Cardiac complications relating to pregnancy and recurrence of disease in the offspring of women with atrioventricular septal defects

Willem Drenthen1,*, Petronella G. Pieper1, Karin van der Tuuk1, Jolien W. Roos-Hesselink2, Adriaan A. Voors1, Bianca Mostert2, Barbara J.M. Mulder3, Philip Moons4, Tjark Ebels5, Dirk J. van Veldhuisen1 on behalf of the ZAHARA Investigators

1Department of Cardiology, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
2Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
3Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
4Department of Cardiology, University Hospitals of Leuven, Leuven, Belgium
5Department of Thoracic Surgery, University Hospital Groningen, Groningen, The Netherlands

Received 16 March 2005; revised 30 June 2005; accepted 7 July 2005; online publish-ahead-of-print 17 August 2005.

* Corresponding author. Tel: +31 50 361 0248; fax: +31 50 361 4391. E-mail address: w.drenthen{at}thorax.umcg.nl

This paper was guest edited by Prof. M.A. Gatzoulis, Royal Brompton Hospital, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims In most pregnancy reports, atrioventricular septal defects (AVSD) are not differentiated from more simple septal defects, thus underestimating the risks of pregnancy. To investigate the magnitude and determinants of risk during pregnancy in female patients with balanced AVSD.

Methods and results Using a nation-wide registry (CONCOR), 79 female patients with balanced/isolated AVSD were identified. A total of 29 patients had 62 pregnancies, including 12 miscarriages (19%) and two elective abortions. Detailed recordings of each completed (>20 weeks gestation) pregnancy (n=48, 26 women) were obtained. Cardiovascular events complicated almost 40% of the completed pregnancies. In particular, post-partum persistence of pregnancy-related New York Heart Association (NYHA) class deterioration [23% mainly patients with residual atrial septal defects (ASD)] and deterioration of pre-existing left AV-valvular regurgitation (17%) were frequently recorded. Additional cardiac complications were arrhythmias (19%) and symptomatic heart failure (2%). Congenital heart disease (CHD) recurred in six children (12%): AVSD (n=4, three with left-sided hypoplasia), patent ductus arteriosus (n=1), and ASD (n=1). Three children died including two children with left-sided hypoplasia.

Conclusion Pregnancy is not always well tolerated in women with AVSD, predominantly due to NYHA class deterioration and worsening of pre-existing AV-valvular regurgitation. Offspring mortality is high (6.3%), primarily due to recurrence of complex CHD.

Key Words: Congenital heart disease • Pregnancy • Atrioventricular septal defect


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The presence of an ovoid-shaped common atrioventricular (AV) junction coexisting with deficient AV septation unifies a spectrum of lesions called AV septal defects (AVSD), which accounts for ~3% of congenital cardiac malformations. In AVSD, the architecture of the fibrous skeleton of the heart is structurally different from that in the other congenital heart disease (CHD) patients and healthy controls. AVSD can be divided in either partial or complete variants based on the arrangement of the valve leaflets and valvular tissue in the AV-orifice. In partial AVSD, two separate orifices exist with distinguishable right and left AV-valves, whereas patients with complete AVSD have a common AV-orifice.1

The majority of AVSD patients reach childbearing age in relative good health, making pregnancy and fertility important issues for women with AVSD. Nearly all pregnancy trials consider AVSD to be merely simple (secundum atrial and ventricular) septal defects while in addition to the structural differences mentioned earlier, surgical repair and residual defects may differ substantially. Therefore, the assumption that these defects are similar may lead to an underestimation of pregnancy risks. Only one available report (by Zuber et al.) differentiates AVSD from simple septal defects, but this report lacks a detailed description of complications and the number of complications investigated is limited.2

It may be speculated that the additional circulatory burden of pregnancy (e.g. volume load, increased cardiac output, and decreased systemic vascular resistance) augments the development of heart failure and arrhythmia, which subsequently can threaten the health of both mother and her offspring with AVSD. In addition to this circulatory burden, an elevated recurrence risk of CHD is reported in female patients with AVSD, but incidences vary markedly (2.6–14.1%).25

The objective of the present study is to investigate the magnitude (and determinants) of cardiac and non-cardiac risks during pregnancy in women with isolated AVSD and their offspring, including the prevalence of subfertility/infertility and CHD recurrence risk.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
For the present study, 86 patients with isolated AVSD (age 21–58) were identified using the CONCOR (CONgenital CORvitia) database. This nation-wide registry of CHD patients receiving care in (tertiary) medical centres in the Netherlands (informed consent rate 97%) is funded by the Netherlands Heart Foundation. All patients contacted for the present study are treated in one of the six participating tertiary centres. Institutional review board or Ethics Committee at each site approved the protocol. Overall, 79 of the 86 patients provided written informed consent and were enrolled in this study (participation rate 92%).

