Evaluation of maternal-fetal outcomes in pregnancy complicated with severe pulmonary hypertension and its influencing factors: a single-center retrospective study in China

Abstract Objective Pregnancy is not recommended for patients with severe pulmonary hypertension (PH) due to the significant risks it poses to both the mother and fetus. The objective of this study is to describe the maternal-fetal outcomes in pregnant women with PH and identify the factors that influence these outcomes. Method This retrospective study analyzed clinical data from 25 patients with severe PH who were admitted to our hospital between January 2018 and December 2022. The data we used came from a public general hospital in Fujian Province. Results The mean systolic pulmonary artery pressure (sPAP) of 25 patients was 105.12 ± 22.70 mmHg. All patients had received one or more multidisciplinary team (MDT) treatments before terminating their pregnancies. Among the pregnant women, four experienced a pulmonary hypertensive crisis (PHC), seven had heart failure, and one had postpartum hemorrhage (PPH). Among them, seven (28%) pregnant women died primarily due to heart failure and PHC. Among the fetal outcomes, twelve resulted in therapeutic abortion, and eleven resulted in preterm birth. Among the perinatal complications, eleven infants (84.6%) were born prematurely, six infants (46.2%) experienced neonatal asphyxia, eight infants (61.5%) had low birth weight, and two infants (15.4%) died during the perinatal period. According to the etiology, seven individuals had idiopathic pulmonary arterial hypertension (iPAH), ten had pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH), six had pulmonary hypertension associated with left heart disease (LDH-PH), and two had pulmonary arterial hypertension caused by other diseases (oPAH). The sPAP levels of iPAH and CHD-PAH were significantly higher than those of LDH-PH and oPAH (p < 0.05). Additionally, the gestational weeks of LDH-PH were higher than those of iPAH (p < 0.05). The number of patients with New York Heart Association (NYHA) heart function grade III-V was higher in the death group compared to the non-death group (p < 0.05). Conclusion Pregnancy in women with severe PH carries a high risk of mortality. Therefore, contraception is strongly recommended for these women. NYHA cardiac function grade III-IV was useful in predicting the risk of mortality.


Introduction
Maternal mortality has been a widely discussed issue worldwide.Pregnancy combined with cardiac disease continues to be the leading non-obstetric cause of maternal death [1,2].The mortality rate of pregnant patients with pulmonary hypertension (PH) is estimated to be around 16% to 30% [3].With improved treatment of PH and new approaches to managing women during pregnancy and the peri-partum period, maternal mortality has declined but remains high, ranging from 11% to 25% [4].The World Health Organization lists PH as a contraindication during pregnancy.Most of the available articles currently focus on studying the medical records of patients with mild-to-moderate PH.However, it is important to note that patients with severe PH may experience worse pregnancy outcomes.Unfortunately, there is a lack of discussion regarding outcomes in cohorts consisting solely of patients with severe PH.During clinical work, many patients with severe PH still face challenges related to pregnancy and delivery.To explore the etiology and pregnancy outcomes in women with severe PH, we retrospectively analyzed the medical records of 25 pregnant patients with severe PH who were admitted to our hospital in the past 5 years.This study aims to investigate the management of pregnant women with severe PH and provide clinical evidence to optimize treatments and enhance maternal and fetal outcomes.

