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Congenital heart disease
Original research
Predictors of spontaneous pregnancy loss in single ventricle physiology
  1. Yasmine Wazni1,
  2. Christopher Sefton2,
  3. Betemariam Sharew3,
  4. Elizabeth Ghandakly2,
  5. Patricia Blazevic4,
  6. Nandini Mehra5,
  7. Justin R Lappen6,
  8. Cara D Dolin6,
  9. Adina Kern-Goldberger6,
  10. Stephen Bacak6,
  11. Margaret Fuchs5,
  12. Kenneth Zahka7,
  13. Amy McKenney8,
  14. Larisa G Tereshchenko5,9,
  15. Katherine Singh6,
  16. Peter F Aziz7 and
  17. Joanna Ghobrial5
  1. 1Georgetown University, Washington, District of Columbia, USA
  2. 2Department of Medicine, Cleveland Clinic, Cleveland, Ohio, USA
  3. 3Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
  4. 4University of Toledo College of Medicine, Toledo, Ohio, USA
  5. 5Department of Cardiology, Heart Vascular & Thoracic Institute, Cleveland, Ohio, USA
  6. 6Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, Cleveland, USA
  7. 7Department of Pediatric Cardiology, Cleveland Clinic Children’s, Cleveland, Ohio, USA
  8. 8Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
  9. 9Lerner Research Institute, Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
  1. Correspondence to Dr Joanna Ghobrial; joannaghobrial{at}gmail.com

Abstract

Background Pregnant patients with single ventricle (SV) physiology carry a high risk of spontaneous pregnancy loss (SPL), yet the clinical factors contributing to this risk are not well defined.

Methods Single-centre retrospective study of pregnant patients with SV physiology seen in cardio-obstetrics clinic over the past 20 years with chart review of their obstetric history. Patients without a known pregnancy outcome were excluded. Univariable Bayesian panel-data random effects logit was used to model the risk of SPL.

Results The study included 20 patients with 44 pregnancies, 20 live births, 21 SPL and 3 elective abortions. All had Fontan palliation except for two with Waterston and Glenn shunts. 10 (50%) had a single right ventricle (RV). 14 (70%) had moderate or severe atrioventricular valve regurgitation (AVVR). Atrial arrhythmias were present in 16 (80%), Fontan-associated liver disease (FALD) in 15 (75%) and FALD stage 4 in 9 (45%). 12 (60%) were on anticoagulation. Average first-trimester oxygen saturation was 93.8% for live births and 90.8% for SPL. The following factors were associated with higher odds of SPL: RV morphology (OR 1.72 (95% credible interval (CrI) 1.0008–2.70)), moderate or severe AVVR (OR 1.64 (95% CrI 1.003–2.71)) and reduced first-trimester oxygen saturation (OR 1.83 (95% CrI 1.03–2.71) for each per cent decrease in O2 saturation.

Conclusion Pregnant patients with SV physiology, particularly those with RV morphology, moderate or severe AVVR, and lower first-trimester oxygen saturations, have a higher risk of SPL. Identifying these clinical risk factors can guide preconception counselling by the cardio-obstetrics team.

  • Heart Defects, Congenital
  • Pregnancy
  • Fontan Procedure

Data availability statement

Data are available upon reasonable request. The data generated and analysed during the current study are available from the corresponding author upon reasonable request. Researchers who wish to access the data should provide a detailed research proposal and demonstrate a commitment to maintaining confidentiality and using the data solely for the proposed research purposes. The data will be provided in a deidentified format to ensure participant privacy and comply with ethical guidelines.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/openhrt-2024-002768

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Patients with single ventricle (SV) physiology and Fontan palliation have a high risk of spontaneous pregnancy loss (SPL).

