 vs 26.8 kg/m2 , P = 0.003). Median gestational age at intervention was 26 + 4 (range, 20 + 3 to 33 + 1) weeks. Median anesthesia time in all procedures was 59 (range, 11–235) min; pulmonary valve dilation tended to take longer (109 (range, 64–146) min; P = 0.06). With increasing experience we observed a significant learning curve: duration of aortic balloon valvuloplasty was significantly shorter after the first 15 procedures were carried out (80 min vs 51 min, P = 0.036). There was no significant correlation between BMI and duration of intervention. Thirty-nine of 47 patients continued pregnancy; intrauterine fetal death (IUFD) within 7 days of intervention occurred in seven (14.8%) patients and one IUFD was observed 20 days later. Preterm contractions were
Fetal cardiac interventions per year (n)
10
9
9
8
8 7
6
6
5
5
4
4 3 2 1 0
8
7
2 1
1
1
1 0
2000
2001
2002
2003
2004
2005
2006 Year
2007
2008
2009
2010
2011
2012
Figure 1 Number of fetal cardiac interventions performed per year in our department since program initiation. Table 1 Characteristics of the 47 patients who underwent fetal cardiac surgery, according to type of intervention
Characteristic Patients continuing pregnancy Maternal age at intervention (years) GA at intervention (weeks) Body mass index (kg/m2 ) Gravidity Parity Smoker ASA physical status 1 2
AS (n = 39)
PA-IVS (n = 6)
HLHS-IAS (n = 2)
All patients (n = 47)
32 27 (19–38) 26 + 4 (20 + 3 to 33 + 1) 26.8 (19.3–39.5) 1 (1–7) 0 (0–3) 1 (2.6)
6 29 (25–34) 29 + 0 (25 + 1 to 32 + 0) 20.6 (17.5–24.4) 2 (1–2) 1 (0–1) 0 (0)
1 31 (28–35) 26 + 3 (26 + 0 to 26 + 6) 25.7 (24.6–26.8) 2.5 (2–3) 1 (0–2) 0 (0)
39 28 (19–38) 26 + 4 (20 + 3 to 33 + 1) 26.1 (17.5–39.5) 1 (1–7) 0 (0–3) 1 (2.1)
32 (79.5) 7 (20.5)
6 (100) —
2 (100) —
40 (85) 7 (15)
Data are given as median (range), n or n (%). AS, critical aortic stenosis; ASA, American Society of Anesthesiologists; GA, gestational age; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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Table 2 Procedure information and maternal morbidity and mortality in the 53 fetal cardiac interventions performed in the study AS (n = 43)
PA-IVS (n = 7)
HLHS-IAS (n = 3)
All interventions (n = 53)
55 (11–235) 2 (1–6) 0 2 2 7 0 11 14 0 0 0 0 0
109 (64–146) 2 (1–2) 0 0 0 0 0 1 2 0 0 0 0 0
71 (31–104) 2 (1–5) 0 0 0 1 0 2 1 0 0 0 0 0
59 (11–235) 2 (1–6) 0 2 2 8 0 14 17 0 0 0 0 0
Variable Duration of intervention (min) Time interval between intervention and discharge (days) Preterm prelabor rupture of membranes Threatened premature labor Tocolysis Intrauterine fetal death Digitalis-associated complications/intoxication Postoperative nausea and vomiting Postoperative pain Bleeding requiring blood transfusion Intensive care unit stay (days) Chorioamnionitis Wound infection Intra-/perioperative maternal mortality
Data are presented as n or median (range). AS, critical aortic stenosis; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
observed in two patients following intervention. In both cases, tocolysis with hexoprenaline (Gynipral®) was subsequently initiated and preterm labor was successfully alleviated. One patient continued pregnancy for 6 weeks before premature contractions recurred and was delivered at 33 weeks. The second patient continued pregnancy until term. In the 53 interventions carried out in our department, no PPROM was observed as being directly related to the procedure. No major maternal bleeding occurred and none of the patients received blood products following fetal cardiac surgery. One of the IUFD patients – induced on the first day after intervention – had a severe postpartum hemorrhage because of retained placental tissue and uterine atony, necessitating curettage, six units of packed red cells and pooled plasma. She left the operating theater hemodynamically stable, could be transferred to the general ward and was discharged 4 days later. Intensive care admission was not necessary in any patient. Fourteen (29.8%) women reported postoperative nausea and vomiting on the day of intervention and were given antiemetic treatment. Seventeen (36.2%) patients reported abdominal pain or headache after surgery that was easily controlled by acetaminophen in 14 patients with mild pain (World Health Organization (WHO) pain management step 1). In three patients who described moderate to severe pain, a single dose of opioids (piritramide, Dipidolor® (WHO step 3)) was administered; all patients confirmed proper pain relief. There was no correlation between pain and duration of intervention (P = 0.37). No major anesthesia-associated complications were observed (aspiration, anaphylactic reaction, cardiovascular collapse, damage to teeth, laryngeal damage, awareness or hypoxic brain damage); perioperative maternal mortality was zero. Chorioamnionitis or wound infection was not observed. Thirty-one patients were given digoxin after intervention until delivery, for positive inotropic stimulation of the fetal heart transplacentally via the mother. In one patient, digitoxin was given
