Pulmonary hypertension (PH) is defined as an elevation in mean pulmonary arterial pressure to $\ge$25 mmHg at rest as assessed by right heart catheterization [1]. The 6th World Symposium on Pulmonary Hypertension recommended the upper limit of normal mean pulmonary arterial pressure to be 20 mmHg [2]. The worldwide prevalence of PH is estimated to be 1% overall, rising to 10% in elderly people over 65 years old, and to at least 50% in patients with heart failure [3]. Based on etiology, PH can be categorized into 5 groups. Group 1 is pulmonary arterial hypertension (PAH), the causes of which include idiopathic, heritable, drug- and toxin-induced, connective tissue diseases, human immunodeficiency virus (HIV) infection, portal hypertension, congenital heart disease. Group 2 refers to pulmonary hypertension associated with left-sided heart diseases, which is usually a consequence of heart failure or valvular heart disease. Pulmonary hypertension due to lung disease, pulmonary obstructive disease such as pulmonary embolism, and unclear mechanisms, are categorized into Groups 3, 4, and 5 respectively [4]. The overall estimated prevalence of PAH is ranging from 10 to 52 cases per million worldwide [5]. PAH is a life-threatening disease with increased pulmonary vascular resistance leading to right ventricular failure and even death, with a survival rate of 68% to 93% at 1 year and 39% to 77% at 3 years [3, 6].

In women of childbearing age, the most common cause of PH relates to the late consequences of Eisenmenger’s syndrome with heart disease. Hemodynamic changes during pregnancy and the peripartum, poor adaptation of the right heart, and insufficient compliance of pulmonary vasculature seem to be associated with poor tolerance in these patients. The maternal mortality rates of patients with PH have been reported to be as high as 30–56% in the last decade [7]. Therefore, pregnancy in the presence of PAH is contraindicated and recommended for early termination within current guidelines [2]. However, for patients with a high desire for pregnancy and for those who first presented with PH after conception, rational treatment is important to improve clinical outcomes.

The management of PH has evolved considerably in recent years. Due to the utilization of multidisciplinary therapies, maternal mortality rates in PH have been documented as declining to 9–25% [8, 9].

Successful pregnancies have been reported in small series or case reports to date, but data are incomplete for maternal and fetal outcomes in these patients, especially in developing countries. Therefore, the purpose of this study is to determine maternal and fetal outcomes in patients with pulmonary hypertension in west China.

This study was approved by the Institutional Review Board of West China Second University Hospital. The medical records of pregnant women with Hospitalized at West China Second University Hospital from January 2011 and May 2016 were retrospectively analyzed.

Our current study demonstrated that a history of prior cardiac events and right ventricular systolic dysfunction and/or baseline NYHA function class III or IV were the main determinants of adverse maternal cardiac events in pregnancies complicated with PH. Furthermore, late diagnosis and maternal severe PH and/or right ventricular systolic dysfunction were significantly associated with adverse fetal/neonatal outcomes in our series. Some studies have identified risk factors for adverse maternal outcomes in pregnancies complicated by heart diseases, including baseline NYHA functional class III or IV, and prior cardiac events [11]. Our findings in pregnancies complicated with PH were similar.

Right heart catheterization (RHC) is known as the gold standard for the diagnosis of PH [12]. The essential role of RHC in the diagnosis, management decision making, and assessment of the response to interventional procedures in patients with PH is well established. However, as an invasive technique, RHC also has catheter-related complications. In our study, transthoracic echocardiography (TTE) is used to diagnose PH. TTE is noninvasive, reproducible, and is the preferred imaging method during pregnancy. TTE has a pooled sensitivity of 85%, and a pooled specificity of 74% in the diagnosis of PH [13].

Pregnancy places a significantly physiologic load on the cardiovascular system with circulating blood volume increased by nearly 50%. The increased intravascular volume in those whose cardiac output is limited predisposes them to acute pulmonary edema, congestive cardiac failure, and a high mortality rate. The maternal mortality rate was 4.23% in our study, which is consistent with a previous study that reported an incidence of 4.8–9% [8, 14]. This was not consistent with the previous studies which revealed significantly higher maternal mortality rates of around 30% for Eisenmenger’s and primary PH, and 52% for secondary PH [8]. This might be due to the comparatively small number of idiopathic PH (2.8%) and Eisenmenger’s syndrome cases (4.2%) in our study population.

