Journal Reading Stase Obgyn

MATERNAL OUTCOMES AMONG PREGNANT WOMEN WITH CONGENITAL HEART

DISEASE-ASSOCIATED PULMONARY HYPERTENSION

Penyaji : Benny Afriansyah

Pembimbing: dr. Mondale Saputr, Sp.OG, Subsp. F.E.R

PROGRAM STUDI JANTUNG DAN PEMBULUH DARAH

PROGRAM SPESIALIS
FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS
2024

1
 KATA PENGANTAR

Puji Syukur penulis panjatkan kehadirat Allah SWT karena berkat Rahmat dan
hidayah-Nya tinjauan kepustakaan stase Obstetri dan Ginekologi pada Program Studi
Jantung dan Pembuluh Darah program Spesialis ini dengan Judul “MATERNAL OUTCOMES
AMONG PREGNANT WOMEN WITH CONGENITAL HEART DISEASE-ASSOCIATED
PULMONARY HYPERTENSION ” ini dapat diselesaikan pada waktu sebagaimana mestinya.

Penulisan tinjauan kepustakaan ini tidak luput dari bantuan dr. Mondale Saputra,
Sp.OG, Subsp. F.E.R selaku pembimbing penulis selama berada di stase ini yang telah
memberikan masukin dan bimbingannya, sehingga Penulis juga tidak lupa mengucapkan
Terima kasih yang sebesar-besarnya kepada beliau.
Tinjauan kepustakaan ini tentu masih memiliki kekurangan dan masih
membutuhkan masukan dari pembaca. Pemberian kritik dan saran terbuka sifatnya bagi
pembaca kepada penulis baik secara langsung maupun secara tidak langsung.
Demikian yang dapat penulis sampaikan, semoga tulisan ini dapat memberikan
manfaat bagi pembaca.

Padang, 20 Juni 2024

Penulis

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 DAFTAR ISI

Kata Pengantar ............................................................................................... i

Daftar isi ....................................................................................................... ii
PENDAHULUAN..........................................................................................1
JURNAL BAHASA INGGRIS .......................................................................2

ii
 Circulation

ORIGINAL RESEARCH ARTICLE

Maternal Outcomes Among Pregnant Women

With Congenital Heart Disease–Associated
Pulmonary Hypertension
Qian Zhang , MD*; Fang Zhu , MD*; Guocheng Shi, MD*; Chen Hu, MD; Weituo Zhang, PhD; Puzhen Huang, MD; Chunfeng Zhu , MD, PhD;Hong
Gu, MD, PhD; Dong Yang, MD, PhD; Qiangqiang Li, MD; Yonghua Niu, MD; Hao Chen , MD; Ruixiang Ma, MD;
Ziyi Pan, MD; Huixian Miao, MD; Xin Zhang, MD; Genxia Li, MD; Yabing Tang, MD; Guyuan Qiao, MD; Yichen Yan , MD;
Zhongqun Zhu, MD, PhD; Hao Zhang , MD, PhD; Fengzhen Han , MD; Yanna Li, MD; Jianhua Lin, MD, PhD; Huiwen Chen , MD, PhD

BACKGROUND: Studies focused on pregnant women with congenital heart disease (CHD)–associated pulmonary hypertension (PH) are
scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women
with CHD with and without PH.
METHODS: Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectivelyfrom 2017
to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal
death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and
moderate-to-severe PH.
RESULTS: A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729
women, including 398 with mild PH (right ventricle to right atrium gradient 30–50 mm Hg) and 331 with moderate- to-severe PH
(right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and
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no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD- associated pulmonary arterial
hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with
moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac
complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide
>100 ng/L (odds ratio, 1.9 [95% CI, 1.0–3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6–
5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a
multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2–0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3–0.7],
P=0.001) were protective.
CONCLUSIONS: Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-
associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality
risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk
stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may
also help to mitigate the risk of adverse maternal cardiac events.

Key Words: brain natriuretic peptide■ congenital heart disease ■ multimodality risk assessment ■ pregnancy ■ pulmonary hypertension ■ gender

Editorial, see p 562

Correspondence to: Huiwen Chen, MD, PhD, Department of Cardiothoracic Surgery, Heart Center, Shanghai Children’s Medical Center, Guizhou Branch of Shanghai Children’s Medical Center,
Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai, China 200127, Email [email protected]; or Jianhua Lin, MD, PhD, Department of Obstetrics and
Gynecology, Renji Hospital, Shanghai Medical Center for Critical Pregnancy, Shanghai Obstetrical Cardiology Intensive Care Center, Shanghai Jiao Tong University School of Medicine, 160 Pujian
Road, Shanghai, China 200125, Email [email protected]; or Yanna Li, MD, Department of Obstetrics and Gynecology, Anzhen Hospital, Beijing Medical Center for Critical Pregnancy, Capital
Medical University, 2 Anzhen Road, Beijing, China 100029, Email [email protected]; or Fengzhen Han, MD, Department of Obstetrics and Gynecology, Guangdong Provincial People's
Hospital, Guangdong Academy of Medical Sciences, Guangdong Medical Center for Critical Pregnancy, Southern Medical University, 106 Zhongshan Second Road, Guangzhou, China 510080,
Email [email protected]
*Q. Zhang, F. Zhu, and G. Shi contributed equally.
This article is part of the Science Goes Red™ collection. Science Goes Red™ is an initiative of Go Red for Women®, the American Heart Association’s global movementto end heart
disease and stroke in women.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.122.057987.For
Sources of Funding and Disclosures, see page 560.
© 2023 American Heart Association, Inc.
Circulation is available at www.ahajournals.org/journal/circ