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
accidentally instead of digoxin in a referral hospital, necessitating inpatient treatment. Procedure information and maternal morbidity and mortality are presented in detail in Table 2. Median gestational age at delivery was 37 + 2 (range, 32 + 6 to 40 + 3) weeks. Twenty-three per cent were preterm deliveries (before 37 + 0 weeks) for obstetric reasons (intrauterine growth restriction (IUGR), non-reassuring fetal assessment or preterm labor). Of the 39 patients with continuing pregnancy after intervention, 25.6% of children were born by spontaneous vaginal delivery, with Cesarean section (CS) carried out in 74.4%. Median birth weight was 2895 (range, 1720–3950) g. Of the 16 parturients who delivered in Linz, six had vaginal delivery (37.5%) and 10 had CS (62.5%). Of those with CS, none was because of prior fetal cardiac intervention: in four patients it was because of a history of previous CS, three patients had elective CS, one patient had CS after myomectomy and recommendation for primary CS, in one case CS was performed because of breech presentation and one child was delivered by CS because of IUGR. Delivery information is given in Table 3.
DISCUSSION Since the initial heroic trials in fetal cardiac surgery, interventions have become more common and indications extended. Beneficial effects on the unborn child altering natural disease progression have been reported8,14 – 16,19 . But what about maternal risks? Until now, no investigation has focused on the impact of fetal cardiac interventions on the mother, who takes all the risks of anesthesia and surgery for her unborn child. Since January 2000, a multidisciplinary team at the Children’s Heart Center, Linz, has offered fetal aortic and pulmonary balloon valvuloplasty for unborn children that are considered to benefit from surgery, as well as BAS in HLHS with restrictive foramen ovale. While experiences in fetal and neonatal outcome have been published before,
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Table 3 Delivery details in 39 pregnancies which continued to delivery following fetal cardiac surgery, according to type of intervention
Variable Gestational age at birth (weeks) Time interval between intervention and birth (days) Mode of delivery Spontaneous vaginal Cesarean section Birth weight (g)
AS (n = 32)
PA-IVS (n = 6)
HLHS-IAS (n = 1)
All interventions (n = 39)
37 + 2 (32 + 6 to 40 + 0) 61 (25–115)
37 + 4 (37 + 1 to 40 + 3) 77 (35–84)
37 + 0 51
37 + 2 (32 + 6 to 40 + 3) 59 (25–115)
28.1 71.9 2940 (1720–3950)
16.7 83.3 2810 (2610–3105)
0 100 2480
25.6 74.4 2895 (1720–3950)
Data are given as median (range) or %. AS, critical aortic stenosis; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
in the present study we took a precise and self-critical look at each of the 53 cases, carefully evaluating maternal aspects. No invasive procedure is without risk; however, percutaneous ultrasound-guided fetal cardiac intervention seems to be safe for the mother. In 53 procedures we did not observe any major anesthesia- or intervention-related maternal complications. With the use of relatively large needle trocars (18 and 19 gauge) and intrauterine manipulation for an increased time period compared with a regular second-trimester amniocentesis, one might expect an obviously higher complication rate. However, in none of our interventions did PPROM or infection occur. Depending on fetal lie and placental position, transplacental puncture (45% were located mainly anterior) is sometimes inevitable; we did not observe any major bleeding or placental hematoma. Premature labor was temporarily observed in two patients after intervention. In both cases contractions could be alleviated successfully. However, because of the as-yet-limited number of procedures, we cannot exclude that the complication rate is slightly increased compared with second-trimester amniocentesis20,21 . Fetal interventions at our department are carried out under general anesthesia, providing maternal and fetal anesthesia, analgesia and relaxation. Alternatively, local or regional anesthesia could be applied to the mother, although the fetus needs to be separately anesthetized and given muscle relaxants via additional cannulations through the umbilical vein or intramuscularly. We decided to induce general anesthesia in all cases to ensure rapid and effective anesthesia induction in the mother and the fetus, and avoid maternal movements and stress, in a quiet and controlled environment. General anesthesia seems to be well tolerated by the mothers and experienced teams can reduce intervention and thereby anesthesia time. Digoxin therapy was initiated after all successful intrauterine valvuloplasties. The rationale for its use is the known positive inotropic effect and the idea that it may lower the filling pressure by decreasing the catecholamine response22 . The approach to administer digoxin in this setting, however, is solely empirical and unique in our center. The usual duration of hospital stay was 4 days under optimal circumstances, with admission and evaluation on
