Pregnancy in patients with pulmonary hypertension: a systematic review and meta-analysis with meta-regression

Introduction

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest as determined by right heart catheterization (RHC) (1). It is classified by the World Health Organization (WHO) according to the underlying pathology into five groups: (I) pulmonary arterial hypertension (PAH); (II) PH secondary to left heart disease; (III) PH due to lung disease and/or hypoxia; (IV) chronic thromboembolic pulmonary hypertension (CTEPH); and (V) PH with unclear and/or multifactorial mechanisms (1).

Regardless of the classification, pregnancy in patients with PH is associated with substantial risks, including high maternal mortality and fetal loss. The CARPREG II score considers PH as a significant risk factor, assigning points to it within the scoring system, indicating that pregnant women with PH are at a higher risk of experiencing cardiac complications during pregnancy (2). These risks are due to the physiological changes that occur during pregnancy and the peripartum period, which are poorly tolerated in these patients. Consequently, the American Heart Association and the European Society of Cardiology/European Respiratory Society recommend that women of childbearing potential with PH receive counseling at the time of diagnosis regarding the risks and uncertainties of pregnancy, including advice to avoid becoming pregnant (1,3). Despite these recommendations, some women with PH choose to become pregnant, while others may be diagnosed with PH during pregnancy. In such cases, the current consensus is to discuss the option of termination (1). If the pregnancy is to continue, the patient must be referred to specialized centers with multidisciplinary teams experienced in managing PH in pregnancy, ensuring close monitoring throughout pregnancy, childbirth, and the postpartum period (1).

Nevertheless, there has been an increase in the number of pregnant patients with PH carrying their pregnancies to term in recent years (4,5). Historically, the mortality rate for pregnant patients with PH was extremely high (6,7). However, recent studies have suggested a relative improvement in mortality rates, attributed to the implementation of multidisciplinary teams, and specific PAH therapies (8-10).

Given these recent findings, we conducted a systematic review and meta-analysis with meta-regression to evaluate the current evidence on pregnant patients with PH. Our goal was to assess the outcomes for this high-risk group, incorporate the latest studies, and identify risk factors associated with increased morbidity and mortality. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-430/rc) (11).

Methods

Search strategies

An unrestricted search of MEDLINE, EMBASE, and Cochrane bibliographic databases was performed for studies examining the outcomes of pregnant patients with PH from the inception through May 30, 2024, using the following MeSH terms and keywords: “pregnancy” AND “pulmonary hypertension”. References of the included studies and narrative reviews were also assessed for additional studies.

Study selection and eligibility criteria

Two investigators (M.E.I. and R.G.) independently screened studies for inclusion based on pre-specified eligibility criteria: (I) studies reporting the outcomes of pregnant patients with PH during pregnancy, delivery, and postpartum; (II) studies with post-partum/puerperium follow-up and (III) studies that included more than 10 patients. Exclusion criteria included studies evaluating only inpatient data during delivery without clear postpartum outcomes, studies published in languages other than English, and abstracts without accompanying manuscripts.

Data extraction and quality assessment

Two of the authors (M.E.I. and R.G.) extracted the following details from each study: publication year, country, study design, sample size, mean age, inclusion and exclusion criteria, gravidity, underlying etiologies of PH, mortality rate, neonatal mortality rate, preterm delivery rate, abortion rate, C-section rate, small gestational age rate, and hemodynamic parameters. Data on PH severity classification and the criteria used by various authors were also gathered. For our analysis, studies were categorized into two groups—mild/moderate and severe—based on the authors’ classification of PH severity in pregnant patients. To evaluate the quality of evidence, studies were assessed using the Newcastle-Ottawa scale (NOS) for cohort and case-control studies. A cutoff of 7 or higher was considered good quality, whereas <7 was considered poor quality.