Diagnosis and subgroups of PH
According to the "2022 ESC/ERS Guidelines for the Diagnosis and Treatment of PH", the hemodynamic diagnostic criterion for PH is a mean pulmonary artery pressure �20 mmHg, as measured by right cardiac catheterization (RHC) at rest and sea level [4].RHC is widely recognized as the "gold standard" for diagnosing PH.However, due to the invasiveness of the RHC, it is not feasible to routinely perform cardiac catheterization to obtain pulmonary artery pressure readings in pregnant women.In our study, we utilized echocardiography to estimate the systolic pulmonary artery pressure (sPAP), which has been demonstrated to have a strong correlation with results from RHC [5,6].An sPAP of �30 mmHg was used as the diagnostic threshold for PH [7,8].According to the 2016 China Specialist Consensus and the severity of sPAP, patients with a sPAP of �80 mmHg were defined as having severe PH [7].The sPAP was indirectly evaluated by measuring the pressure difference of tricuspid regurgitation using spectral continuous wave Doppler performed by an experienced sonographer from our hospital.Patients who did not have the necessary data or had elevated right ventricular systolic pressure due to outflow tract obstruction or pulmonary stenosis were excluded.
According to the most recent consensus document, our study divided patients into two groups based on their pathogenesis.Group 1 included patients with pulmonary arterial hypertension (PAH), further categorized into three subgroups: idiopathic PAH (iPAH), PAH associated with congenital heart disease (CHD-PAH), and PAH associated with other diseases (oPAH).Group 2 consisted of patients with PH caused by left heart disease (LHD-PH), which could be attributed to left ventricular systolic dysfunction, valvular disease, congenital or acquired left heart inflow or outflow tract obstructions, or congenital cardiomyopathies.None of the other diagnoses mentioned in the consensus documents were present in our study population [9,10].
The etiology of PH was determined by cardiologists by integrating a patient's heart color Doppler reports with their clinical manifestations and symptoms.
Pulmonary hypertensive crisis (PHC) is a clinical state characterized by elevated pulmonary circulation resistance and blocked right heart blood pump, resulting in sudden PH and low cardiac output.This crisis state can be induced by factors such as PH, hypoxia, pulmonary embolism, and infection.Heart failure refers to a clinical syndrome characterized by specific symptoms, such as dyspnea and fatigue, and signs, such as fluid retention (edema) and rales, observed during physical examination.The diagnosis of both PHC and heart failure was made by cardiologists and documented in the medical records.Postpartum hemorrhage (PPH) is defined as excessive bleeding of more than 500 ml for vaginal deliveries and more than 1000 ml for cesarean sections (CS), occurring within the first 24 h after delivery.Low birth weight is defined as a birth weight less than 2500 g.

Statistical analysis
Count data were analyzed using frequencies and percentages, and statistical differences among groups were compared using Fisher's exact tests.The measurement data were represented by the mean ± standard deviation or the median (interquartile range).The mean difference among groups was tested using oneway ANOVA, Dunnett's T-test, or rank sum (Kruskal-Wallis H) test.Pairwise multiple comparisons were conducted using either the LSD-t test or the Nemenyi method.A two-sided p-value less than 0.05 is considered statistically significant.All analyses were performed using SPSS statistical software.

Baseline characteristics
A total of 25 pregnant women who experienced complications with severe PH were enrolled in the present study.The mean sPAP of 25 pregnant patients was 105.12 ± 22.70 mmHg, as determined by echocardiography analysis.Among all patients, fourteen (56%) were classified as having New York Heart Association (NYHA) cardiac function grade III-IV.Fourteen (56%) were diagnosed with PH before pregnancy, while eleven (34%) were diagnosed with PH during pregnancy.
Compared to the sPAP values of all groups, the iPAH and CHD-PAH groups had significantly higher values than the LHD-PH and oPAH groups (p < 0.05).Patients with LDH-PH experienced a longer terminal week compared to those with iPAH (p < 0.05).(Table 1).
Out of our study cohort, seven patients unfortunately passed away during the course of this research period, accounting for a 28% mortality rate.Details about these cases are provided in Table 3.When comparing individuals who died during the study period with those who survived (Table 2), we observed that NYHA class was the only significant difference between the two groups.

Maternal outcomes
The average gestational age of the 25 pregnancies was 24.04 ± 10.24 weeks.The LHD-PH group had a higher gestational age at delivery compared to the iPAH group, but there were no significant differences among the other groups.The gestational age of patients diagnosed with PH before pregnancy was significantly lower than those diagnosed during pregnancy, and the difference was statistically significant (p < 0.05).Their gestational week at delivery was 20.14 ± 10.30 and 29.00 ± 8.09, respectively.

Delivery and method of anesthesia.
There were five cases of early induced abortion and twenty cases of late-term pregnancies.One of the deliveries was vaginal, and 19 deliveries involved CS, including three emergency operations.The method of anesthesia typically used for patients undergoing early termination of pregnancy is general anesthesia.In the middle and late stages, fourteen procedures (73.7%) were performed using intravertebral anesthesia, while the remaining five (26.3%) were performed using general anesthesia.

Complication
Among the complications, PHC occurred in four patients (16%), and heart failure occurred in seven patients (28%).There was one case of PPH (4%).