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
day 1, intervention on day 2, follow-up echo on day 3 and discharge on day 4. However, the fetus has to be in a favorable position for percutaneous intervention. In some cases waiting for suitable fetal lie took several days, explaining the relatively long hospitalization time in some patients. Percutaneous intrauterine cardiac intervention does not influence the mode of delivery. Nevertheless, only 25.6% of the infants were delivered vaginally, compared with a 75.9% vaginal delivery rate in the general population during the same time period. We assume that CS was carried out more often as a result of superior perinatal management and optimal timing in severely ill neonates, as none of the CS in Linz was performed because of previous fetal intervention per se. The small number of complications observed in this study, however, may not be applicable to less-experienced departments; we thus recommend limiting fetal cardiac interventions to very few dedicated centers worldwide and discourage inexperienced units from performing small numbers of this complex procedure. The most important limitation is still the small number of patients in combination with the extremely low incidence of anesthesia- and surgery-related complications in general. Figure 1 demonstrates that fetal cardiac interventions remain rarely performed procedures, even in specialized centers. We observed a decrease in the number of referred patients from abroad because of an increasing number of centers offering fetal valvuloplasties. We conclude that percutaneous needle-guided fetal cardiac surgery seems to be safe for the mother. In 53 procedures we did not observe any major maternal complications. Nevertheless, as an otherwise healthy woman takes the risks of operation- and anesthesia-associated complications, careful patient selection and a thorough discussion of possible risks and benefits remain central issues of medical counseling.
REFERENCES ¨ 1. Makikallio K, McElhinney DB, Levine JC, Marx GR, Colan SD, Marshall AC, Lock JE, Marcus EN, Tworetzky W. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation 2006; 113: 1401–1405.
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Maternal aspects of fetal surgery 2. Selamet Tierney ES, Wald RM, McElhinney DB, Marshall AC, Benson CB, Colan SD, Marcus EN, Marx GR, Levine JC, Wilkins-Haug L, Lock JE, Tworetzky W. Changes in left heart hemodynamics after technically successful in-utero aortic valvuloplasty. Ultrasound Obstet Gynecol 2007; 30: 715–720. 3. Deprest JA, Flake AW, Gratacos E, Ville Y, Hecher K, Nicolaides K, Johnson MP, Luks FI, Adzick NS, Harrison MR. The making of fetal surgery. Prenat Diagn 2010; 30: 653–667. 4. Maxwell D, Allan L, Tynan MJ. Balloon dilatation of the aortic valve in the fetus: a report of two cases. Br Heart J 1991; 65: 256–258. 5. Tulzer G, Arzt W, Franklin RCG, Loughna PV, Mair R, Gardiner HM. Fetal pulmonary valvuloplasty for critical pulmonary stenosis or atresia with intact septum. Lancet 2002; 360: 1567–1568. 6. Mizrahi-Arnaud A, Tworetzky W, Bulich LA, Wilkins-Haug LE, Marshall AC, Benson CB, Lock JE, McElhinney DB. Pathophysiology, management, and outcomes of fetal hemodynamic instability during prenatal cardiac intervention. Pediatr Res 2007; 62: 325–330. 7. Arzt W, Tulzer G, Aigner M, Mair R, Hafner E. Invasive intrauterine treatment of pulmonary atresia/intact ventricular septum with heart failure. Ultrasound Obstet Gynecol 2003; 21: 186–188. 8. Marshall AC, van der Velde ME, Tworetzky W, Gomez CA, Wilkins-Haug L, Benson CB, Jennings RW, Lock JE. Creation of an atrial septal defect in utero for fetuses with hypoplastic left heart syndrome and intact or highly restrictive atrial septum. Circulation 2004; 110: 253–258. 9. Marshall A, Levine J, Morash D. Results of in utero atrial septoplasty in fetuses with hypoplastic left heart syndrome. Prenat Diagn 2008; 28: 1023–1028. 10. Rychik J, Rome JJ, Collins MH, DeCampli WM, Spray TL. The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome. J Am Coll Cardiol 1999; 34: 554–560. 11. Vlahos AP, Lock JE, McElhinney DB, van der Velde ME. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: outcome after neonatal transcatheter atrial septostomy. Circulation 2004; 109: 2326–2330.