Statistical analysis

The event rate was calculated as the number of patients with the outcome of interest divided by the total number of pregnancies with PH. To maintain consistency across outcomes and published studies, rates per 100 pregnancies with PH were reported. The event rate analysis utilized the DerSimonian-Laird random effects model, incorporating the Freeman-Tukey arcsine transformation. Sampling error was assessed using 95% confidence intervals (CIs) around risk estimates.

For two-group comparisons, odds ratio (OR) and their 95% CI were calculated using the Review Manager 5 (RevMan 5) Version 5.4. (Copenhagen: The Cochrane Collaboration, 2020). DerSimonian and Laird method random-effects model was used and a P value <0.05 was considered significant. Heterogeneity was assessed using the I² and the Cochran Q-statistic and I²>50% was considered significant.

Meta-regression was performed as classically described (12) using Comprehensive Meta-analysis version 4 (Biostat, Englewood, NJ, USA), using covariates in logistic regression models to uncover correlations that might explain heterogeneity. The correlation coefficient (R²) was employed to evaluate the relationship between variables, where a value of 0 indicates no correlation.

Results

Study selection

Our search identified 6,681 records. After duplicate removal, screening of the titles, and sometimes the abstracts, 115 manuscripts were fully assessed for eligibility. Fifty-one studies met our inclusion criteria (Figure 1).

Figure 1 Flow diagram of record allocation.

Study characteristics and patient population

Fifty-one studies involving 4,583 pregnant patients with PH were included, all of which were observational and predominantly retrospective (Appendix 1). The study populations were sourced from Asia, North America, South America, Africa, and Australia, with 20 studies conducted at centers in China.

The mean maternal age was 28 years with 39% of the women being multigravida. The mean systolic pulmonary artery pressure (sPAP) was 65 mmHg. PH was diagnosed during pregnancy in 41% of the patients. Congenital heart disease (CHD) was the leading cause of PH during pregnancy, accounting for 65% of cases, followed by left-sided valvular heart disease (VHD) at 16%, idiopathic pulmonary artery hypertension (IPAH) at 7%, heart failure/cardiomyopathy at 5%, connective tissue disorders at 4%, and other causes at 1% (Table 1). Additionally, five studies focused exclusively on patients with Eisenmenger syndrome (ES) (13-17) which was present in 386 pregnant patients with PH (1% of the entire cohort). The mean sPAP of the ES patients across the studies was 107 mmHg (13,14,16-19).

Quality of evidence

Based on NOS scoring, 65% of the studies were classified as good quality of the evidence, and the remaining 35% are poor (Table 2). The main areas of weakness identified were a lack of a clear definition of PH, different classifications of PH severity, small sample sizes, and the absence of a comparison group in some of the studies.

The definition of PH varied across the studies. Eight studies defined PH based on a mean pulmonary artery pressure (mPAP) greater than 25 mmHg (8,30,33,34,44,46,48,58). In four of these studies, sPAP was used as a surrogate measure when RHC was not performed (33,46,51,58). Additionally, eleven studies relied on sPAP (10,26,32,42,43,49,53,55-57,59), and five studies used right ventricular systolic pressure (RVSP) (28,38,45,50,60) as alternative diagnostic criteria for PH in pregnant patients. The cutoff values for both sPAP and RVSP differed among the studies (Table S1).

In the studies that classified PH, the cutoff points for different severity classes varied widely across studies, regardless of whether mPAP, sPAP, or RVSP was used as the parameter. Investigators introduced 22 distinct classifications, each based on one of these measures, with differing cutoff values (Table S2). For example, severe PH was defined based on sPAP in 20 studies, with cutoff values of 70 mmHg in eight studies (27,30,34-36,55,59,60), 80 mmHg in six studies (32,49,51,53,57,58), 50 mmHg in three studies (26,42,43), 75 mmHg in 2 studies (33,40), and 60 mmHg in one study (10).