Management
All cases underwent one or more Multidisciplinary Team (MDT) before the termination of pregnancy.Our MDT comprises experts in obstetrics, cardiovascular medicine, critical care medicine, anesthesiology, rheumatology, immunology, neonatology, medical management, and the extracorporeal membrane oxygenation team, among others.
In our cohort, thirteen patients received perioperative treatment with PAH medications.They were sorted and organized into Table 4.The eighteen surviving patients were followed up for an average of 27.39 ± 13.26 months.Their condition remained relatively stable.Five patients with iPAH and two cases of CHD-PAH were treated with oral targeted drugs.Five cases of LDH-PH were observed, with three patients undergoing surgical treatment within 1-6 months after their CS.However, two patients refused surgical treatment due to financial constraints.One case of oPAH, diagnosed with systemic lupus erythematosus, is currently being managed with oral medication, and the patient's condition is regularly monitored.

Fetal outcomes
Among the fetal outcomes, there were thirteen perinatal infants with an average birth weight of  1940.77± 732.13 g.The incidence of preterm birth was eleven (84.6%).Neonatal asphyxia affected six infants (46.2%); eight infants (61.5%) had low birth weight, and two infants (15.4%) experienced perinatal death.The eleven surviving children were followed up for a median of 22 (5, 40) months.Out of the total sample, five participants (45.45%) were found to be stunted in terms of height or weight, while the remaining participants were within the normal range.Additionally, no abnormalities, including congenital heart disease, were detected.

Discussion
According to the modified World Health Organization (mWHO) classification of maternal cardiovascular risk, PH is classified as mWHO Class IV.These patients are at an extremely high risk of maternal mortality or severe morbidity, with an estimated maternal cardiac event rate of 40% to 100% during pregnancy [4].
Compared to men, women are two to four times more likely to develop PH.Moreover, women affected by PH are often young and in their childbearing age [11][12][13].
Although recent studies suggest that pregnancy may not be an absolute contraindication in women with mild and moderate PH [14], maternal mortality remains high in pregnant patients with severe PH.According to our 2016 China specialist consensus, the maternal antenatal cardiac disease risk classification grade for severe PH patients with a sPAP of �80 mmHg is grade V. Once diagnosed, termination of pregnancy should be discussed, and strong contraceptive measures are recommended [7].However, some women with this condition also have fertility concerns and may conceal their condition from their doctors in order to become pregnant.They may experience accidental pregnancy or an exacerbation of sPAP during pregnancy but refuse to terminate the pregnancy.There was also severe PH that was unexpectedly discovered during pregnancy.This presents significant  challenges for both patients and doctors.This group of people deserves our attention and careful management, which is the focus of this study.

MDT management
It is believed that the decline in maternal mortality depended on the developments in treatment alternatives and MDT management [15].In our study, we identified two categories of patients who had been diagnosed with PH before pregnancy and require further consideration.The first category consisted of four cases of unplanned pregnancy, two of which were iPAH and two were CHD-PAH.After an MDT consultation in early pregnancy, the pregnancies were promptly terminated.The follow-up period ranged from 14 to 32 months.In the second category, three patients chose to continue their pregnancies despite the risk of severe PH.These patients concealed their heart disease during pregnancy and received irregular antenatal care.When patients exhibited clear symptoms of cardiopulmonary insufficiency, they were referred to our hospital.At that time, they were in the middle and third trimester of pregnancy, experiencing NYHA grade III-IV cardiac function and at risk of premature labor.After an emergency MDT meeting, we actively improved cardiac function, such as diuresis, maintaining systemic circulation pressure and using targeted drugs to reduce sPAP during the emergency period and then the pregnancy was terminated.But the targeted drugs used at this time did not significantly improve sPAP, so despite receiving active MDT treatment, all three patients died between 6 and 21 days after giving birth.The pregnancy outcomes of these two groups of patients made us realize the importance of standardized pre-pregnancy education and MDT assessment in early pregnancy [1].If pregnancy is confirmed, it is advisable to consult a cardiologist before or as soon as possible during pregnancy.This will ensure an accurate diagnosis and assessment of the impact of pregnancy on any existing cardiovascular conditions.It will also allow for appropriate medical or surgical interventions to optimize heart health.Additionally, an MDT should assess the management plan to determine the associated risks and make an informed decision regarding the continuation of the pregnancy.Close monitoring and follow-up of maternal drug therapy, as well as individualized treatment, are essential for a successful pregnancy.If the condition of patients in the first and second trimesters of pregnancy is relatively stable and they have a strong intention to continue their pregnancy, the entire hospital should focus its efforts on providing accurate management.Doctors in various fields should not only focus on conducting vertical diagnosis, decision-making, and treatment of problems in their specialty, but also engage in horizontal scientific management of other related professional issues, including the unique aspects of pregnancy.Mutual communication and effective cooperation are key to the diagnosis and treatment processes.