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537 12. Glatz JA, Tabbutt S, Gaynor JW, Rome JJ, Montenegro L, Spray TL, Rychik J. Hypoplastic left heart syndrome with atrial level restriction in the era of prenatal diagnosis. Ann Thorac Surg 2007; 84: 1633–1638. 13. Golombeck K, Ball RH, Lee H, Farrell JA, Farmer DL, Jacobs VR, Rosen MA, Filly RA, Harrison MR. Maternal morbidity after maternal-fetal surgery. Am J Obstet Gynecol 2006; 194: 834–839. 14. Arzt W, Wertaschnigg D, Veit I, Klement F, Gitter R, Tulzer G. Intrauterine aortic valvuloplasty in fetuses with critical aortic stenosis: experience and results of 24 procedures. Ultrasound Obstet Gynecol 2011; 37: 689–695. 15. Wilkins-Haug LE, Tworetzky W, Benson CB, Marshall AC, Jennings RW, Lock JE. Factors affecting technical success of fetal aortic valve dilation. Ultrasound Obstet Gynecol 2006; 28: 47–52. 16. McElhinney DB, Marshall AC, Wilkins-Haug LE, Brown DW, Benson CB, Silva V, Marx GR, Mizrahi-Arnaud A, Lock JE, Tworetzky W. Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. Circulation 2009; 120: 1482–1490. 17. Arzt W, Tulzer G. Fetal surgery for cardiac lesions. Prenat Diagn 2011; 31: 695–698. 18. Tita A, Andrews W. Diagnosis and management of clinical chorioamnionitis. Clin Perinatol 2010; 37: 339–354. 19. Tworetzky W, McElhinney DB, Marx GR, Benson CB, Brusseau R, Morash D, Wilkins-Haug LE, Lock JE, Marshall AC. In utero valvuloplasty for pulmonary atresia with hypoplastic right ventricle: techniques and outcomes. Pediatrics 2009; 124: e510–518. 20. Kollmann M, Haeusler M, Haas J, Csapo B, Lang U, Klaritsch P. Procedure-related complications after genetic amniocentesis and chorionic villus sampling. Ultraschall Med 2013; 34: 345–348. 21. Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev 2003; CD003252. 22. Huhta JC. Guidelines for the evaluation of heart failure in the fetus with or without hydrops. Pediatr Cardiol 2004; 25: 274–286.
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Maternal aspects of fetal cardiac intervention C. WOHLMUTH*†, G. TULZER*, W. ARZT‡, R. GITTER* and D. WERTASCHNIGG*†‡ *The Children’s Heart Center, Linz, Austria; †Department of Obstetrics and Gynecology, Paracelsus Medical University, Salzburg, Austria; ‡Department of Prenatal Medicine, Women’s and Children’s Hospital, Linz, Austria
K E Y W O R D S: fetal cardiac intervention; fetal surgery; intrauterine valvuloplasty; maternal–fetal surgery; maternal morbidity; percutaneous ultrasound-guided procedure
ABSTRACT Objectives Fetal cardiac interventions have the potential to alter natural disease progression and reduce morbidity and mortality in children. Although there are already encouraging data on fetal outcome, information on maternal morbidity and mortality after intervention is scarce. The aim of the present study was to assess maternal aspects, pregnancy-associated risks and adverse events in 53 intrauterine cardiac interventions. Methods Between October 2000 and December 2012, 53 fetal cardiac interventions were performed in 47 patients (43 aortic valve dilations in 39 patients, seven pulmonary valve dilations in six patients and three balloon atrioseptostomies in two patients). Median gestational age was 26 + 4 (range, 20 + 3 to 33 + 1) weeks. Interventions were performed by an ultrasound-guided percutaneous approach under general anesthesia. All medical records and patient charts were analyzed retrospectively. Results All women were considered to be healthy in the preoperative assessment; 39 (83%) patients continued pregnancy until term and eight of 47 patients had an intrauterine fetal death (IUFD) and were induced. Postoperative nausea was reported in 29.8% of patients and abdominal pain in 36.2% of patients on the day of surgery. Preterm contractions were observed in two patients; no preterm prelabor rupture of membranes occurred. One severe postpartum hemorrhage was observed in a patient with IUFD and subsequent induction; however, this was unrelated to the balloon valvuloplasty. No intensive care unit admission and no major anesthesia-associated complications (aspiration, anaphylactic reaction, cardiovascular collapse, damage to teeth, laryngeal damage, awareness or hypoxic brain damage) were observed. Maternal mortality was zero. A significant learning curve was observed in terms of duration of intervention.
