Predictors of spontaneous pregnancy loss in single ventricle physiology

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.

Correspondence to Dr Joanna Ghobrial; [email protected]

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 WHO^7–10 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.

Table 1

Baseline maternal demographics and cardio-obstetrics visits

Baseline characteristics
Patients	N=20
Maternal age in years, median	24 (19–41)
Race/ethnicity, n (%)
White	14 (70%)
Black	3 (15%)
Hispanic	2 (10%)
Multiracial	1 (5%)
Education, n (%)
Completed HS	8 (40%)
Completed college	7 (35%)
Unknown	5 (25%)
Insurance status, n (%)
Private	7 (35%)
Medicare	4 (20%)
Medicaid	5 (25%)
Other/unknown	4 (20%)
Cardio-obstetrics clinic visits per pregnancy	N=80
Preconception, n (%)	17 (21%)
Pregnancy visits, n (%)	32 (40%)
Postpartum visit, n (%)	31 (39%)

Table 2

Pre-pregnancy maternal clinical characteristics

Baseline risk factors, n (%)	All (n=20)
Baseline BMI, mean (SD)	22 (3.8)
Diabetes mellitus	1 (5%)
On oral medications	0
On insulin	1 (5%)
Renal disease	2 (10%)
Pulmonary disease	5 (25%)
CAD	2 (10%)
Hypertension (pre-pregnancy)	12 (60%)
Stroke	3 (15%)
Sleep apnoea	4 (20%)
Smoking	9 (45%)
Alcohol	10 (50%)
Other substance misuse yes/no	4 (20%)

BMI, body mass index; CAD, coronary artery disease.

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).

Table 3

Maternal congenital cardiac characteristics

Congenital history, n (%)	All patients N=20	Live births N=20	SPL N=21
Single ventricle repaired with systemic shunt (Waterston shunt)	1 (5%)	4 (20%)	0
Single ventricle with cavopulmonary shunt (Glenn)	1 (5%)	2 (10)%	0
Single ventricle with Fontan palliation	18 (90%)	14 (70%)	21 (100%)
Type Fontan
Atrio-pulmonary (RA-PA) Fontan	2 (10%)	4 (20%)	2 (9.5%)
Lateral tunnel	15 (5%)	9 (45%)	20 (95%)
Extracardiac	1 (5%)	1 (5%)	0
Single left ventricle	10 (50%)	11 (55%)	9 (43%)
Single right ventricle	10 (50%)	8 (40%)	12 (57%)
Known residual fenestration	2 (10%)	2 (10%)	3 (14%)
Known venovenous collaterals	11 (55%)	9 (45%)	14 (67%)
Known ventricular dysfunction EF <50%	5 (25%)	2 (10%)	6 (29%)
Known ventricular dysfunction EF <30%	1 (5%)	0	1 (4.7%)
Known ≥moderate AVVR	14 (70%)	15 (75%)	18 (86%)
History of atrial arrhythmias	16 (80%)	18 (90%)	19 (90%)
History of Fontan/Glenn thrombus	1 (5%)	1 (5%)	0
FALD—Fontan-associated liver disease	15 (75%)	11 (55%)	16 (76%)
Stage 4 fibrosis/cirrhosis	9 (45%)	5 (25%)	9 (43%)

AVVR, atrioventricular valvular regurgitation; EF, ejection fraction; SPL, spontaneous pregnancy loss.

Table 4

Pre-pregnancy maternal medications

Baseline medications, n (%)*	N=20
Warfarin	11 (55%)
DOAC (apixaban or rivaroxaban or other DOAC)	1 (5%)
Aspirin	13 (65%)
Rate-controlling or antiarrhythmic	15 (75%)
Beta-blocker (excluding labetalol)	8 (40%)
Other antiarrhythmic (sotalol, dofetilide, propafenone)	5 (25%)
Amiodarone	2 (10%)
Antihypertensive	15 (75%)
Beta-blocker (including labetalol)	10 (50%)
Calcium channel blocker (nifedipine, amlodipine)	1 (5%)
Other antihypertensive	4 (20%)

*Missing data n=3.

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).

Table 5

Maternal obstetric data and pregnancy outcomes

Pregnant patients	N=20
Maternal age at delivery (median, range)	24 (18–41)
Gravidity (median, range)	2 (1–6)
Parity (median, range)	1 (0–4)
Multigestation pregnancy	0
Gestational diabetes (n, %)	1 (5%)
Gestational hypertension (n, %)	3 (15%)
Maternal anaemia requiring therapy (iron or blood) (n, %)	11 (55%)
Pregnancies	N=44
SPL, n (%)	21 (48%)
Elective abortions, n (%)	3 (7%)
Ectopic pregnancy	1
Live births, n (%)	20 (45%)
Term delivery	5 (25%)
Preterm delivery	15 (75%)
Vaginal	9 (45%)
C-section	11 (55%)
Gestational age at delivery (weeks) (mean, SD)	32.3 (±3.9)
Gestational age at SPL or abortion (weeks) (mean, SD)	8 (±1.7)
Prepartum admission for cardiac reason*	3 (6.8%)
Most common diagnosis: arrhythmia	3
Admission for obstetric reason during pregnancy	5 (11.4%)
Most common diagnosis: bleeding	3 (6.8%)
Postpartum haemorrhage	2 (4.5%)
Blood transfusion given	4 (9.1%)
ICU admission (yes)†	10 (22.7%)
Total maternal ICU length of stay in days (mean)	3.6
Pressor or inotrope administration	5 (11%)
Vasodilator administration	5 (11%)
Mechanical circulatory support	1 (2%)
Delivery at hospital with Cardio-OB care	9 (20.5%)

*Missing data n=4.