    WHAT THIS STUDY ADDS

    • We identify three maternal factors associated with increased risk of SPL in patients with SV physiology: an SV with right ventricular morphology, moderate to severe atrioventricular valve regurgitation and lower oxygen saturations.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • These clinical risk factors can guide the cardio-obstetrics team in tailoring preconception counselling and early pregnancy management. Furthermore, identifying and modifying some of these risk factors pre-pregnancy may be a goal for the cardio-obstetrics team.

    Introduction

    More than 80% of patients with single ventricle (SV) physiology survive into adulthood, including women of childbearing age.1 2 In SV patients, palliation most commonly involves the Fontan procedure, which involves separating the pulmonary and systemic circulation using a direct cavopulmonary anastomosis. In the absence of a pumping chamber, the pulmonary circulation depends on an increase in venous filling pressure to allow for forward flow. The clinical consequences of the Fontan palliation include chronically elevated venous pressures and an inability to mount adequate cardiac output (CO) in the setting of increased demand.3 The SV can be either left (LV) or right ventricular (RV) morphology. The SV, whether a morphologic RV or LV, becomes chronically underloaded with the risk of long-term diastolic and systolic dysfunction. The single hypertrophied RV is at higher risk of ischaemic insult over time with its single coronary supply, as it is less adept at handling systemic circulation.4 Cyanosis in SV physiology post Fontan palliation is partly due to the emptying of the coronary sinus into the systemic circulation, leading to an oxygen (O2) saturation in the 88%–95% range. The O2 saturation can be lower in venovenous collaterals, arteriovenous malformation, residual Fontan fenestrations or non-shunt mediated due to pulmonary oedema from ventricular dysfunction or valve dysfunction. Other common clinical consequences include atrial arrhythmias, atrioventricular valvular regurgitation (AVVR), multiorgan dysfunction with liver fibrosis, renal disease, protein-losing enteropathy (PLE) and thromboembolic disease.3

    The haemodynamic changes of pregnancy, during labour and in the early postpartum period include a decrease in systemic vascular resistance, an increase in blood volume and heart rate, all resulting in an increased CO. There is also an associated increase in ventricular muscle mass, and end-diastolic volumes, with improved systolic function, but without a pathological increase in end-diastolic pressures. Furthermore, pregnancy is a prothrombotic state.5 These haemodynamic and anatomic alterations may not be tolerated in SV physiology with a Fontan repair with its inherent lack of CO reserve, cyanosis and prothrombotic state. This leads to increased maternal cardiac, obstetric and fetal complications, including a high risk of spontaneous pregnancy loss (SPL).6

    There is a lack of evidence providing an adequate risk stratification to guide preconception counselling for patients with SV physiology and Fontan palliation. Current risk calculators such as CARPREG2, ZAHARA and the modified WHO7–10 classify all SV patients as high-risk or do not include them at all. This study seeks to identify clinical factors that increase the risk of SPL for patients with SV physiology. In larger studies, these factors can be used to develop and validate a risk-scoring system for pregnant patients with SV physiology.

    Methods

    This is a single-centre retrospective study of patients with SV physiology seen by cardio-obstetrics specialists between 2005 and 2023 with prior pregnancies, with a chart review of their clinical history. Patients without a known pregnancy outcome were excluded. Baseline data was obtained from chart review within the 12 months prior to pregnancy.

    Data collection included outpatient visits in the cardio-obstetrics clinic, maternal demographics, cardiac risk factors, congenital cardiac anatomy and echocardiographic data, medications and obstetric data. Oximetry data was averaged after obtaining all resting oxygen saturation and categorised into pre-pregnancy (within 12 months before pregnancy), each trimester during pregnancy and post partum (within 6 months postdelivery). Pregnancy outcomes included data at delivery hospitalisation. SPL was defined if occurring before 20 weeks gestation. Venovenous collaterals were documented if present on prior catheterisation or imaging data. Fontan-associated liver disease (FALD), with its stages, was documented if present in the chart documentation, on liver imaging or biopsy-proven, when available. Postpartum haemorrhage was documented if blood loss was ≥1000 mL at vaginal delivery or caesarean section.