Conclusion In our experience, percutaneous needleguided fetal cardiac intervention seems to be a safe procedure for the mother. In 53 procedures no major maternal complication directly related to the intervention was observed. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION As a result of the increasingly widespread offer of prenatal scanning and great technical progress in imaging facilities, a growing number of congenital anomalies are diagnosed and observed early before birth. With better understanding of the natural course and often unsatisfactory intrauterine disease progression1,2 , attempts to influence specific conditions and alter disease progression before birth have been initiated3 . In 1991, Maxwell and coworkers reported technically feasible and successful fetal balloon dilation of the aortic valve for the first time4 . Since then, several dedicated centers have repeatedly performed fetal cardiac surgery in a selected patient collective. Newer attempts allowed intervention not only in aortic stenosis, but also in right outflow tract obstruction and hypoplastic left heart syndrome (HLHS) with restrictive foramen ovale5 – 9 . Prenatal balloon valvuloplasty of stenotic or atretic semilunar valves performed in a timely manner may alter natural disease history, prevent evolution of end-stage hypoplastic left or right heart syndrome and direct treatment towards postnatal biventricular repair under optimal circumstances. In fetuses with HLHS, an intact or restrictive atrial septum is a strong risk factor for poor outcome caused by lymphangiectasia, muscularized pulmonary veins and elevated pulmonary vascular resistance, even with timely prenatal diagnosis and early postnatal intervention10 – 12 . Fetal cardiac intervention is an invasive procedure performed to treat the fetus while the anesthetized mother
¨ Correspondence to: Dr C. Wohlmuth, Department of Obstetrics and Gynecology, Paracelsus Medical University, Mullner Hauptstraße 48, 5020 Salzburg, Austria (e-mail: [email protected]) Accepted: 30 May 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Maternal aspects of fetal surgery who undergoes surgery is solely a bystander; the procedure is without direct benefit to her and thus is an altruistic act by the mother on behalf of her unborn child13 . Hence, it is especially critical to know the possible adverse effects on both mother and pregnancy to ensure appropriate pre-interventional counseling and accurate risk–benefit consideration. Whilst there are already experiences on technical success and outcome of the children following fetal cardiac interventions8,14 – 16 , there is currently still a paucity of data concerning maternal aspects. The Children’s Heart Center Linz is one of the few dedicated fetal cardiac surgery centers worldwide, with referrals from many European countries. The purpose of this study was to assess maternal aspects, maternal morbidity and mortality, as well as complications in pregnancy after fetal cardiac interventions. We provide a single-center experience on outcome of mother and pregnancy after intrauterine balloon valvuloplasties and balloon atrioseptostomies (BAS) between 2000 and 2012.
METHODS Between October 2000 (the first procedure) and December 2012, 53 percutaneous ultrasound-guided fetal cardiac interventions were carried out. All patients undergoing fetal cardiac intervention in our department were included in this study. Medical records and patient charts were analyzed retrospectively. All potential candidates underwent fetal echocardiography at our department at their first visit. They were evaluated carefully, by both a pediatric cardiologist and a maternal–fetal medicine specialist, to establish whether they met the inclusion criteria for intervention. The criteria for patient selection and intervention were as previously published17 . Maternal exclusion criteria were any disease that significantly increases the risk of undergoing general anesthesia (defined as American Society of Anesthesiologists (ASA) physical status > 2) or impaired psychological state. No patients were excluded for a maternal reason. Our local Ethics Committee endorsed the study protocol before data acquisition, and informed consent was obtained after careful discussion before intervention. In a detailed counseling session, parents were offered three possibilities: (1) close prenatal follow up and optimal timing of delivery; (2) fetal cardiac intervention; and (3) termination of pregnancy. The following data were collected: maternal age, gestational age at intervention and delivery, body mass index (BMI), mode of delivery, ASA physical status classification, duration of intervention (defined as anesthesia time), postoperative nausea and vomiting (PONV; assessed by anti-emetic requirement on the day of intervention), postoperative pain (assessed by analgesia requirement on the day of intervention), aspiration, death, need for blood transfusions within 1 week of intervention, intensive care unit admission, mode of anesthesia, anesthesia-associated complications, preterm labor, administered tocolytics, preterm prelabor rupture of membranes (PPROM),
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chorioamnionitis (defined as the presence of typical clinical findings: fever, uterine fundal tenderness, maternal tachycardia (>100/min), fetal tachycardia (>160/min)18 ), length of hospital stay and administration of digitalis. Patients were divided into three groups according to the type of fetal cardiac surgery: aortic valvuloplasty; pulmonary valvuloplasty; and BAS. Fetal lie and anatomy were assessed by ultrasound (Voluson E8; GE Healthcare GmbH, Solingen, Germany). When the fetus was considered to be in a suitable position, general anesthesia of the mother (and transplacentally of the fetus) was induced with either propofol or thiopental, depending on the anesthesiologist’s preference. Continuous anesthesia and uterine relaxation were achieved by volatile anesthetics (Sevoflurane®), and analgesia of the fetus was accomplished by remifentanil-perfusor 0.1 μg/kg/h via the mother. No additional premedication was applied to the fetus. Before 24 weeks of gestation, a 19-gauge needle was used; in all other patients an 18-gauge needle (Cook Medical® Trocar Needle; Cook Medical Inc., Bloomington, IN, USA) was introduced under ultrasound guidance through the maternal abdomen and then through an intercostal space or through the fetal abdomen, as soon as fetal movement stopped following anesthesia induction. Depending on the type of fetal cardiac intervention, the tip of the needle was placed in the left ventricle, directly in front of the stenotic aortic valve (critical aortic stenosis), in the right ventricle through the pulmonary valve into the right ventricular outflow tract (pulmonary atresia) or through the right atrium across the atrial septum into the left atrium (BAS). A balloon catheter with a diameter of 3.00–4.48 mm was introduced through the needle, manipulated across the point of constriction and dilated three to five times. After a successful procedure, the whole ensemble was withdrawn from the heart. Postoperative care included close maternal and fetal monitoring. Before discharge, in all fetuses positive inotropic treatment with digoxin was initiated via the mother after obtaining a maternal electrocardiogram and exclusion of contraindications. Digoxin 0.2 mg was administered intravenously three times a day for 2 days and then digoxin 0.1 mg was given orally four times a day until delivery. Mothers were followed up by the instructed general practitioner or the referral hospital with a weekly routine check of the digoxin serum level on a regular appointment basis.