Maternal mortality

The overall maternal mortality rate was 6%, yielding an event rate of 7.6% (95% CI: 5.8–9.9%) (Table 3). Most deaths (93%) occurred in the postpartum period. The mean sPAP among those who died was 106 mmHg. Heart failure was identified as the leading cause of death followed by pulmonary hypertensive crisis (Table 4).

From the underlying etiology perspective, ES was associated with the highest mortality rate of 18% among pregnant women with PH, followed by IPAH with a maternal mortality rate of 17%. From a severity perspective, studies were divided into two groups—mild/moderate and severe—based on the authors’ classification of PH severity in pregnant patients. ES patients were considered in the severe category. In the severe group, the maternal mortality rate was 12%, while in the mild/moderate group, the rate was 1%. Thus, severe PH was associated with a significantly higher rate of maternal mortality compared to mild/moderate PH with an OR of 5.57 (95% CI: 3.12–9.94) (Figure 2).

Figure 2 Maternal mortality rate in severe PH vs. mild/moderate PH (16,55). CI, confidence interval; M-H, Mantel-Haenszel; PH, pulmonary hypertension.

Meta-regression

A meta-regression analysis was conducted using the following covariates in different models: mean age, multiparity, multigravidity, prenatal care, post-pregnancy PH diagnosis rate, sPAP, ES rate, IPAH rate, C-section rate, general anesthesia use, and use of phosphodiesterase type 5 (PDE5) inhibitors.

Two covariates were found to have a significant correlation with maternal mortality: sPAP and ES rate. Higher sPAP in the studied cohort was associated with an increased mortality rate, with a regression coefficient R²=0.96 in the 26 studies included in the model (see Figure S1). Similarly, a higher proportion of ES cases was linked to a higher maternal mortality rate, with R²=1 in the 28 studies included in the model (Figure S2).

Perinatal outcome

The analysis revealed a neonatal mortality rate of 5% among pregnant patients with PH with an event rate of 6.4% (95% CI: 4.7–8.7%), along with a premature delivery rate and a small-gestational-age (SGA) incidence of 36% for both. Regarding the timing of fetal and neonatal deaths, 35% were attributed to intrauterine fetal death or spontaneous abortion, 26% occurred during the neonatal period, 23% were classified as stillbirths, and 22% involved death alongside maternal death during pregnancy or delivery (Table S3). Severe PH was associated with a higher rate of premature delivery and SGA than mild/moderate PH with OR 2.52 (95% CI: 1.66–3.81) and OR 3.96 (95% CI: 2.96–5.29), respectively (Figures S3,S4).

Meta-regression using the covariates mentioned above showed that ES was associated with a higher neonatal rate and premature delivery rate. The increase in ES rate in the studies was associated with increased neonatal mortality and premature delivery rate with R²=1 (Figures S5,S6).

Obstetric complication

The abortion rate among pregnant patients with PH was 14% in our analysis with event rate 16.2% (95% CI: 12.4–20.8%) (Table 3). Severe PH was associated with higher abortion compared to mild/moderated PH with an OR of 3.64 (95% CI: 2.61–5.09) (Figure S7). Meta-regression revealed a strong correlation between the rate of ES and abortion, with higher ES rates associated with increased abortion rates (R²=1) (Figure S8). The cesarean section rate was 81%, with no significant difference between mild/moderate and severe PH (OR =1.27, 95% CI: 0.81–1.99) (Figure S9). General anesthesia was used in 13% of cases, and postpartum hemorrhage occurred in 7% of patients.

Medication use and impact on outcomes

There was a significant amount of missing data regarding medical therapy in the studies. The most frequently reported medication was anticoagulation therapy, which appeared in 32 studies involving 379 patients. This was followed by PDE5 inhibitors in 17 studies with 189 patients, calcium channel blockers in 15 studies with 27 patients, and prostanoids: epoprostenol in 14 studies (45 patients), iloprost in 13 studies (25 patients), and treprostinil in 12 studies (9 patients). Although the impact of each medication on maternal mortality was evaluated using meta-regression, no significant effects were found.