Data were collected using medical records. Questionnaires by telephone were only used to complete the data retrieved from the medical records. Recorded baseline data included prior surgical procedures, comorbidity, and medical history using the European Paediatric Cardiac Coding; age at inclusion; medication; fertility (infertility: >2 years of pregnancy attempts and documented by gynaecologist); miscarriages (spontaneous foetal loss before 20 weeks gestation); and elective abortions.

Detailed information concerning each completed pregnancy (>20 weeks of gestation) was recorded (when applicable/available pre-, peri- and post-partum values): mode of delivery; parity status; use of cigarettes, alcohol, and drugs; use of medication; New York Heart Association (NYHA) functional class; physical examination (including blood pressure, heart rate, and central venous pressure); 12-lead ECG and 24 h ECG (Holter) registrations. Transthoracic echocardiographic qualitative assessment of left and right ventricular systolic function and dimensions of both ventricles (apical four-chamber view) were recorded. In addition, we recorded qualitative Doppler imaging of pulmonary, aortic, and especially left and right AV-valvular dysfunction.6 Although echocardiograms were available in all patients, we used only those recorded <2 years prior to pregnancy and those technically adequate to assess aforementioned parameters.

Documented complications were grouped into cardiac, general, obstetric, and neonatal events. Cardiac complications: clinically significant symptomatic arrhythmia or symptomatic heart failure requiring treatment (according to attending cardiologist); NYHA class deterioration (as evaluated by their cardiologist during trimesters and comparison of pre-pregnancy and post-partum on average >1 year post-delivery values); qualitative (absent, mild, moderate, and severe) deterioration of left AV-valve (LAVVR) and right AV-valve regurgitation (RAVVR); the need for post-partum surgical intervention owing to pregnancy-related cardiac complications; myocardial infarction; and endocarditis. General complications: pregnancy-induced hypertension (PIH, new onset hypertension after ≥20 weeks of gestation: blood pressure >140 mmHg systolic or 90 mmHg diastolic without significant proteinuria); pre-eclampsia (PIH criteria and >0.3 g of proteinuria/24 h); eclampsia (pre-eclampsia with grand mal seizures); haemolysis elevated liver enzymes low platelets (HELLP) syndrome; thrombo-embolic complications; stroke; and gestational diabetes. Obstetric complications: assisted delivery (forceps/vacuum/caesarean); premature rupture of membranes (PROMs, membrane rupture before the onset of uterine contractions); prolongation of second stage of delivery (nullipara >2 h and multipara>1 h according to the gynaecological guidelines); premature labour (spontaneous onset of labour <37 weeks gestation); antepartum vaginal bleeding; post-partum haemorrhage [vaginal delivery>500 mL, caesarean section (CS)>1000 mL, documented by gynaecologist and requiring transfusion]. Neonatal complications: premature birth (delivery <37 weeks of gestation); small for gestational age birth weight (<10th percentile); recurrence of CHD; foetal demise (intra-uterine death ≥20 weeks of gestation); and neonatal death (within the first year after birth).

Clintrial data entry program was used to record information and was converted to SPSS (version 11.0) for statistical analysis. Descriptive statistics for nominal data were expressed in absolute numbers and percentages. After checking for normality, mean values and standard deviations were calculated for normally distributed continuous variables. Medians and ranges were computed for continuous variables with non-normal distribution. Comparison of baseline characteristics and aforementioned complications were performed using {chi}2 test and Fisher's exact test. Baseline characteristics that were included in the analysis were history of arrhythmia, history of miscarriages, type of repair, prior rashkind/blalock procedure, use of cigarettes/alcohol/medication, and parity. Complications were compared separately as well as in groups: cardiac, general pregnancy, obstetric, and neonatal complications. All test were two-tailed and a P-value <0.05 was considered statistically significant.

Clinical outcome data were compared with known incidences of normal pregnancies in the western world and available literature on ASD and pregnancy.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Baseline characteristics of the enrolled 79 patients with isolated AVSD are summarized in Table 1. Seventeen patients with Down syndrome were excluded from further analysis. Thirty-six patients of the remaining 62 patients were childless and 35 of them (97.2%) wished to have children in the future. Table 2 depicts the patients' main reasons for being childless. Infertility was the main reason for being childless in two patients: both patients had endometriosis.