Statistical analysis Continuous data are expressed as mean ± SD or median with range, as appropriate. Differences between two groups were compared using the unpaired Student’s t-test. Differences between more than two groups were analyzed by ANOVA. If a significant difference was evident, Tukey- or Games–Howell post-hoc tests were carried out, as appropriate. Correlation was determined using the Pearson correlation coefficient. All calculations were carried out with SPSS 21.0 (IBM, Armonk, NY,
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USA). P < 0.05 was considered to indicate a statistically significant difference, as generally accepted; a trend was defined as P = 0.10–0.05.
RESULTS Between October 2000 and December 2012, 53 fetal cardiac interventions were carried out in 47 patients (six patients underwent a repeat procedure because of either technical failure during the first procedure or disease progression), as follows: 43 aortic valve dilations in 39 patients; seven pulmonary valve dilations in six patients; and three BAS in two patients. The number of interventions per year in our department is shown in Figure 1. We performed percutaneous needle-guided surgery in all cases, in contrast to the Boston group15,16,19 , in which minilaparotomy was carried out in some cases to improve position and imaging. Twenty-one (44.7%) patients were Austrian citizens; the remaining 26 were referred from other European countries and all were Caucasian. Median maternal age at intervention was 28 (range, 19–38) years; and 53% of
women were nulliparous, 32% were para 1, 13% para 2 and 2% para 3. Patient characteristics are given in Table 1. In the preoperative anesthesiology assessment, all women were considered to be in good health. Placental location was described as mainly anterior in 45% and mainly posterior in 55%, respectively. There was no difference in maternal age among the three groups. BMI was lower in the pulmonary valvuloplasty compared with the aortic stenosis group (20.6 vs 26.8 kg/m2 , P = 0.003). Median gestational age at intervention was 26 + 4 (range, 20 + 3 to 33 + 1) weeks. Median anesthesia time in all procedures was 59 (range, 11–235) min; pulmonary valve dilation tended to take longer (109 (range, 64–146) min; P = 0.06). With increasing experience we observed a significant learning curve: duration of aortic balloon valvuloplasty was significantly shorter after the first 15 procedures were carried out (80 min vs 51 min, P = 0.036). There was no significant correlation between BMI and duration of intervention. Thirty-nine of 47 patients continued pregnancy; intrauterine fetal death (IUFD) within 7 days of intervention occurred in seven (14.8%) patients and one IUFD was observed 20 days later. Preterm contractions were
Fetal cardiac interventions per year (n)
10
9
9
8
8 7
6
6
5
5
4
4 3 2 1 0
8
7
2 1
1
1
1 0
2000
2001
2002
2003
2004
2005
2006 Year
2007
2008
2009
2010
2011
2012
Figure 1 Number of fetal cardiac interventions performed per year in our department since program initiation. Table 1 Characteristics of the 47 patients who underwent fetal cardiac surgery, according to type of intervention
Characteristic Patients continuing pregnancy Maternal age at intervention (years) GA at intervention (weeks) Body mass index (kg/m2 ) Gravidity Parity Smoker ASA physical status 1 2
AS (n = 39)
PA-IVS (n = 6)
HLHS-IAS (n = 2)
All patients (n = 47)
32 27 (19–38) 26 + 4 (20 + 3 to 33 + 1) 26.8 (19.3–39.5) 1 (1–7) 0 (0–3) 1 (2.6)
6 29 (25–34) 29 + 0 (25 + 1 to 32 + 0) 20.6 (17.5–24.4) 2 (1–2) 1 (0–1) 0 (0)
1 31 (28–35) 26 + 3 (26 + 0 to 26 + 6) 25.7 (24.6–26.8) 2.5 (2–3) 1 (0–2) 0 (0)
39 28 (19–38) 26 + 4 (20 + 3 to 33 + 1) 26.1 (17.5–39.5) 1 (1–7) 0 (0–3) 1 (2.1)
32 (79.5) 7 (20.5)
6 (100) —
2 (100) —
40 (85) 7 (15)
Data are given as median (range), n or n (%). AS, critical aortic stenosis; ASA, American Society of Anesthesiologists; GA, gestational age; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
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Table 2 Procedure information and maternal morbidity and mortality in the 53 fetal cardiac interventions performed in the study AS (n = 43)