Discussion

In our systematic review and meta-analysis on outcomes in pregnant patients with PH, we found a maternal mortality rate of 6%. ES was linked to a higher maternal mortality rate, as well as increased neonatal mortality, abortion rates and premature delivery. Severe PH was associated with a greater than five-fold increase in maternal mortality compared to mild or moderate PH, with sPAP emerging as a strong predictor of mortality. PH was also associated with a higher incidence of obstetric and perinatal complications, although the neonatal mortality rate seems to be improving.

Maternal mortality trends

Our analysis found a lower mortality rate at 6% compared to previous meta-analyses, despite our stricter inclusion criteria. We excluded studies that used international classification of disease codes to identify delivery as the index hospitalization for pregnant patients with PH without clear postpartum data. This approach aimed to avoid underestimating mortality rates, as most maternal deaths occur during the postpartum period. Notably, the mortality rate in pregnant patients with PH has declined over time (8-10). In a 2021 meta-analysis by Low et al., the pooled mortality rate across 13 studies was 12% (61). A more recent systematic review by Cruz et al. in 2024 reported a lower rate of approximately 8%, further highlighting this downward trend (62). The reason for improved outcomes is likely multifactorial including increased use of cardiac imaging and early diagnosis of PH, increased awareness of providers, and improved prenatal care with early involvement of multidisciplinary teams.

Maternal mortality in relation to PH severity and etiology

The severity of PH plays a critical role in determining pregnancy outcomes. The 2022 European Society of Cardiology guidelines recommend using a combination of factors to stratify patients with PH into low, intermediate, and high-risk categories, considering disease type, WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, and hemodynamic measurements (1). However, the classification of PH in the included studies varied significantly, as previously noted, with each study using different parameters for grouping. Despite this variability, most studies relied on sPAP measurements, primarily obtained via echocardiography during the initial evaluation, for patient stratification. Our study showed severe PH in pregnant patients is linked to a more than five-fold increase in maternal mortality compared to mild or moderate PH. A proposed estimate for sPAP cutoff of 70 mmHg was the most consistently used and inclusive threshold to define severe PH across the included studies (27,30,32,34-36,49,51,53,55,57-60).

sPAP reflects the afterload on the right ventricle. During pregnancy, women undergo significant hemodynamic changes, including increased total blood volume, cardiac output, and heart rate, reduced systemic and pulmonary vascular resistance, and increased blood coagulability (63). In pregnant patients with PH, these physiological changes are incomplete or poorly tolerated, leading to elevated sPAP and an increased risk of developing right heart failure. Conversely, a lower sPAP may reflect a better controlled PH disease in pregnant patient and is associated with better outcome. Therefore, sPAP serves as a valuable prognostic tool when assessing the risks of pregnancy in patients with PH.

Our study found that ES is associated with the highest maternal mortality rate and serves as a strong marker of poor prognosis. It is linked to an increased rate of neonatal death, abortion, and prematurity. Patients with ES are highly susceptible to hemodynamic fluctuations caused by pregnancy and delivery. Even a slight reduction in systemic vascular resistance (SVR) can exacerbate right-to-left shunting, potentially resulting in circulatory collapse. During pregnancy, the natural decrease in SVR intensifies right-to-left shunting, leading to reduced pulmonary perfusion, hypoxia, and worsening of both maternal and fetal conditions (13,64). Despite improvements in the mortality rate compared to previous reports (6,14), it remains alarmingly high. Although the literature lacks a universally defined risk threshold for ES, our findings suggest that markedly elevated sPAP may serve as a useful indicator for identifying higher-risk ES cases. These results reinforce the recommendation that patients with ES should avoid pregnancy due to the significantly increased risks to both mother and fetus.