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Table 1 Baseline characteristics of the patients with AVSD
 

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Table 2 Primary reasons for being childless
 
A total of 62 pregnancies were documented, including 48 completed pregnancies, 12 spontaneous miscarriages (nine patients, including one patient who remained childless), and two elective abortions. Both elective abortions were performed for non-cardiac reasons (e.g. socio-economic factors: divorce and financial) and both patients remained childless after. Baseline characteristics for all completed pregnancies (n=48, 26 patients) are outlined in Table 3, and Table 4 describes cardiac, general, obstetric, and neonatal complications per patient.


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Table 3 Baseline characteristics and outcome of the complete pregnancies in women with AVSDa
 

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Table 4 Overview of pregnancies with complications in women with AVSD
 
Cardiac complications
Although palpitations were frequently reported in the outpatient setting (20 pregnancies, 41.7%), the cardiologist initiated arrhythmia work-up in only five patients (A–E). This resulted in the documentation of clinically significant arrhythmias during nine of the 10 pregnancies (incidence 18.8%) recorded in these five patients. In six of the pregnancies complicated by an arrhythmia, the mother had a history (outside of pregnancy) of clinically significant arrhythmia (P=0.005). In four patients (A–D), recurrence of supraventricular arrhythmia was recorded, including episodes of AV-nodal re-entry tachycardia (n=1), atrial fibrillation combined with runs of ventricular tachycardia (n=1), and atrial flutter (n=2). Moderate LAVVR may have led to the ‘de novo’ development of supraventricular tachycardia (SVT) (non-specified, 24 h ECG) during the second trimester of patient E's first pregnancy, which resurfaced during two consecutive gestations. The SVT was successfully treated by digoxin therapy during pregnancy and left AV valvuloplasty after her third pregnancy.

Temporary deterioration of NYHA class was observed in 29 pregnancies (60.4%, 17 pregnancies by one class). Perseverance of NYHA class deterioration (on average >1 year) was observed after 11 gestations [22.9%; in nine (34.6%) different patients]. Persistent NYHA class deterioration was slightly more predominant in patients with (residual) ASD (P=0.049). Comparison of pre- and post-partum NYHA class confirmed a significant deterioration (P=0.005, Figure 1).



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Figure 1 Pre- to post-pregnancy deteriotation of NYHA class in women with AVSD.

 
Deterioration of the left ventricular function in combination with LAVVR led to hospital admission for symptomatic heart failure during patient F's first pregnancy. Complaints of dyspnoea and limitations of exercise tolerance disappeared after diuretic therapy (furosemide).

Eighteen patients (28 pregnancies, 58.3%) were known to have (residual) LAVVR before pregnancy, and the presence of LAVVR was associated with more interventions during delivery (P=0.043). The severity of LAVVR rated mild prior to most pregnancies, but moderate (n=6) and severe (n=5) regurgitation were also recorded. Comparison of echocardiographic data before and after pregnancy showed deterioration of left AV-valve function after nine pregnancies. In 14 patients (17 pregnancies), RAVVR was reported prior to gestation. Pregnancies complicated by deterioration of right AV-valve function (n=6) also had LAVVR deterioration (except for one patient).

Deterioration of LAVVR (n=3, patients D, I, and L) and development of heart failure (n=1, patient F) were the main reasons for the attending cardiologists to discourage future pregnancies. Two other patients received the advice to postpone a future pregnancy pending the outcome of planned left AV-valve surgery and the need for teratogenic medication to treat a non-pregnancy-related arrhythmia.

No episodes of myocardial infarction, endocarditis, or stroke were documented.

General pregnancy complications
Eight pregnancies [16.7%; in six (23.1%) different patients] were complicated by hypertension-related disorders, mostly gestational hypertension (n=7) and pre-eclampsia (n=1). No episodes of eclampsia, HELLP-syndrome, or thrombo-embolic complications were reported. Three patients (6.3%) developed gestational diabetes for which sugar-free diets were prescribed.

Overall, 11 (22.9%) of the 48 completed pregnancies were complicated by general complications. In comparison with partial AVSD, the presence of complete AVSD was associated with more general complications (P=0.033; three of four complete AVSD vs. eight of 44 partial AVSD pregnancies), primarily concerning hypertension-related disorders (P=0.012, three of four complete AVSD vs. five of 44 partial AVSD pregnancies).