PA-IVS (n = 7)
HLHS-IAS (n = 3)
All interventions (n = 53)
55 (11–235) 2 (1–6) 0 2 2 7 0 11 14 0 0 0 0 0
109 (64–146) 2 (1–2) 0 0 0 0 0 1 2 0 0 0 0 0
71 (31–104) 2 (1–5) 0 0 0 1 0 2 1 0 0 0 0 0
59 (11–235) 2 (1–6) 0 2 2 8 0 14 17 0 0 0 0 0
Variable Duration of intervention (min) Time interval between intervention and discharge (days) Preterm prelabor rupture of membranes Threatened premature labor Tocolysis Intrauterine fetal death Digitalis-associated complications/intoxication Postoperative nausea and vomiting Postoperative pain Bleeding requiring blood transfusion Intensive care unit stay (days) Chorioamnionitis Wound infection Intra-/perioperative maternal mortality
Data are presented as n or median (range). AS, critical aortic stenosis; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
observed in two patients following intervention. In both cases, tocolysis with hexoprenaline (Gynipral®) was subsequently initiated and preterm labor was successfully alleviated. One patient continued pregnancy for 6 weeks before premature contractions recurred and was delivered at 33 weeks. The second patient continued pregnancy until term. In the 53 interventions carried out in our department, no PPROM was observed as being directly related to the procedure. No major maternal bleeding occurred and none of the patients received blood products following fetal cardiac surgery. One of the IUFD patients – induced on the first day after intervention – had a severe postpartum hemorrhage because of retained placental tissue and uterine atony, necessitating curettage, six units of packed red cells and pooled plasma. She left the operating theater hemodynamically stable, could be transferred to the general ward and was discharged 4 days later. Intensive care admission was not necessary in any patient. Fourteen (29.8%) women reported postoperative nausea and vomiting on the day of intervention and were given antiemetic treatment. Seventeen (36.2%) patients reported abdominal pain or headache after surgery that was easily controlled by acetaminophen in 14 patients with mild pain (World Health Organization (WHO) pain management step 1). In three patients who described moderate to severe pain, a single dose of opioids (piritramide, Dipidolor® (WHO step 3)) was administered; all patients confirmed proper pain relief. There was no correlation between pain and duration of intervention (P = 0.37). No major anesthesia-associated complications were observed (aspiration, anaphylactic reaction, cardiovascular collapse, damage to teeth, laryngeal damage, awareness or hypoxic brain damage); perioperative maternal mortality was zero. Chorioamnionitis or wound infection was not observed. Thirty-one patients were given digoxin after intervention until delivery, for positive inotropic stimulation of the fetal heart transplacentally via the mother. In one patient, digitoxin was given
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accidentally instead of digoxin in a referral hospital, necessitating inpatient treatment. Procedure information and maternal morbidity and mortality are presented in detail in Table 2. Median gestational age at delivery was 37 + 2 (range, 32 + 6 to 40 + 3) weeks. Twenty-three per cent were preterm deliveries (before 37 + 0 weeks) for obstetric reasons (intrauterine growth restriction (IUGR), non-reassuring fetal assessment or preterm labor). Of the 39 patients with continuing pregnancy after intervention, 25.6% of children were born by spontaneous vaginal delivery, with Cesarean section (CS) carried out in 74.4%. Median birth weight was 2895 (range, 1720–3950) g. Of the 16 parturients who delivered in Linz, six had vaginal delivery (37.5%) and 10 had CS (62.5%). Of those with CS, none was because of prior fetal cardiac intervention: in four patients it was because of a history of previous CS, three patients had elective CS, one patient had CS after myomectomy and recommendation for primary CS, in one case CS was performed because of breech presentation and one child was delivered by CS because of IUGR. Delivery information is given in Table 3.