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

P
ulmonary hypertension (PH) is known to compli- cate
pregnancy and has historically been associ- ated with
ORIGINAL RESEARCH

unacceptably high maternal mortality

ARTICLE

(around 25%–56%) because of clinical decompen- sation

secondary to intolerance of the hemodynamic stresses of
pregnancy, labor, and delivery.1–3 Patients with PH of any
cause have therefore been classified at the highest risk level
CHD-associated pulmonary hypertension (PH) in in the Modified World Health Orga-nization Classification of
China. Maternal Cardiovascular Risk (mWHO).1 At this risk level,
The number of women with CHD-associated PH pregnancy is considered to be contraindicated, and if
pregnancy occurs, consensus statements and guidelines
recommend that termination be discussed.1,4 Despite these
CHD-associated moderate-to-severe PH.
risks, the incidence of pregnancy in women with pulmonary
arterial hyperten- sion (PAH) is increasing.5 Accordingly,
there is an unmetneed for identifying and providing optimal
Pregnancy outcomes in women with CHD-associ- care for thissubset of patients.
Emerging data have also identified notable differences in
maternal outcomes when stratifying pregnant women with PH
on the basis of disease subcategory and sever- ity.3,6–8
Heart Association functional class. Congenital heart disease (CHD)–associated PAH is the most
common pathogenesis, accounting for ~65% of PAH during
pregnancy.9 There is some evidence that rates of adverse
cardiac complications. cardiac events and mortality may be lower relative to other
forms of PAH.10,11 For example, in the Registry of Pregnancy
classified as Modified World Health Organization and Cardiac Disease, survival in pregnant women with CHD-
Classification of Maternal Cardiovascular Risk
associated PAH was 96% versus 57% in those with
class IV, where pregnancy is considered contra-
idiopathic PAH.3
There is also some suggestion that patients with lesssevere
PH may have more favorable outcomes versus those with
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more severe PH.6,9–12 However, studies of PH severity are

lower risk than previously reported. limited by small sample sizes. The medical com- munity has
therefore highlighted the importance of better identifying
individuals in whom pregnancy counseling may be more
Nonstandard Abbreviations and Acronyms nuanced, versus completely contraindicated.9,13 We therefore
hypothesized that pregnancy outcomes in women with CHD-
ANC antenatal care associated PH would differ by PH severity.
BNP brain natriuretic peptide
CHD congenital heart disease
CHD-PAH pulmonary arterial hypertension associ- METHODS
ated with congenital heart disease Study Design and Participant Population
HF heart failure This is a retrospective multicenter observational study focused on
IQR interquartile range pregnant women diagnosed with CHD-associated PH at 7 tertiary
LVEF left ventricular ejection fraction hospitals in China from April 1993 to December 2019 (Figure S1).
The registry was initiated by Shanghai Children’s Medical Center,
MDT multidisciplinary team
Shanghai Renji Hospital, and Beijing Anzhen Hospital in March
mWHO Modified World Health Organization 2017. Cases were collected retrospectively from 1993 to 2016 and
Classification of Maternal Cardiovascu- prospectively from 2017 to 2019. The study was approved by the
lar Risk Shanghai Children’s Medical Center institutional review board and by
NYHA New York Heart Association the institutional review boards of other participating centers. All
PAH pulmonary arterial hypertension participants enrolled after 2017 gave written informed consent, and
PH pulmonary hypertension informed consent was waived for those enrolled before 2017.
Pregnant women with CHD with and without PH present- ing to
RV-RA right ventricle to right atrium
our hospitals were enrolled. Exclusion criteria (Figure 1) were (1)
patients who had incomplete medical records; (2) patients who
had miscarriages (fetal death at <24 weeks of

Circulation. 2023;147:549–561. DOI: 10.1161/CIRCULATIONAHA.122.057987 February 14, 2023 549

 Zhang et al Pregnancy Outcomes in CHD-PH Women

ORIGINAL RESEARCH
ARTICLE
Figure 1. Flow chart of inclusion.
A total of 461 cases were prospectively collected (2017–2019), whereas 1759 were retrospectively collected (1993–2016). In total, 535 women with CHD-
associated PH had uncompleted pregnancies including 41 miscarriages at a median gestational week of 12 (IQR, 8 –19), and494 TOP at a median gestational
week of 13 (IQR, 9–19). Miscarriages were observed in 7 women with mild PH and 34 women with moderate-to-severe PH, whereas TOP was performed in
34 women with mild PH and 460 women with moderate-to-severe PH. CHD indicates congenital heart disease; PH, pulmonary hypertension; RV-RA, right
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ventricle to right atrium; TOP, termination of pregnancy; and TRVmax, peak tricuspid regurgitation velocity.

gestation) or termination of pregnancy that was not because of PH; echocardiography.3,17 Patients with PH were further divided into mild PH
and (3) patients who were lost to follow-up before deliveryor within (mean pulmonary arterial pressure by catheterization 20–40 mmHg, or
6 weeks postpartum. We used the cutoff time of 6 weeks echocardiographically estimated RV-RA pressure gradient 30–50 mmHg at
postpartum because this is a critical phase when mater- nal and rest [peak tricuspid regurgitation velocity 2.74-3.53 m/s]) and moderate-to-
newborn deaths often occur.14 severe PH (mean pulmonary arterial pressure
>40 mmHg by catheterization or echocardiographically estimated RV-
RA pressure gradient >50 mmHg at rest [peak tricuspid regur- gitation
Data Access and Collection velocity >3.53 m/s]).3,17,18 Of note, if there was presence of right
The data supporting the study findings are available from the pri- mary
ventricular outflow tract obstruction or pulmonary stenosis, the estimation
corresponding author (H.W.C.) on reasonable request. The baseline
of PH was adjusted as the result of RV-RA pressure gradi- ent minus the right
visit was the first antenatal care (ANC) visit to 1 of our 7 hospitals. ventricular outflow tract obstruction.19
Data collected included patient baseline characteris-tics (demographics, According to the updated classification of PH,17 CHD-
CHD diagnosis, New York Heart Association [NYHA] functional class,
associated PH in this series was subcategorized into CHD-PAH
history of arrhythmias), blood tests (brain natriuretic peptide [BNP]
([group 1], including PAH related to the systemic-to-pulmonary
level), and findings from the echocar- diography (left ventricular
shunt, Eisenmenger syndrome, repaired CHD, and small car- diac
ejection fraction [LVEF; for systemic right ventricles, ejection fraction
defects) and CHD–other PH (including PH related to left heart
was visually estimated15], severity of valvular regurgitation, and
disease [group 2], pulmonary arterial obstructions [group 4], and
estimates of right ventricle to right atrium [RV-RA] pressure gradient)
complex CHDs [group 5]). Delayed diagnosis of PH was defined as
and electrocardiography, and right heart catheterization if available. Of
PH diagnosed during pregnancy. Late presentation (also referred to
note, BNP was routinely tested in a structured way after 2006 using
as delayed first ANC visit) was defined as the first prenatal visit to
the Triage B-Type Natriuretic Peptide test (Biosite Inc, San Diego,
one of the study-associated hospitals that was after the 20th
CA).16
gestational week irrespective of whether they had previously seen
doctors in other hospitals (eg, local hospitals). The multidisciplinary
PH Diagnosis and Definitions team (MDT) included adult cardiologists (including PH experts),
PH was defined as mean pulmonary arterial pressure 20 mmHg on congenital heart specialists, obstetricians, neonatologists, and
catheterization or RV-RA pressure gradient 30 mmHg at rest, on the anesthetists who provided a network of ter- tiary care. Strict antenatal
basis of tricuspid regurgitation jet velocity 2.74 m/s by supervision was defined according to