    Statistical analysis was performed using STATA V.18.0 MP (StataCorp, College Station, TX). Categorical variables are expressed as absolute numbers and percentages; continuous variables are expressed as median (IQR) or mean (SD). Unadjusted Bayesian panel-data random-effects logit model was used to evaluate the risk of SPL. The two patients with Waterston and Glenn shunt palliation were excluded from final oxygen saturation assessment due to different underlying physiology and missing data. The list of predictor variables included preselected high-risk features: O2 saturations as a continuous variable, and the following binary variables: systemic ventricular type (RV vs LV), ventricular ejection fraction (EF) <50%, atrioventricular valve ≥moderate regurgitation, pre-pregnancy anticoagulation, atrial arrhythmias, FALD stage 4. OR with 95% credible interval (CrI) was reported. P value <0.05 was considered statistically significant.

    Results

    After excluding 11 patients with unknown or incomplete pregnancy outcomes, a total of 44 pregnancies in 20 patients were identified. The median age was 24 years, predominately white (70%). Of the 44 pregnancies, 21% had preconception visits, 40% had visits during pregnancy and 39% had postpartum visits in the cardio-obstetrics clinic (table 1). Baseline risk factors (table 2) demonstrated that 60% of patients (n=12) carried a pre-pregnancy diagnosis of hypertension, and nearly half had used tobacco or alcohol.

    View this table:
    Table 1

    Baseline maternal demographics and cardio-obstetrics visits

    View this table:
    Table 2

    Pre-pregnancy maternal clinical characteristics

    Of the 20 patients with SV physiology, one was palliated with a Waterston shunt, another with a Glenn shunt, while the remainder had a Fontan palliation (n=18), with a median of 20 years (IQR 7 years) from surgery to pregnancy and delivery. Of those with Fontan palliation, 2 had atriopulmonary Fontan, 15 had lateral tunnel Fontan and 1 had extracardiac Fontan. Half of the patients had RV morphology of their SV, 5 had a ventricular EF <50% and 14 (70%) had moderate to severe AVVR. The majority (80%) had a history of atrial arrhythmias and FALD (75%) (table 3). At baseline, twelve patients were on systemic anticoagulation, primarily warfarin, except for one on a direct oral anticoagulant; chart review shows clinicians switched the anticoagulants to subcutaneous enoxaparin during the first-trimester pregnancy. Most patients (75%) were on rate-controlling or antiarrhythmic medications, predominately beta-blockers (n=8). 15 patients (75%) were on antihypertensives, including selective and non-selective beta-blockers and calcium channel blockers (table 4).

    View this table:
    Table 3

    Maternal congenital cardiac characteristics

    View this table:
    Table 4

    Pre-pregnancy maternal medications

    Median maternal gravidity was two, and parity was one. Of the total 44 pregnancies, there were 21 SPL (48%), three elective abortions including one ectopic pregnancy. The mean gestational age for SPL was 8±2 weeks gestation. There were 20 live births (45%); the majority were preterm deliveries (75%) at a mean gestational age of 32.3±4 weeks and predominately via caesarean delivery (55%). The most common obstetric reason for hospital admission was bleeding; three patients had placental abruption, one had placenta accreta and one had placenta previa (table 5).

    View this table:
    Table 5

    Maternal obstetric data and pregnancy outcomes

    There were three hospital admissions for atrial arrhythmias (6.8%), and three for bleeding (6.8%). Intensive care unit admission was required for 10 patients during their pregnancy or post partum, in the setting of heart failure and bleeding, with an average stay of 3.6 days, requiring pressor, inotropic or vasodilator support (table 5).

    Average pre-pregnancy oxygen (O2) saturation for live births and SPL was 92.3% and 90.8%, respectively. Average first-trimester O2 saturation for live births and SPL was 93.8% and 90.8%, respectively. Average post-partum O2 saturation for live births and SPL was 91.2% and 89.3%, respectively (table 6).