DISCUSSION Since the initial heroic trials in fetal cardiac surgery, interventions have become more common and indications extended. Beneficial effects on the unborn child altering natural disease progression have been reported8,14 – 16,19 . But what about maternal risks? Until now, no investigation has focused on the impact of fetal cardiac interventions on the mother, who takes all the risks of anesthesia and surgery for her unborn child. Since January 2000, a multidisciplinary team at the Children’s Heart Center, Linz, has offered fetal aortic and pulmonary balloon valvuloplasty for unborn children that are considered to benefit from surgery, as well as BAS in HLHS with restrictive foramen ovale. While experiences in fetal and neonatal outcome have been published before,
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Table 3 Delivery details in 39 pregnancies which continued to delivery following fetal cardiac surgery, according to type of intervention
Variable Gestational age at birth (weeks) Time interval between intervention and birth (days) Mode of delivery Spontaneous vaginal Cesarean section Birth weight (g)
AS (n = 32)
PA-IVS (n = 6)
HLHS-IAS (n = 1)
All interventions (n = 39)
37 + 2 (32 + 6 to 40 + 0) 61 (25–115)
37 + 4 (37 + 1 to 40 + 3) 77 (35–84)
37 + 0 51
37 + 2 (32 + 6 to 40 + 3) 59 (25–115)
28.1 71.9 2940 (1720–3950)
16.7 83.3 2810 (2610–3105)
0 100 2480
25.6 74.4 2895 (1720–3950)
Data are given as median (range) or %. AS, critical aortic stenosis; HLHS-IAS, hypoplastic left heart syndrome with intact atrial septum; PA-IVS, pulmonary atresia with intact interventricular septum.
in the present study we took a precise and self-critical look at each of the 53 cases, carefully evaluating maternal aspects. No invasive procedure is without risk; however, percutaneous ultrasound-guided fetal cardiac intervention seems to be safe for the mother. In 53 procedures we did not observe any major anesthesia- or intervention-related maternal complications. With the use of relatively large needle trocars (18 and 19 gauge) and intrauterine manipulation for an increased time period compared with a regular second-trimester amniocentesis, one might expect an obviously higher complication rate. However, in none of our interventions did PPROM or infection occur. Depending on fetal lie and placental position, transplacental puncture (45% were located mainly anterior) is sometimes inevitable; we did not observe any major bleeding or placental hematoma. Premature labor was temporarily observed in two patients after intervention. In both cases contractions could be alleviated successfully. However, because of the as-yet-limited number of procedures, we cannot exclude that the complication rate is slightly increased compared with second-trimester amniocentesis20,21 . Fetal interventions at our department are carried out under general anesthesia, providing maternal and fetal anesthesia, analgesia and relaxation. Alternatively, local or regional anesthesia could be applied to the mother, although the fetus needs to be separately anesthetized and given muscle relaxants via additional cannulations through the umbilical vein or intramuscularly. We decided to induce general anesthesia in all cases to ensure rapid and effective anesthesia induction in the mother and the fetus, and avoid maternal movements and stress, in a quiet and controlled environment. General anesthesia seems to be well tolerated by the mothers and experienced teams can reduce intervention and thereby anesthesia time. Digoxin therapy was initiated after all successful intrauterine valvuloplasties. The rationale for its use is the known positive inotropic effect and the idea that it may lower the filling pressure by decreasing the catecholamine response22 . The approach to administer digoxin in this setting, however, is solely empirical and unique in our center. The usual duration of hospital stay was 4 days under optimal circumstances, with admission and evaluation on
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day 1, intervention on day 2, follow-up echo on day 3 and discharge on day 4. However, the fetus has to be in a favorable position for percutaneous intervention. In some cases waiting for suitable fetal lie took several days, explaining the relatively long hospitalization time in some patients. Percutaneous intrauterine cardiac intervention does not influence the mode of delivery. Nevertheless, only 25.6% of the infants were delivered vaginally, compared with a 75.9% vaginal delivery rate in the general population during the same time period. We assume that CS was carried out more often as a result of superior perinatal management and optimal timing in severely ill neonates, as none of the CS in Linz was performed because of previous fetal intervention per se. The small number of complications observed in this study, however, may not be applicable to less-experienced departments; we thus recommend limiting fetal cardiac interventions to very few dedicated centers worldwide and discourage inexperienced units from performing small numbers of this complex procedure. The most important limitation is still the small number of patients in combination with the extremely low incidence of anesthesia- and surgery-related complications in general. Figure 1 demonstrates that fetal cardiac interventions remain rarely performed procedures, even in specialized centers. We observed a decrease in the number of referred patients from abroad because of an increasing number of centers offering fetal valvuloplasties. We conclude that percutaneous needle-guided fetal cardiac surgery seems to be safe for the mother. In 53 procedures we did not observe any major maternal complications. Nevertheless, as an otherwise healthy woman takes the risks of operation- and anesthesia-associated complications, careful patient selection and a thorough discussion of possible risks and benefits remain central issues of medical counseling.
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