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

the American College of Obstetricians and Gynecologists guide-lines20 clinically significant episodes of arrhythmia requiring treatment,
as 1 cardiology evaluation during follow-up in patients with endocarditis, cardiac surgery or interventional treatment dur- ing
mWHO class I, 3 evaluations in patients with mWHO class II and II- pregnancy, decline of 2 NYHA functional classes during
ORIGINAL RESEARCH

III, 5 evaluations in patients with mWHO class III, and pregnancy, thromboembolic event, and myocardial infarction.
ARTICLE

10 evaluations in patients with mWHO class IV. The BNP level was NYHA deterioration during pregnancy was comprehensively
divided into 3 categories (low <35 ng/L, medium 35–100ng/L, and evaluated by experienced cardiologists on the basis of close
high >100 ng/L) and was defined to be elevated when it was >35 antenatal supervision. Obstetric events included pregnancy- induced
ng/L.21 Women with Eisenmenger syndrome were cyanotic patients hypertension (new-onset hypertension: systolic blood pressure >140
who had large nonrestrictive systemic-to-pul- monary shunts with mm Hg or diastolic >90 mm Hg without pro- teinuria after 20
pulmonary vascular resistance at systemic levels and shunt reversal weeks of gestation), preeclampsia (a combi- nation of pregnancy-
(right-to-left).1 CHD was classified into 4 subcategories (shunt lesions, induced hypertension and >0.3 g protein in 24-hour urine sample),
left heart abnormality, right heart abnormality, and other CHDs; Figure eclampsia (preeclampsia with grand mal seizures), hemolysis
2). This was done because the well-established European Society of elevated liver enzymes low platelets syndrome, postpartum
Cardiology22 (mild, mod- erate, severe CHD) and anatomic- hemorrhage (vaginal delivery >500 mL and cesarean section >1000
physiological classifications23 include PH as part of the classification mL until 6 weeks postpartum), and preterm delivery (<37 weeks of
system, which would havecomplicated the planned analyses. gestation). Preterm deliv- ery was further classified into extremely
preterm (<28 weeks), very preterm (28–32 weeks), and moderate or
late preterm (32–37 weeks). Offspring events included (1) fetal
Outcomes mortality (demise from in utero [>20 weeks of gestation] to the first
Outcome events were analyzed individually and grouped as year postpartum), including both spontaneous miscarriage and ter-
(1) maternal death or heart failure (HF), (2) other cardiac mination of pregnancy; (2) low birth weight (<2500 g), includ- ing
events, (3) obstetric events, and (4) offspring events. Other cardiac very low birth weight (<1500 g) and extremely low birth weight
events (diagnosed by expert cardiologists) included (<1000 g); and (3) fetal CHD.
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Figure 2. Classification of CHD diagnosis.

Left, The 4 subcategories of CHD as well as the detailed diagnosis in each subcategory in patients with CHD and no PH, CHD-associated mild PH, and
CHD-associated moderate-to-severe PH. Right, Pie charts, percentage of unrepaired CHD in each subcategory in the entire cohort and CHD-associated PH
subcohort. Tricuspid/mitral/aortic valve lesion indicated that valvar stenosis or regurgitation cannot be identified. AI indicates aortic valve insufficiency;
ALCAPA, anomalous left coronary artery from the pulmonary artery; APVC, anomalous pulmonary venous connection; AS, aortic valve stenosis; ASD, atrial septal
defect; AVSD, atrioventricular septal defect; CAVSD, complete atrioventricular septal defect; CHD, congenital heart disease; CHD-oPH, CHD-other PH;
CHD-PAH, pulmonary arterial hypertension associated with congenital heart disease; CoA, coarctation of aorta; DCRV, double chambered right ventricular;
DORV, double outlet right ventricle; L-TGA, L-looped transposition of the great arteries; MI, mitral valve insufficiency; MS, mitral valve stenosis; PA, pulmonary
atresia; PAS, pulmonary artery stenosis; PAVSD, partial atrioventricular septal defect; PDA, patent ductus arteriosus; PH, pulmonary hypertension; PI, pulmonary
valve insufficiency; PS, pulmonary valvar stenosis; TGA, transposition of the great arteries; TI, tricuspid valve insufficiency; TOF, tetralogy of Fallot; and VSD,
ventricular septal defect.