The neonatal outcomes were poor in our series, with a high incidence of preterm birth at 34.4%, and cases of small for gestational age (SGA) at 18.8%. Increased risk of SGA was found to be especially high for women with moderate or severe PH (with PASP higher than 50 mmHg), as opposed to those with mild PH (with PASP less than 49 mmHg). In a prior series of 20 women with PH, two patients in the pulmonary hypertension group had congestive cardiac failure, which was not significantly higher than those without pulmonary hypertension, but one was associated with the only maternal death and the other with the only perinatal death [15]. Another study found that well-controlled PH, particularly in long-term responders to calcium channel blockers, were factors of better maternal outcomes [16]. In our series, diagnosis after the third trimester, and severe PH and/or right ventricular systolic dysfunction were determined to be maternal predictive factors of adverse fetal/neonatal events, Importantly, a history of prior cardiac events and right ventricular systolic dysfunction and/or baseline NYHA function class III or IV were the main determinants of adverse maternal cardiac events.

Due to the high mortality, pregnancy is strongly discouraged in patients with baseline NYHA functional class III or IV or severe PH [8, 9]. Termination in the first trimester is a safer option. Termination of pregnancy in its mid and late phases, with the concomitant volume and hormonal fluctuations, also poses a high risk to the mother. It may be reasonable to continue a pregnancy, however, after the risks of termination are balanced against the risks of continuation of the pregnancy.

It is noted that PH presence late in pregnancies could pose extreme difficulty in treatment. Patients with PH should be cared for by a systematic multidisciplinary team including cardiologists, obstetricians, maternal-fetal medicine, cardiac ultrasound specialists, cardiology service lines, cardiac surgery, cardiac anesthesiologists, and neonatal specialists to minimize maternal and fetal mortality [17, 18].

The timing and mode of delivery remain controversial. Scheduled cesarean delivery during combined spinal-epidural anesthesia has been reported to be a preferable choice [19]. For the 64 ongoing pregnancies in our series, 62 (96.9%) were delivered by caesarean section. Epidural anesthesia was the most commonly used technique in the study population.

Several limitations should be taken into account when interpreting the results of the study. First, the hemodynamic data were collected retrospectively. Hemodynamic data before pregnancy were often not available. Second, due to the invasiveness and high risk, right heart catheterization did not perform routinely on pregnant women in our institute. The estimation of pulmonary artery pressure was based on the Doppler pressure gradients across the tricuspid valve. Third, a referral bias may exist as a consequence that patients included in this study were treated at a tertiary care center. Finally, the small sample size in the present study could also affect the statistical analysis. A further prospective study with larger sample size and more sensitive diagnostic methods is needed in the future.

In this study, we found that pregnancy in women with PH was associated with significant cardiac and neonatal morbidity. Early diagnosis was essential for a better outcome. A pre-pregnancy baseline assessment could identify women at high risk for adverse outcomes. Pregnancy should therefore be strongly discouraged in patients with baseline NYHA functional class III or IV or severe PH and/or right ventricular systolic dysfunction. Cardiac interventions should be considered before conception for women with high risk for cardiac events.

All authors contributed and participated in the preparation of the manuscript and research steps in the present study as follows: Conception and design of the research—HL, XDW and HYY; acquisition of data collection and statistical analysis—HL, QH and CYD; writing of original draft—HL; Reading, Revising and Final approval for submission—All.

This study was conducted with the written informed consent of all participants, and the data collection procedure obtained permission from the Ethics Committee of West China Second University Hospital (approval number: 2022-133) and performed in accordance with the 1964 Declaration of Helsinki and its later amendments.

We are grateful to the doctors and staff involved in this work. We thank all the peer reviewers for their opinions and suggestions.

This study was supported by the Academic and Technical Leader’s Foundation of Sichuan Province (No.2017-919-25).

The authors declare no conflict of interest.