    View this table:
    Table 6

    Oximetry data through pregnancy

    The following factors were associated with significantly higher odds of SPL: single right ventricular morphology (OR 1.72 (95% CrI 1.0008–2.70)), moderate or severe AVVR (OR 1.64 (95% CrI 1.003–2.71)) and reduced first-trimester O2 saturation (OR 1.83 (95% CrI 1.03–2.71) for each per cent decrease in O2 saturation).

    Seven placentas of patients with live births were available for review by the perinatal pathologist. Six demonstrated subchorionic haemorrhage. Three had changes consistent with maternal vascular malperfusion with accelerated villous maturation. Three had evidence of placental insufficiency with delayed villous maturation. One SPL placenta had a charted pathology report demonstrating visible subchorionic haemorrhage (figure 1).

    Figure 1
    Figure 1

    Placental pathology specimen with subchorionic haemorrhage. This placenta was small for age, with a stable subchorionic haemorrhage. At pathological examination, a 13 cm subchorionic haematoma was found at the margin, with diffuse choriamniotic hemosiderosis of the membranes and chorionic plate. The image shows numerous brown haemosiderin-laden macrophages in the chorionic plate (100× magnification, H&E stain).

    Discussion

    In our cohort of 20 patients with 44 pregnancies, we observed a high rate of SPL at 48%, and in those with live births (45%), a high rate of preterm delivery at 75% at a mean of 32 weeks gestation. In those with live births, only a small number had significant cardiovascular or obstetric complications, including arrhythmias (6.8%) and postpartum haemorrhage (4.5%). This may be partly because those with successful deliveries had better underlying physiology, cardiac compensation and oxygen saturations. Our study was not powered to detect a statistically significant effect of the multidisciplinary care offered in cardio-obstetrics clinic and delivery planning.

    Similarly, prior published data on pregnancy outcomes in patients with SV physiology post-Fontan palliation has consistently demonstrated a high risk of SPL (50%–60%) and preterm delivery at 24–36 weeks of gestation, with more use of caesarean delivery. Frequent maternal complications included arrhythmias, heart failure and postpartum haemorrhage, with the majority of patients on anticoagulants, similar to our group at 60%.11–13 Our study adds to this body of literature by demonstrating specific predictors of this high SPL risk, which included an SV with RV morphology, moderate to severe AVVR, and lower O2 saturations in the first trimester. Our study was likely not powered to detect the effect of systemic anticoagulation and advanced FALD on pregnancy outcomes. This is consistent with known high-risk features in patients with Fontan palliation that include ventricular dysfunction, valvular dysfunction, atrial arrhythmias, advanced FALD and PLE.2 4

    In pregnant patients with congenital heart disease, cardiac haemodynamics and their alterations throughout pregnancy have not been well defined. A study by Wald et al14 showed inadequate augmentation of CO from baseline to the third trimester and abnormal umbilical artery Doppler waveforms in mothers with congenital heart disease, which were independent predictors of adverse events. None were SV physiology, but some had systemic RV. Our study revealed that an RV morphology SV was a risk factor for SPL, which may be explained by its inability to mount a sufficient CO in the setting of pregnancy demand, whether from diastolic or systolic dysfunction. AVVR may lead to decreased CO with reduced forward flow but can also increase pulmonary venous pressures, leading to pulmonary oedema and cyanosis.