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

Statistical Analysis PH Pathogenesis and Timing of Diagnosis

ORIGINAL RESEARCH
Categorical data were presented as frequencies (numbers) and Of the 729 women with CHD-associated PH, 619 had
percentages, whereas continuous data were presentedas mean±SD CHD-PAH, and 110 had CHD–other PH. Systemic- to-

ARTICLE
or median (interquartile range [IQR]) values. Comparisons between
2 groups were performed using the Student t test or Wilcoxon rank
pulmonary shunt-related PAH was most common (75.4%;
test for continuous variables and the chi-square or Fisher exact test for 467/619) in the CHD-PAH group, whereas left heart
categorical variables. Comparisons among multiple groups were disease–related PH was the most common (50.9%; 56/110)
performed using the ANOVA or Kruskal-Wallis test for in the CHD–other PH group. Delayed diagnosis of PH,
continuous variables and the chi-square or Fisher exact test for defined as a PH diagnosis made during pregnancy, occurred
categorical variables. Normality of continuous data was checked in 228 women (31.3%; 228/729), among whom 149
with Kolmogorov- Smirnov tests. To identify the risk factors for (20.4%) were diagnosed after their 20th gestational week.
cardiac outcomes, univariable and multivariable analyses were First visit to a specialty hospi- tal after 20 weeks (delayed
performed through logistic regression. The candidate variables first ANC visit) occurred in 68.6% in the PH subcohort.
included demo- graphics, general and lesion-specific cardiac Underlying CHD pathogen-esis is shown in Figure 2.
characteristics, and laboratory examinations. Univariable predictors
of adverse cardiac events with P values of <0.1 were selected and
entered in the multivariable logistic regression model with a level of Management
sig- nificance at 0.05. Odds ratios and 95% CIs were reported in a
forest plot. Subgroup analyses were performed by comparing the The median duration of follow-up during pregnancy from first
incidence of maternal cardiac events in each subgroup of ANC visit to delivery was 98 (IQR, 70–140) days, and the
pregnancies with mild PH. We applied propensity score match- ing median duration of postpartum follow-up was 53 (IQR, 48–
analyses between the no-PH group and mild-PH group. Each 59) days. Around two-thirds of the 729 women with PH were
patient’s propensity score was estimated by a multivari- able logistic followed with strict antenatal supervision, meeting the
regression model with covariates. Patients with no PH were matched minimum number of visits recommended in American
in a 1:1 ratio with no replacement to patients with mild PH using the College of Obstetricians and Gynecologists guidelines (Table
nearest-neighbor algorithm. Two-tailed P values <0.05 were 2), and 537 (74%) had at least 2 echo- cardiographic
considered statistically significant. All sta- tistical analyses were examinations. PH severity was unchanged for most women
performed with R Project Software (ver-sion 3.6.3, R Foundation).
(89%) between the first and last ANC visits during
pregnancy, whereas 11% changed PH se- verity category
RESULTS (Figure S3).
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Population Oxygen supplementation and diuretics were pro- vided to

462 (63.4%) and 347 (47.6%) of patients with PH,
A total of 2220 pregnancies in women with CHD were respectively, during pregnancy, and all women with PH were
included in the main analyses. Mean maternal age was ~28 counseled to avoid excessive physical activity. PH targeted
years, and most (60%) were nulliparous. No women had therapy was received by 128 women (17.6%, 128/729),
multiple pregnancies during the study. The diagnosis of PH including 29 (7%) women with mild PH and 99 (30%)
(probable PH) was based on echocar- diogram in most, women with moderate- to-severe PH (Table 2). Intensive
although catheterization was used for diagnosis when care unit admission was required in 6.5% (26/398) of
performed (N=58; correlation versus echocardiogram r=0.83, women with mild PH and 68.3% (226/331) of women
P<0.001, Figure S2). Patients were further divided into mild with moderate- to-severe PH, and the median length of
PH (N=729, median RV- RA pressure gradient 37 mm Hg hospital stay was 7 (IQR, 5–10) and 10 (IQR, 6–13) days
[IQR, 33.0–43.0]) and moderate-to-severe PH [N=331, in the mild and moderate-to-severe PH subgroups,
median RV-RA pres- sure gradient 72 mm Hg (IQR, 56.0– respec-tively.
96.5]) (Figure 1). The severity of PH could not be Most women in all 3 groups were delivered by cesar- ean
identified in 27 pa- tients because of missing data about the section using regional anesthesia, with cesarean section used
RV-RA pres- sure gradient; thus, these patients were in 83%, 89%, and 92% of women with no, mild, and
excluded from the main analyses. moderate-to-severe PH (P<0.05 for compari- son between no
Detailed patient demographics are shown in Table 1. Most PH and mild PH; Table 2). Preterm and very preterm
women with PH had a normal LVEF (96.7%), defined as deliveries were more common in women with moderate-to-
an ejection fraction >50%, regardless of the severity of PH. severe PH (Table 2).
Women with moderate-to-severe PH had poorer NYHA
functional class (30.2% versus 3.3%, P<0.001) and higher
BNP level (>100 ng/L; 24.8% versus 13.3%, P<0.001) Maternal Outcomes
than those in the mildPH group. Maternal mortality occurred in 1 (0.1%), 0, and 19
(5.7%) women with CHD and no, mild, or mod- erate-to-
severe PH, respectively (P<0.001 for

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

Table 1. Baseline Characteristics

No PH Mild PH Moderate-to-Severe
ORIGINAL RESEARCH

(N=1464) (N=398) PH (N=331) P value* P value†

ARTICLE

Age,‡ y, mean±SD 28.3±4.4 28.2±4.5 27.6±4.6 0.72 0.075

Hypertension or diabetes, n (%) 96 (6.6%) 21 (5.3%) 36 (10.9%) 0.42 0.006

Previous arrhythmia, n (%) 200 (13.7%) 72 (18.1%) 32 (9.7%) 0.001 <0.001

Unrepaired CHD, n (%) 712 (48.6%) 259 (65.1%) 274 (82.8%) <0.001 <0.001
Cyanotic CHD, n (%) 189 (12.9%) 54 (13.6%) 32 (9.7%) 0.19 0.064
RV-RA pressure gradient,§ mm Hg, median (IQR) 24.0 (22.0–27.0) 37.0 (33.0–43.0) 72.0 (56.0–96.5) <0.001 <0.001
NYHA, n (%) 0.014 <0.001
I–II 1443 (98.6%) 383 (96.2%) 204 (61.6%) … …

III–IV 19 (1.3%) 13 (3.3%) 100 (30.2%) … …

LVEF, n (%) 0.067 0.81
0%–50% 14 (1.0%) 9 (2.3%) 9 (2.7%) … …

>50% 1446 (98.8%) 387 (97.2%) 318 (96.1%) … …

… …
BNP∥, n (%), ng/L
<35 928 (63.4%) 178 (44.7%) 132 (39.9%) <0.001 0.40

35–100 375 (25.6%) 164 (41.2%) 102 (30.8%) <0.001 0.013

>100 158 (10.8%) 53 (13.3%) 82 (24.8%) 0.15 <0.001

Nulliparity, n (%) 891 (60.9%) 238 (59.8%) 203 (61.3%) 0.73 0.70
Multiple gestation, n (%) 29 (2.0%) 4 (1.0%) 5 (1.5%) 0.28 0.74