†Missing data n=7.

ICU, intensive care unit; SPL, spontaneous pregnancy loss.

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).

Table 6

Oximetry data through pregnancy

Oximetry (mean %)	All	Live birth	SPL	Elective abortion
Pre partum	92.4	92.3	90.8	94.5
First trimester	93.2	93.8	90.8	93.2
Second trimester	94.7	94.6	N/A	N/A
Third trimester	93.4	93.8	N/A	N/A
Post partum 6 months	91.6	91.2	89.3	97

SPL, spontaneous pregnancy loss.

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).

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.

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.

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

Not applicable.

Ethics approval

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

References

¹ Khairy P, Ionescu-Ittu R, Mackie AS, et al. Changing mortality in congenital heart disease. J Am Coll Cardiol 2010; 56: 1149–57. doi:10.1016/j.jacc.2010.03.085

² Rychik J, Atz AM, Celermajer DS, et al. Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association. Circulation 2019; 140: e234–84. doi:10.1161/CIR.0000000000000696

³ Gewillig M, Brown SC. The Fontan circulation after 45 years: update in physiology. Heart 2016; 102: 1081–6. doi:10.1136/heartjnl-2015-307467

⁴ Said SM, Dearani JA, Silversides CK, et al. Longer-term issues for young adults with hypoplastic left heart syndrome: contraception, pregnancy, transition, transfer, counselling, and re-operation. Cardiol Young 2011; 21 Suppl 2: 93–100. doi:10.1017/S1047951111001661

⁵ Ouzounian JG, Elkayam U. Physiologic changes during normal pregnancy and delivery. Cardiol Clin 2012; 30: 317–29. doi:10.1016/j.ccl.2012.05.004

⁶ Wichert-Schmitt B, D’Souza R, Silversides CK. Reproductive Issues in Patients With the Fontan Operation. Can J Cardiol 2022; 38: 921–9. doi:10.1016/j.cjca.2022.04.020

⁷ Kim YY, Goldberg LA, Awh K, et al. Accuracy of risk prediction scores in pregnant women with congenital heart disease. Congenit Heart Dis 2019; 14: 470–8. doi:10.1111/chd.12750

⁸ Drenthen W, Boersma E, Balci A, et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010; 31: 2124–32. doi:10.1093/eurheartj/ehq200

⁹ Denayer N, Troost E, Santens B, et al. Comparison of risk stratification models for pregnancy in congenital heart disease. Int J Cardiol 2021; 323: 54–60. doi:10.1016/j.ijcard.2020.09.033

¹⁰ Silversides CK, Grewal J, Mason J, et al. Pregnancy Outcomes in Women With Heart Disease: The CARPREG II Study. J Am Coll Cardiol 2018; 71: 2419–30. doi:10.1016/j.jacc.2018.02.076

¹¹ Cauldwell M, Steer PJ, Bonner S, et al. Retrospective UK multicentre study of the pregnancy outcomes of women with a Fontan repair. Heart 2018; 104: 401–6. doi:10.1136/heartjnl-2017-311763

¹² Garcia Ropero A, Baskar S, Roos Hesselink JW, et al. Pregnancy in Women With a Fontan Circulation: A Systematic Review of the Literature. Circ Cardiovasc Qual Outcomes 2018; 11: e004575. doi:10.1161/CIRCOUTCOMES.117.004575

¹³ Bonner SJ, Asghar O, Roberts A, et al. Cardiovascular, obstetric and neonatal outcomes in women with previous fontan repair. Eur J Obstet Gynecol Reprod Biol 2017; 219: 53–6. doi:10.1016/j.ejogrb.2017.10.013

¹⁴ Wald RM, Silversides CK, Kingdom J, et al. Maternal Cardiac Output and Fetal Doppler Predict Adverse Neonatal Outcomes in Pregnant Women With Heart Disease. J Am Heart Assoc 2015; 4: e002414. doi:10.1161/JAHA.115.002414

¹⁵ Presbitero P, Somerville J, Stone S, et al. Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus. Circulation 1994; 89: 2673–6. doi:10.1161/01.cir.89.6.2673

¹⁶ Arif S, Chaudhary A, Clift PF, et al. Pregnancy outcomes in patients with a fontan circulation and proposal for a risk-scoring system: single centre experience. J Congenit Heart Dis 2017; 1: 10. doi:10.1186/s40949-017-0012-8

¹⁷ Redline RW, Roberts DJ, Parast MM, et al. Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease. Am J Obstet Gynecol 2023; 228: 187–202. doi:10.1016/j.ajog.2022.08.010

¹⁸ Yokouchi-Konishi T, Ohta-Ogo K, Kamiya CA, et al. Clinicopathologic Study of Placentas From Women With a Fontan Circulation. Circ J 2021; 86: 138–46. doi:10.1253/circj.CJ-21-0133

¹⁹ Phillips AL, Cetta F, Kerr SE, et al. The placenta: A site of end-organ damage after Fontan operation. A case series. Int J Cardiol 2019; 289: 52–5. doi:10.1016/j.ijcard.2019.02.002