    There has been conflicting data on whether cyanosis is a predictor of worse pregnancy outcomes in patients with congenital heart disease as a whole. Some reports have argued that there is an increased risk of SPL and preterm delivery in those with cyanosis,10 15 while others have not noted a clear association.16 Our study demonstrates that the degree of cyanosis affects pregnancy outcomes in SV physiology mothers, with lower saturations in the first trimester increasing the risk of SPL. The association between low O2 saturations and SPL needs to be further defined. Specifically, it is unclear whether cyanosis leads to worse pregnancy outcomes due to insufficient oxygen delivery capacity in the high-demand state of pregnancy versus it serving as a marker of underlying poor physiology and haemodynamics. The poor haemodynamics in SV physiology, especially with Fontan palliation, may result from elevated Fontan pressures, venovenous collateral formation and right to left shunting versus pulmonary oedema from ventricular dysfunction or AVVR. It is unknown, though an intriguing proposition for a future study, whether addressing cyanosis by tackling anaemia to improve oxygen-carrying capacity, pre-pregnancy fenestration and collateral occlusion when haemodynamically safe or oxygen supplementation in those with non-shunt mediated cyanosis would affect pregnancy outcomes.

    Few studies examine placental pathology in pregnant patients with SV physiology.17 In one study examining eight placentas from live births in pregnant patients post Fontan palliation with worse outcomes, there was evidence of subchorionic haematomas, as well as hypoxic lesions with maternal vascular malperfusion, with immunohistochemistry for hypoxia-inducible factor-1α antibodies confirming these findings.18 In another study of 7 patients and 13 deliveries, subchorionic fibrin deposition and villous hypoplasia were a consistent feature in examined placentas.19 Our review of seven placental pathologies also demonstrates subchorionic haematomas, vascular malperfusion and delayed villous maturation. Further data on placental findings may shed additional light on the effect of cyanosis and the biology of adverse pregnancy outcomes.

    Our data requires validation in larger studies, but our findings can provide a useful framework in preconception counselling by identifying patients with the highest risk of SPL. In addition, these risk factors can serve as potential pre-pregnancy modifiers that may improve pregnancy outcomes, whether with medications, or interventional and surgical techniques.

    Limitations

    Our study was retrospective and susceptible to missing data, including, but not limited to, medication use, liver status and invasive haemodynamics before each pregnancy. Furthermore, it is a single-centre experience that may not reflect other centres’ patient populations. This study was small in number of patients and gestations; the small sample size limits the conclusions that can be drawn. Given that some patients present to our centre for cardio-obstetrical care during pregnancy only for delivery planning, pre-pregnancy functional class data is lacking and longer-term follow-up is often limited by geographical distance. The demographic diversity of the patient sample is also limited.

    Conclusion

    Patients with SV physiology, including Fontan-palliated ones, need specialised pre-pregnancy care due to their high risk of poor pregnancy outcomes. Single right ventricular morphology, moderate or severe AVVR, and lower first-trimester oxygen saturations are associated with an increased risk of SPL. These clinical risk factors can guide the cardio-obstetrics team in tailoring preconception counselling and early pregnancy management.

    Data availability statement

    Data are available upon reasonable request. The data generated and analysed during the current study are available from the corresponding author upon reasonable request. Researchers who wish to access the data should provide a detailed research proposal and demonstrate a commitment to maintaining confidentiality and using the data solely for the proposed research purposes. The data will be provided in a deidentified format to ensure participant privacy and comply with ethical guidelines.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Institutional Review Board Cleveland Clinic Study Number 21-636 retrospective.

    Acknowledgments

    We extend our heartfelt gratitude to our patients with congenital heart disease for their courage in facing life's challenges and for placing their trust in our care.

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    Footnotes

    • X @Tereshchenkolab, @JGhobrialMD

    • Contributors Concept and design: JG. Acquisition of data: YW, CS, BS,EG, PB, NM, AM, JG. Analysis and interpretation of data: LGT, JG. Drafting of the manuscript: YW, LGT, KS, JRL, CDD, AK-G, SB, MF, KZ, PFA, AM, JG. Critical revision of the manuscript for important intellectual content: JG. Statistical analysis: LGT. Study supervision: JG. JG is the guarantor for this work and accepts full responsibility for the conduct of the study, had access to the data and controlled the decision to publish.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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