Assisted reproduction, n (%) 41 (2.8%) 11 (2.8%) 5 (1.5%) 1.000 0.31

Abnormal pregnancy history,fj n (%) 157 (10.7%) 31 (7.8%) 44 (13.3%) 0.091 0.020
Follow-up time after delivery,§ d, median (IQR) 53 (47–59) 53.5 (47–60) 54 (49–59) 0.31 0.80

Follow-up time after the first ANC visit,§ d, median (IQR) 160.5 (128.0–213.3) 162.5 (124.0–217.0) 136.0 (104.0–189.0) 0.69 <0.001
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ANC indicates antenatal care; BNP, brain natriuretic peptide; CHD, congenital heart disease; IQR, interquartile range; LVEF, left ventricular ejection fraction; NYHA,
New York Heart Association; PH, pulmonary hypertension; and RV-RA, right ventricle to right atrium.
*P value between patients in no PH group and mild PH group.
†P value between patients in mild PH group and moderate-to-severe PH group.
‡Comparisons of maternal age between 2 groups (no PH versus mild PH; mild PH versus moderate-to-severe PH) were performed using the Student t-test.
§Comparisons of RV-RA pressure gradient, follow-up time after delivery, and follow-up time after the first ANC visit between 2 groups (no PH versus mild PH; mild
PH versus moderate-to-severe PH) were performed using the Wilcoxon rank test.
∥BNP data obtained at a median of 23 (IQR, 18–27) weeks of gestation for patients recruited after year 2000 and were available in 2173 of 2220 (overall patient
population) and in 711 of the 729 patients with PH.
fjAbnormal pregnancy history, included the history of miscarriage, ectopic pregnancy, fetal abnormalities, or intrauterine death.

moderate-to-severe versus mild and versus no PH; Table 2). offspring events, and obstetric events compared with the
Three of 19 deaths (16%) in PH women occurred during mild PH group. In contrast, women with mild PH had a
the delivery, whereas the remainder occurred during the significantly higher event rate versus patients with CHD
postpartum period (Table S1, de- tailed causes of death). and no PH only in the combined other car- diac events
Among the 535 women with uncompleted pregnancies category.
(miscarriage or termina- tion of pregnancy), maternal Factors associated with maternal cardiac complica- tions
mortality occurred in 16 of 494 women in the moderate- in the cohort overall and in the PH associated with CHD
to-severe PH group (3.2%), versus no women in the no subcohort are shown in Figure 4. In the multivari- able
PH and mild PH groups (Figure S4, outcomes for completed analysis including all 2220 patients (Figure 4B), maternal
and un- completed pregnancies combined). cardiac events were significantly associated with moderate-
HF, arrhythmia requiring treatment, and decline of to-severe PH, increased BNP level (>35 ng/L), NYHA
2 NYHA functional classes also occurred more often in class III to IV, unrepaired CHD, LVEF
women with moderate-to-severe PH (Table 2), whereas there <50%, and delayed first ANC visit, but not with mild PH
were no significant differences in these individual end points (P=0.70). Follow-up with the MDT and with strict antena- tal
for the women with CHD and no PH versus mild PH. When supervision were both protective. Within the PH sub- cohort
analyzed by event category (Figure 3), women with (N=729), increased BNP >100 ng/L and NYHA III to IV
moderate-to-severe PH had worse outcomes for death/HF, remained risk predictors for maternal cardiac events, but
other cardiac events, BNP levels of 35 to 100 ng/L and LVEF
<50% were not (Figure 4D).

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

Table 2. Clinical Outcomes and Management in Pregnancies With No PH, Mild PH, and Moderate-to-Severe PH

ORIGINAL RESEARCH
No PH Mild PH Moderate-to-severe
(N=1464) (N=398) PH (N=331) P value* P value† P value‡

ARTICLE
Clinical outcomes
Maternal cardiac events, n (%)

Death 1 (0.1%) 0 (0.0%) 19 (5.7%) 1.00 <0.001 <0.001

Heart failure 94 (6.4%) 31 (7.8%) 128 (38.7%) 0.37 <0.001 <0.001
Arrhythmia requiring treatment 36 (2.5%) 16 (4.0%) 20 (6.0%) 0.12 0.23 0.002
Endocarditis 2 (0.1%) 1 (0.3%) 3 (0.9%) 0.51 0.34 0.046
Cardiac surgery during the prenatal 16 (1.1%) 8 (2.0%) 4 (1.2%) 0.21 0.56 0.78
period

Decline of 2 NYHA functional class dur- 25 (1.7%) 12 (3.0%) 85 (25.7%) 0.11 <0.001 <0.001
ing the antepartum period
Thromboembolic event 5 (0.3%) 2 (0.5%) 1 (0.3%) 0.63 1.00 1.00
Cerebrovascular event 1 (0.1%) 0 (0.0%) 0 (0.0%) 1.00 1.00 1.00
Myocardial infarction 6 (0.4%) 2 (0.5%) 2 (0.6%) 0.65 1.00 0.63

Obstetric events, n (%)

Preterm delivery (<37 wk) 204 (13.9%) 67 (16.8%) 144 (43.5%) 0.15 <0.001 <0.001

Very preterm (28–32 wk) 16 (1.1%) 9 (2.3%) 44 (13.3%) 0.085 <0.001 <0.001
Extremely preterm (<28 wk) 2 (0.1%) 1 (0.3%) 1 (0.3%) 0.51 1.00 0.46
Postpartum hemorrhage 73 (5.0%) 9 (2.3%) 37 (11.2%) 0.019 <0.001 <0.001

Pregnancy induced hypertension 49 (3.3%) 14 (3.5%) 12 (3.6%) 0.88 1.00 0.74

Preeclampsia 44 (3.0%) 8 (2.0%) 23 (6.9%) 0.39 0.001 0.002

HELLP 0 (0.0%) 0 (0.0%) 5 (1.5%) 1.00 0.019 <0.001

Offspring events, n (%)