The analysis of death group
The mortality rate for PH in our study was 28%, which is higher than the 12-20% reported in a recent metaanalysis [16].This can be attributed to the high concentration of severe PH in our patients, with an average sPAP of 105.12 ± 22.70 mmHg.The main causes of death were heart failure and PPH, except for one death that occurred during surgery.All other deaths occurred after delivery, with a median time of 9 (6, 21) days.This not only highlights the importance of intraoperative monitoring but also emphasizes the need to closely monitor postpartum hemodynamic changes that may worsen the condition of PH.In women with PH, the majority of pregnancy-related deaths occur during the early postpartum period [17].Therefore, it is recommended that patients like these receive close monitoring and care during this critical time.Patients should be treated in the intensive care unit until they are stable, and then they can be transferred to the general ward.
The study found no significant differences in sPAP or mean gestational age at termination between the death and non-death groups.In the death group, all cases except one abortion after 10 weeks of gestation were delivered via CS during the middle and late stages of pregnancy.However, among non-death groups, four terminated their pregnancies during the first trimester.This suggests that terminating a pregnancy in a timely manner during the early stages of pregnancy may improve the outcome to some extent.As gestational age increases, pregnant women experience significant changes in hemodynamics.These changes include an increase in total blood volume, cardiac output, and heart rate, as well as a decrease in systemic vascular resistance and blood hypercoagulability.These changes reach their peak at around 32 weeks of gestation [18].Due to PH's failure to adapt to these physiological changes, the risk of developing refractory right heart failure, PHC, pulmonary embolism, and even death increases.The second trimester is generally recognized as the earliest period of heart function deterioration [19].Therefore, patients with contraindications to pregnancy should be promptly evaluated and informed.With increasing gestational age, patients who have contraindications for pregnancy still face a higher risk of mortality even if they choose to terminate the pregnancy.Termination of pregnancy in the early stages can significantly reduce the mortality rate of critically ill pregnant women and enhance their chances of survival.All maternal deaths occurred in women classified as having cardiac function (NYHA classification) class III-IV upon admission.These women exhibited obvious cardiopulmonary dysfunction, including Eisenmenger syndrome.The difference of cardiac function between the death and non-death groups was statistically significant (p < 0.05).Therefore, the NYHA cardiac function classification can serve as a risk factor for poor outcomes.Previous studies have also shown this to be true.There was no significant difference in N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels between the two groups (p ¼ 0.130).However, the median value in the death group was 1151 pg/ml, which was higher than the median value of 349 pg/ml in the non-death group.Due to the limited sample size, it is not yet possible to confirm the predictive ability of NT-proBNP for mortality cases, and further studies are needed [20,21].
A CS may be chosen as a delivery method during the middle and late stages of pregnancy.CS can expedite delivery, prevent hemodynamic changes caused by prolonged uterine contractions, and reduce the increase in oxygen consumption due to fatigue and pain [22].On the other hand, vaginal delivery, particularly during the second stage of labor, substantially increases the cardiac workload, making it more susceptible to heart failure and sudden death.The primary causes of emergency CS were the patients' critical conditions, premature labor, and premature rupture of membranes.The patients' cardiac function and pulmonary artery pressure were not adequately controlled.Insufficient preoperative preparation increases the risk of patient mortality during emergency surgery.This suggests that the perioperative period should be optimized to improve the cardiopulmonary function of pregnant women and minimize the need for emergency surgery.

Limitations
The present study was a retrospective investigation conducted at a single center in China, with a limited sample size.As a result, there may be bias in the representation of the study population.The failure to conduct a multifactorial analysis of all indicators may lead to statistical bias in the results.Additionally, our study population consisted only of pregnant women who underwent cardiac color Doppler ultrasonography.A small number of patients also underwent right heart catheter monitoring during pregnancy or surgery.

Conclusion
Pregnancy in women with severe PH carries a high risk of mortality.Contraception is recommended.If pregnancy is diagnosed, a discussion of termination should be considered.NYHA cardiac function grade III-IV was useful in predicting the risk of mortality.

Ethical approval
The studies involving human participants were reviewed and approved by the Ethics Committee of Fujian Medical University Union Hospital.Written informed consent was not required for participation in this study, in accordance with national regulations and institutional policies.

Table 1 .
Baseline characteristics and outcomes of pregnant women with severe PH.

Table 2 .
Characteristics and outcomes of pregnant women with death and non-death group.

Table 4 .
Details of PAH medications used in pregnant women.

Table 3 .
Case data of death group.