Obstetric complications
Most patients were hospitalized during delivery (n=46, 96%), and four primary CS (8%) were performed for maternal cardiac condition (n=2), placenta praevia (n=1), and breech presentation (n=1). Three secondary CS were performed on maternal/foetal indication due to prolongation of second stage of delivery (n=2) and foetal distress (n=1). In addition to CS, assistance was necessary during nine deliveries: forceps (n=5, 12.2%) and vacuum delivery (n=4, 9.8%).

Obstetric complications included prolonged second stage of delivery (n=10, 20.8%, in eight different patients); post-partum haemorrhage (n=10, 20.8%, in eight different patients); and premature labour (n=3, 6.3%, in three different patients). No PROMs were found.

Neonatal complications
Five children (10.4%), born at term, were small for gestational age. Premature delivery occurred in three other pregnancies (6.3%). Children of partial AVSD patients were significantly smaller when compared with children of complete AVSD women (3243±538 vs. 3829±443 g; P=0.038).

Recurrence of CHD was reported in six children (12.5%). Four children had AVSD, including three cases associated with left-sided hypoplasia of the heart, which was further complicated by a coarctation of the aorta in one child. Persistent arterial duct (surgical repair at 2 years of age) and a secundum ASD were diagnosed in the other two children. There was one intra-uterine death at 6 months of pregnancy due to umbilical cord prolapse (2.1%), and two children with left-sided hypoplasia AVSD died within the first year after birth (neonatal mortality=4.2%).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
The key result of this report on AVSD and pregnancy is the fact that pregnancy in women with AVSD is not always well tolerated. A high incidence of clinical significant arrhythmias, persistent NYHA class deterioration, and worsening of pre-existing AV-valvular regurgitation was documented. Furthermore, offspring mortality was high, primarily due to the recurrence of complex congenital malformations. However, infertility appears to be no major problem.

Clinical significant arrhythmias were frequently observed. These arrhythmias are probably related to the additional circulatory burden of pregnancy, and specifically the extra volume load and the enhanced adrenergic receptor excitability mediated by estrogens and progesterone.7,8 Despite improvement of surgical techniques, supraventricular arrhythmias and incisional macro re-entrant tachycardias are well known long-term sequelae after ASD and AVSD repair.9,10 Whittemore et al.2 reported that four (6.1%) of the 66 pregnancies in ASD patients were complicated by arrhythmias. We found a substantially higher incidence of arrhythmia in our AVSD group (18.8%). Coexistence of LAVVR was present in five of the nine pregnancies and may have contributed in the development of arrhythmia. No significant difference in age at repair, a well-known predictor of arrhythmias in post-surgery ASD and AVSD patients, was found between patients with and without arrhythmias. Most patients had a medical history of arrhythmia, which could be helpful in predicting the patients' risk for arrhythmias. All arrhythmias were resolved during pregnancy or shortly after delivery; no persistent/permanent arrhythmias were seen during post-partum follow-up (median 60 months).

Symptomatic heart failure is rarely observed during normal pregnancy. Earlier reports mention that congenital heart failure may develop during pregnancy in women with ASD, particularly when a significant left-to-right shunt is present.2,3 However, our patient developed clinically significant heart failure despite adequate (no residual defects) repair. The episode of heart failure was characterized by progressive development of dyspnoea and orthopnoea and may have been caused by the development of LAVVR during this pregnancy.

NYHA class deterioration was recorded in >50% of pregnancies, which is substantially higher than the reports of 16–20% in ASD II patients.3,11,12 Interpretation of NYHA class deterioration during pregnancy is difficult because of interference of general pregnancy discomforts. Furthermore, NYHA class deterioration may also occur in the natural history and post-surgery follow-up of AVSD patients in the absence of pregnancy. In our opinion, persistence of NYHA class deterioration ≥1 year post-partum, which accounts for serious morbidity and restricts the post-partum lives of the individual patients, is a more reliable parameter. Persistent NYHA class deterioration was reported in 22.9% of the pregnancies, which is much higher than the frequency observed in ASD II patients.11 This high persistence of NYHA class deterioration was associated with the presence of residual ASD on echocardiography, which is a known aetiological factor in the development of heart failure.