Offspring death 7 (0.5%) 1 (0.3%) 4 (1.2%) 1.00 0.18 0.13
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Low birth weight 167 (11.4%) 64 (16.1%) 145 (43.8%) 0.016 <0.001 <0.001
Very low birth weight 13 (0.9%) 8 (2.0%) 36 (10.9%) 0.10 <0.001 <0.001
Extremely low birth weight 8 (0.5%) 2 (0.5%) 8 (2.4%) 1.00 0.049 0.004

Offspring CHD 40 (2.7%) 10 (2.5%) 13 (3.9%) 1.00 0.30 0.28

Management
Antenatal management, n (%)

Late presentation (>20 wk gestation) 969 (66.2%) 250 (62.8%) 250 (75.5%) 0.21 <0.001 0.001
Strict antenatal supervision 1320 (90.2%) 275 (69.1%) 196 (59.2%) <0.001 0.006 <0.001

Total times of antenatal visit,§ mean±SD 8.0±3.3 9.2±3.2 7.6±4.6 <0.001 <0.001 0.091
Total weeks followed from presentation to 15 (11–21) 15 (10–20) 11 (7–16.6) 0.39 <0.001 <0.001
delivery,∥ median (IQR)
MDT 1009 (68.9%) 251 (63.1%) 152 (45.9%) 0.030 <0.001 <0.001
Delivery management, n (%)

Gestational week at delivery,∥ mean±SD 37.8±1.9 37.4±2.1 35.6±3.1 <0.001 <0.001 <0.001

Length of hospital stay,∥ d, median (IQR) 7 (5–9) 7 (5–10) 10 (6–13) 0.18 <0.001 <0.001

Mode of delivery 0.005 0.17 <0.001

Vaginal 246 (16.8%) 44 (11.1%) 26 (7.9%) … … …
Caesarean section 1218 (83.2%) 354 (88.9%) 305 (92.1%) … … …
Anesthesia

General anesthesia 36 (2.5%) 9 (2.3%) 38 (11.5%) 1.00 <0.001 <0.001

Regional anesthesia 1209 (82.6%) 347 (87.2%) 273 (82.5%) 0.027 0.095 1.00
Without anesthesia 219 (15.0%) 42 (10.6%) 19 (5.7%) 0.028 0.022 <0.001

(Continued )

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

Table 2. Continued

No PH Mild PH Moderate-to-severe
ORIGINAL RESEARCH

(N=1464) (N=398) PH (N=331) P value* P value† P value‡

ARTICLE

Drug therapy, n (%)

Targeted therapy … 29 (7.3%) 99 (29.9%) … <0.001 …

Monotherapyfj … 26 (6.5%) 68 (20.5%) … <0.001 …

Combination therapy# … 3 (0.8%) 31 (9.4%) … <0.001 …
Anticoagulation 11 (0.8%) 20 (5.0%) 25 (7.6%) <0.001 0.17 <0.001

CHD indicates congenital heart disease; HELLP, hemolysis elevated liver enzymes low platelets syndrome; IQR, interquartile range; MDT, multidisciplinary team;
NYHA, New York Heart Association; PDE5-i, phosphodiesterase type 5 inhibitor; and PH, pulmonary hypertension.
*P value between patients in no PH group and mild PH group.
†P value between patients in mild PH group and moderate-to-severe PH group.
‡P value between patients in no PH group and moderate-to-severe PH group.
§Comparisons of total times of antenatal visit between 2 groups (no PH versus mild PH; mild PH versus moderate-to-severe PH; no PH versus moderate-to-severe
PH) were performed using the Student t-test.
∥Comparisons of total weeks followed from presentation to delivery, gestational week at delivery, and length of hospital stay between 2 groups (no PH versus mild
PH; mild PH versus moderate-to-severe PH; no PH versus moderate-to-severe PH) were performed using the Wilcoxon rank test.
fjMonotherapy included PDE5-i (including oral sildenafil or tadalafil), inhaled iloprost, intravenous treprostinil, or intravenous alprostadil.
#Combination therapy included PDE5-i and intravenous treprostinil.

Offspring Adverse Events Sensitivity Analyses

The mean gestational week at delivery was 37.8±1.9, Sensitivity analyses were completed to evaluate out- comes
37.4±2.1, and 35.6±2.1 weeks for no PH, mild PH, and after grouping by (1) repaired CHD, (2) unre- paired CHD,
moderate-to-severe PH, respectively. The most frequent and (3) CHD-PAH (ie, excluding patients with other forms of
offspring event was low birth weight (17.2%), and both low PH). In all 3 cases, the moderate-to- severe PH group had
birth weight and combined offspring events over- all higher rates of adverse events for maternal death or heart
occurred more often in the moderate-to-severe PH group failure (combined), other cardiacevents, offspring events, and
(Table 2 and Figure 3). Offspring mortality oc- curred in 7 obstetric events, whereas events for the mild PH and no PH
(0.5%), 1 (0.3%), and 4 (1.2%) women with no PH, mild groups were similar for most end points (Figure S8 through
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PH, and moderate-to-severe PH (P, NS for all comparisons). S10). Outcomes were also generally similar for women with
and without 1 or more previous pregnancies (Figure S11
through S13;Table S3, detailed comparisons between women
Time Trend Analyses with and without previous pregnancies).
During the study period, the proportion of pregnant wom- en
with CHD-associated PH increased from 13.4% for the
earliest study years (1993–2004) to 39.0% in the most Between-Group Comparison in CHD Women With
recent years (2015–2019) (Figure 5A). A greater proportion Mild Versus No PH
of women also had poorer functional class (NYHA III–IV), Propensity score matching resulted in 2 well-balanced groups
an elevated BNP (>35 ng/L), and mod- erate-to-severe PH consisting of 392 patients with CHD-associated mild PH and
(Table S2) in the most recent years.Shunt lesions (repaired or 392 with CHD and no PH. There was no significant
unrepaired) remained the most common subgroup in women difference in maternal death/HF (11.0% ver- sus 7.1%;
with CHD-associated PH, despite a nearly 10% decrease from P=0.08) or offspring outcomes (20.9% versus 16.8%; P=0.17)
1993 to 2004 to 2015 to 2019 (Figure S5). Repaired CHD for the mild versus no PH groups (Table S4). In a separate
increased over time, reaching 23.2% (45/194) for the years analysis exploring subgroups within the mild PH group, a
2015to 2019 (Figure S6). higher rate of adverse maternal events was seen in women
Adverse maternal outcomes in women with moderate- to- with a LVEF <50% (4/9, 44%) and NYHA class III/IV
severe PH declined from 75% in 1993 to 2004 to 39.7% in symptoms (7/13, 54%), although the small number of
2015 to 2019, combining events of maternal death, HF, and patients in these subgroups limits this analysis (Figure S14).
other cardiac events (Figure 5B). This occurred
simultaneously with an increase in termination of pregnancy
among women with moderate-to-severe PH (from 29.4% to
DISCUSSION
68.2%, Figure S6). The event rates for maternal and
offspring outcomes were similar in the retrospectively This nationwide study, to our knowledge, represents the
collected (n=1759) and prospectively collected subcohorts largest study on pregnancy in women with CHD-
(n=461) (Figure S7). associated PH. Herein, the main findings from the