In our analysis of pregnant patients with PH, IPAH exhibited the second-highest mortality rate, following that of ES. Maternal mortality rates for IPAH varied across studies; for instance, Lv et al. reported a mortality rate of approximately 50%, with deceased patients having a mean sPAP of 103 mmHg during pregnancy (56). Conversely, Ekici et al. found a much lower maternal mortality rate of 3% in their study, where 92% of the IPAH patients were classified as mild or moderate, with mortality occurring exclusively in the severe category, which comprised only 7% of the study population (40). In the study by Jaïs et al., the successful pregnancies in patients with IPAH were either those with nearly normal hemodynamic parameters on calcium channel blocker therapy, or patients with well-controlled PAH while receiving advanced targeted therapy (22). Therefore, while pregnancy is generally discouraged for those with IPAH, individualized risk assessment should be considered for patients with well-controlled conditions.

PAH-specific medications are associated with improvement in hemodynamic parameters, which can lead to a decrease in disease severity, ultimately enhancing outcomes for pregnant patients with PH (9,22). However, the studies included in our analysis provide limited data on these medications and their effects on outcomes. We found no significant impact of these treatments on outcomes. Given the small number of reported pregnant patients receiving targeted therapies, it is important to interpret the present study with caution and avoid applying the findings to subsets of patients based on specific medical therapy.

Our analysis showed a significant improvement in neonatal mortality rate with 5% compared to 13% in a prior review of pregnant patients with PH (65). In the study by Chen et al., the improvement in neonatal outcomes was linked to the adoption of a multidisciplinary team approach (10). Similarly, Ekici et al. observed that in their analysis of 45 pregnancies affected by PH, the reduction in neonatal mortality was due to the multidisciplinary team’s decisions regarding the timing of delivery, in addition to diligent fetal monitoring and advancements in neonatal intensive care (40).

Limitations

Several limitations should be acknowledged in this review. Firstly, the definition of PH varied across the included studies, which could affect the comparability of results. Different thresholds for mPAP and alternative diagnostic criteria, such as sPAP or RVSP, were utilized, leading to potential inconsistencies in PH’s classification and severity assessment. The severity classification adopted in our study was based on the authors’ categorization of their patients, which should be interpreted cautiously, as different PH groups may encompass varying sPAP ranges. There is also a lack of confirmation of the PH diagnosis through heart catheterization in most of the studies. Secondly, many studies featured small sample sizes, with a significant portion of the data originating from studies conducted in China, which could restrict the generalizability of the findings to other populations. Thirdly, the outcomes of pregnancies in patients with PH must be interpreted cautiously, considering that some patients may have undergone therapeutic abortion and did not reach delivery. Fourthly, the influence of specific medications for PH on outcomes remains ambiguous. There is a notable lack of comprehensive data regarding the use and effects of these treatments during pregnancy, and our analysis did not find a significant impact of targeted therapies on maternal mortality, possibly due to the limited number of cases reported. Fifthly, missing data on key variables such as prenatal care rates, specific treatments, and hemodynamic parameters (beyond sPAP) may hinder our ability to account for confounding factors, potentially introducing bias and affecting the accuracy of the regression results. Finally, the absence of dynamic evaluations of PH throughout the course of pregnancy is a notable limitation. Monitoring changes in hemodynamic parameters over time would provide a clearer understanding of how the physiological adaptations of pregnancy affect patients with PH.

Conclusions

In conclusion, pregnancy outcomes for patients with PH have improved overall, including a notable reduction in neonatal mortality rates. However, severe PH and especially ES continues to be associated with a high mortality rate, abortion rate, prematurity, and small gestational age. Our study reinforces the recommendation that women with severe PH, including those with ES, should strongly consider avoiding pregnancy due to the significantly increased risks of maternal and fetal mortality and morbidity. Utilizing sPAP as a key prognostic tool can aid in further stratifying risk and allowing for tailored approaches during pregnancy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-430/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-430/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-430/coif). C.G.M. serves as an unpaid editorial board member of Journal of Thoracic Disease from February 2025 to January 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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