LAVVR is a major cause of late morbidity and is commonly observed both before and after AVSD repair.13,14 In our study, LAVVR grade deteriorated during 28.6% of gestations, all had a history of LAVVR before pregnancy. In four of the six patients, who were negatively advised against or advised to postpone future pregnancies following one or more preceding gestations, deterioration of left AV-valvular function was the rationale behind the cardiologist's advice. Three patients needed valvuloplasty after delivery to restore AV-valvular performance. Moreover, patients with LAVVR had more assisted deliveries. Several cardiac complications can, in part, be attributed to the presence of LAVVR, e.g. heart failure, NYHA class deterioration, and arrhythmias. Therefore, in our opinion, left AV-valve surgery before pregnancy should be considered when moderate or severe LAVVR is present.

General pregnancy and obstetric complications also occurred. The observed rate of spontaneous miscarriages (n=12, 19.4%) is slightly higher than expected. Available information of the general western population states that ~13% of the clinically documented pregnancies end in a spontaneous miscarriage. Burn et al.15 also found an identical (19.1%) excess of miscarriages in women with AVSD. In ASD patients, in contrast, miscarriage rates are comparable to those found in the general population.5

Infertility was suspected in six (9.7%) patients; however, only two patients remained childless due to endometriosis. Therefore, we concluded that subfertility/infertility does not appear to be a major problem in the investigated AVSD patients.

Hypertension-related disorders (mostly PIH) were observed in 16.7% of the pregnancies, compared with 8–10% reported in the general population.16 According to Sibai,17 isolated PIH is a relative benign finding producing few adverse effects, with the exception early pregnancy hypertension (<30 weeks) and cases with clinical signs of (pre-) eclampsia. Of the seven PIH patients, only one presented with hypertension before the 30th week of gestation. None had clinical signs of (pre-) eclampsia. In concordance with these observations, no severe maternal or neonatal events associated with hypertension-related disorders were documented.

Paradoxical embolus of a deep venous thrombosis is one of the major concerns if septal defects are still present during pregnancy.18 In our report, only four patients had (residual) ASD. Thrombo-embolic (paradoxical) events did not develop despite the fact that no prophylactic therapy was prescribed.

Assistance (forceps, vacuum, and CS) was needed in approximately one-third of the deliveries, more than expected in a general or ASD II population.5,12,19 In part, the increased need for assistance can be attributed to the high incidence of prolonged second stage of delivery. The gynaecologist's tendency to intervene during the delivery to prevent complications may also have contributed. Other obstetric complications were in accordance with the expected values of the general population.

Several studies have reported on the recurrence risk of CHD in the offspring of mothers with AVSD. Emanuel et al. showed that recurrence risk of CHD in the children of mothers with AVSD is substantially higher than in ASD patients.19 Recurrence risk varied between 7.9 and 11.0%.5,20,21 We found an ‘offspring CHD’ recurrence risk of 12.5%, consisting predominantly of complex AVSD in combination with left ventricular hypoplasia. Two of these children died within the first year after birth, which explains why neonatal mortality was higher than expected.

Limitations: First, the retrospective study design necessitated a review of patients' medical records with the inevitable missing values. However, all complications had to be documented in medical records according to pre-set definitions. Additional records/information was retrieved by interview when medical records did not provide sufficient information. Secondly, the patient sample may not be completely representative owing to selection bias. Only patients receiving care in the tertiary centres in the Netherlands were registered, which may have led to a clinically more complex population. Thirdly, the enrolled patients were relatively young, and many of them will get pregnant in the future, therefore follow-up is not complete. Additional selection bias is introduced by excluding miscarriage/abortion pregnancies and some patients remained childless because of the expected risks associated with pregnancy. Contemporaneous applicability because of the relatively large time span between the first and the last pregnancy may negatively influence the reported complication rate. Finally, possible effects of multitesting need to be taken into account, therefore all conclusions of the present study must be drawn with caution.

In conclusion, women with AVSD have to overcome more obstacles during their pregnancies than either healthy women or women with simpler (atrial) septal defects. Problems are mainly related to the cardiac sequelae of surgical intervention (e.g. arrhythmias and AV regurgitation) and the recurrence of complex CHD in the offspring. It may be useful to identify high-risk patients (e.g. complete AVSD, residual LAVVR/ASD) to prevent complications or to recognize and treat complications in an earlier stage. However, the results of the present study should not be used to discourage AVSD patients to become pregnant. More elaborate prospective research should be performed to address the risks of pregnancy in women with isolated AVSD.


    Acknowledgements
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
P.G.P. and the Interuniversity Cardiology Institute of The Netherlands (ICIN) were supported by Netherlands Heart Foundation Grant 2002 B125. van Veldhuisen is an established investigator for the Netherlands Heart Foundation (grant no. D97.017). Marcelle D. Smit and Nicole Zoon reviewed and revised the manuscript.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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