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

ORIGINAL RESEARCH
ARTICLE
Figure 3. Adverse events in patients with CHD-associated PH and without PH.
For women who completed pregnancy, those with CHD-associated mild PH had similar outcomes compared with those with no PH in terms of maternal and
offspring outcomes, except for a higher incidence of other cardiac event. However, there was a significantly higher incidence of maternal and offspring
complications in those with moderate-to-severe PH than in mild PH. Other cardiac events included clinically significant episodes of arrhythmia, endocarditis,
myocardial infarction, thromboembolic events, decline of 2 New York Heart Association functional classes during pregnancy, and cardiac
surgery/interventional treatment during pregnancy. *Significant difference (P<0.05) between patients with no PH and mild PH. ††Significant difference
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(P<0.01) between patients with mild PH and moderate-to-severe PH. CHD indicates congenital heart disease; HF, heart failure; and PH, pulmonary
hypertension.

analysis of 2220 CHD women with completed preg- spring events remained unacceptably high in these stud-ies. In
nancies (34% with PH versus 66% without PH) are 3-fold. this context, the findings from the present work provide
First, women with mild PH had lower rates of ad- verse important information suggesting that pregnancy outcomes in
outcomes for maternal death, cardiac events, off- spring women with CHD-associated PH may also differ by PH
events, and obstetric events compared with the moderate-to- severity, and that potentially, CHD with mild PH with other
severe PH subgroup, and had similar out- comes versus CHD favorable findings may not be an absolute contraindication to
and no PH in the propensity score–matched analysis. Second, pregnancy.
follow-up with the MDT and with strict antenatal supervision Our study overall has also shown a lower maternal
were both associated with lower rates of maternal cardiac mortality (2.6%) in pregnant women with CHD-associ- ated
complications in patients with CHD-associated PH. Third, PH than previously reported, although still higher than in
taking BNP level and NYHA functional class into healthy pregnant women. We also found that adverse
consideration may help to further risk-stratify pregnant maternal cardiac events declined over time in women with
women with CHD- associated mild or moderate-to-severe moderate-to-severe PH (Figure 5). The lower mortality
PH. rate overall may in part be attributable to the patient
These results suggest that a more individualized population, where the majority of the patients had
approach to pregnancy risk may need to be consid- ered in systemic-to-pulmonary shunt-related PAH (excluding
the future for women with pregnancy and CHD- associated Eisenmenger syndrome) and who, in other studies,3,6,9,25 have
PH. Previous studies have shown declining but still been reported to tolerate pregnancy better related to better
unacceptably high maternal mortality rates for women with right ventricular compensation. However, early assessment by
pregnancy and PH in general, falling from 56% in 1978 to the MDT, including timely first ANC visit, access to tertiary
1996 to 12% in 2008 to 2018.9,24 For the CHD-PAH subset, care, follow-up with the MDT, and strict antenatal
some studies have also suggested an even lower mortality rate supervision, may also have contributed to improved
(3.6%–6.4%).3,25 However, overall maternal morbidity and outcomes. These interventions are in line with current
mortality as well as off- guidelines for the management of

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 Zhang et al Pregnancy Outcomes in CHD-PH Women
ORIGINAL RESEARCH
ARTICLE

Figure 4. Univariable and multivariable analyses of maternal cardiac events in the entire cohort and CHD-associated PH
subcohort.
Univariable and multivariable analyses were performed to explore the risk factors associated with maternal cardiac complications in the overall cohort (A and
B) and in patients with CHD-associated PH (C and D). Missing data for PH severity, BNP level, LVEF, or NYHA class occurred in 93 patients who were
excluded, and thus the analyses were performed in 2127 of 2220 patients (97.8%) overall (B), and in 689 of 729 (94.5%) of patients in the PH associated with
CHD subcohort (D). ORs and 95% CIs were estimated using the logistic regression model. Variables with a P value <0.10 identified in the univariable
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analyses were entered into the multivariable analyses. BNP indicates brain natriuretic peptide; CHD, congenital heart disease; LVEF, left ventricle ejection
fraction; MDT, multidisciplinary team; NYHA, New York Heart Association; OR, odds ratio; and PH, pulmonary hypertension.

pregnant patients with increased risk of cardiovascular increased risk in maternal death/HF or obstetric or fetal
complications,1,4 and were more commonly performed in complications. PH severity was also unchanged for most
women in the more recent years of the study (Table S2). women (84.7%) between the first and last ANC visits, with
Another potential contributor to favorable outcomes may be 89.0% and 80.9% for mild and moderate-to- severe PH,
the liberal use of cesarean section under regionalanesthesia respectively (Figure S3).
(~93%), which potentially avoids mater-nal Recent guidelines for PAH in general (outside of
decompensation in the late stages of pregnancy.Regional pregnancy) have proposed a comprehensive evalua- tion and
anesthesia was preferred over general anes-thesia so as to individualized risk stratification in patients with PAH, with
avoid potential negative effects on car-diac contractility both functional class and BNP levels playing a prominent
and pulmonary vascular resistance,26although there is a lack role in this assessment.4 Correspondingly, our work also
of strong evidence to support thesuperiority of cesarean suggests that multimodality assessment, including disease
section over vaginal delivery orregional versus general severity (mild versus moderate-to- severe PH on the basis of
anesthesia, in terms of improving RV-RA pressure gradient), BNP level, and NYHA class, may
maternal outcomes.27 be useful in assessing risk in pregnancy with CHD-
It is important that women with CHD-associated mild associated PH. BNP is a marker of myocardial stress and is
PH had significantly lower rates of maternal and offspring widely used in the routine practice of specialized PH
complications during pregnancy than those with moderate-to- centers because of its association with mortality and
severe PH (Figure 3). This can likely be attributed to better correlation with pulmo- nary hemodynamics.4,28 Poorer
preserved RV function, result- ing in better compensation NYHA functional class is also a known predictor of major
with the increased cardiac demands seen during pregnancy. adverse cardiac events in pregnant women with cardiac
In addition, after adjustment for the baseline characteristics, disease.29
patients with mild PH had similar outcomes versus those It is interesting that LVEF <50% was not found to be a
hav- ing CHD and no PH, with no evidence of risk predictor for maternal cardiac events. A reasonable
significantly explanation may be that RV size and function are often

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

ORIGINAL RESEARCH
ARTICLE
Figure 5. Time trend analyses of PH prevalence and of maternal cardiac outcomes in the overall cohort (n=2220).
Left, Change of case mix in patients with CHD-associated PH of different degrees (no, mild, moderate-to-severe PH) during the study period. Right,
Incidences of maternal cardiac outcomes in each subgroup in the 4 periods of enrollment (1993–2004, 2005–2009, 2010–2014, and 2015–2019). Maternal
cardiac outcomes included maternal death, heart failure, clinically significant (requiring treatment with at least prescription drugs) episodes of arrhythmia,
endocarditis, cardiac surgery or interventional treatment during pregnancy, decline of 2 New York Heart Association functional classes during pregnancy,
thromboembolic event, and myocardial infarction. **Significant difference between patients in the no PH group and mild PH group (P<0.01). ††Significant
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difference between patients in the mild PH group and moderate-to-severe PH group (P<0.01). Between-group comparisons in the incidences of the maternal
cardiac outcomes were performed using the Fisher exact test. CHD indicates congenital heart disease; and PH, pulmonary hypertension.

better predictors of outcome in CHD with and without PH, CHD may have led to an increase in some subgroups of
whereas LVEF is generally less predictive.30–32 In future patients surviving to adulthood.33
studies, additional echocardiographic measures of cardiac size
and function should be considered for inclu- sion, because
measures such as right atrial size, right ventricular size and
Limitations
function, and pericardial effusion also associate significantly This study has many limitations. First, most patients were
with PH outcomes. diagnosed with PH by echocardiography because of patient or
Of note, it appears to be counterintuitive that women with physician preference. This may have led to overdiagnosis or
moderate-to-severe PH (especially related to unre- paired underdiagnosis, particularly for those with pressures near our
shunt lesion) increased in prevalence over the years, given cutoffs, and it is possible that a subset of patients may have
better prenatal diagnosis of CHD and also corrective repair elevated pulmonary pres- sures primarily caused by
afterwards. Possible explanations are as follows. First, there increased cardiac output (ie, with normal pulmonary vascular
was a lack of access to timelyCHD repair in rural or remote resistance). However, our classification of PH using RV-RA
areas in a portion of these women in this series, potentially pressure gradient without adding the right atrium pressure is
reflecting the socioeco- nomic disparities between the more conser- vative versus other CHD registries. For
developed and developing world. Second, with the example, in the multicenter Registry of Pregnancy and
implementation of regionalization of care for pregnant women Cardiac Disease, an RVSP 30 mm Hg (including estimated
in China in the more recent era, a higher proportion of these right atrium pressure) was used to define PH.4 Second,
women may now be referred to specialty hospitals. Third, a although this study was conducted across 7 Chinese hospitals,
change in the case mix over time may suggest true changes in our sites were mostly high-volume academic medical cen-
the patho- genesis of CHD in women with moderate-to- ters. Thus, the results may not be applicable to hospitals with
severe PH. Last, improved outcomes for more severe forms less extensive resources. Third, patients in this study
of

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 Zhang et al Pregnancy Outcomes in CHD-PH Women

were enrolled across a wide timespan (>2 decades), which Acknowledgments

may have introduced era-related confounding in- fluences The authors sincerely acknowledge all participating hospitals for their contribu- tions to
ORIGINAL RESEARCH

this project. The authors thank all the staff from Clinical Research Center, Shanghai Jiao
such as advancements in diagnostic imaging modality, Tong University School of Medicine, for their great assistance in statistical analysis.
ARTICLE

specialized care, and PH-targeted therapies. Fourth,

although the sensitivity analysis in 535 wom- en who had Sources of Funding
This study was funded by the Chinese National Natural Science Foundations
miscarriage or termination related to PH (moderate-to- (82100409, 81970267, and 81801777), Shanghai Science and Technol- ogy
severe PH: 92.3% [494/535]) showed the results Development Funds (22QA1405800), Clinical Research Fund of Shang- hai Jiao
consistent with the primary analysis, there is still the Tong University School of Medicine (DLY201815, ZH2018ZDA24), and Shanghai
Municipal Planning Commission of Science and Research Funds (20025800300,
potential that higher-risk patients may have been more
2019SY046).
likely to terminate at an early/lower-risk time point in
pregnancy, potentially resulting in a lower over-all mortality Disclosures
risk than would be seen in settings wheretermination is less None.

common or prohibited. Whether our results can be Supplemental Material

extrapolated to other PAH subgroups (ie, idiopathic PAH) is Tables S1–S4 Figures
also unknown. Last, although most postpartum deaths in S1–S14
pregnant women occur within 1
month of delivery, the effects of pregnancy on the car-
diovascular system can persist for several months after
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