Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease

Pregnant Women With PAH Require Careful Monitoring, Management, Says Review

Investigators say more research is warranted to optimize management of patients with pulmonary arterial hypertension (PAH) who become pregnant.

Women with pulmonary arterial hypertension (PAH) are discouraged from getting pregnant due to a high risk of morbidity and mortality for both mother and child. Yet, some patients with PAH choose to become pregnant despite the guidelines. A new review article says such patients can successfully bring a child to term, but only with careful management by a team of physicians.

Corresponding author Wilbert S. Aronow, M.D., of New York Medical College, and colleagues, explained that pregnancy sparks a series of physiological changes, including increased blood volume, heart rate, and cardiac output (CO).

"These changes are necessary to support fetal development, but can exacerbate the already compromised cardiovascular function in PAH patients," they wrote in Cardiology in Review.

Related: How Deep Learning and AI Could Fuel the Next Phase of PAH

DetectionRight ventricular failure, cardiac arrest, pulmonary hypertensive crisis, preeclampsia and sepsis are the primary causes of morbidity and mortality, Aronow and his colleagues noted, citing a 2022 meta-analysis. That study found that while the majority of pregnancies among patients with PAH advanced past 20 weeks, 58% of the pregnancies resulted in premature deliveries, most by cesarean section. They calculated a maternal mortality rate of 12%, a stillbirth rate of 3% and a neonatal mortality rate of 1%.

In the new review, Aronow and colleagues said management of PAH during pregnancy begins by making patients aware of the risks before they decide to become pregnant, including the risk that PAH can worsen even after the pregnancy ends.

"For those who choose to continue with the pregnancy, meticulous planning and continuous monitoring are imperative," they wrote.

They suggest patients be cared for by a multidisciplinary team including obstetricians, cardiologists, anesthesiologists, hematologists and neonatologists. It is common, the authors said, for women to be admitted to the hospital in the second trimester to allow for more careful monitoring, and then again 24 to 48 hours prior to a planned delivery.

"On the day of delivery, patients are taken to the intensive care unit for the insertion of a central venous catheter and an arterial line to facilitate continuous monitoring of central venous pressure, blood pressure, and CO," they wrote.

Additional careful monitoring in an intensive care unit is necessary for several days following the birth, they said, due to the risk of decompensation, among other concerns.

When it comes to treating the PAH itself, the authors said the ideal situation is for the patient to be taking PAH therapy prior to the pregnancy. However, they added that certain PAH therapies — including Adempas (riociguat), endothelin receptor agonists, and guanylate cycle stimulates — should be stopped because they can interfere with fetal development. Prostacyclin analogs and phosphodiesterase type 5 (PDE-5) inhibitors like Viagra (sildenafil) appear to be safe in pregnant patients, the authors said.

During pregnancy, prevention of right ventricular failure should be a key focus, the authors said, and warrants therapies like intravenous epoprostenol and inhaled Ventavis (iloprost), among others. Most patients with PAH are also given an anticoagulant during and after pregnancy, the investigators noted, due to the risk of thromboembolic events. However, they said anticoagulants are typically paused in the period just before and after delivery. They said there is insufficient evidence to say which particular anticoagulants are ideal.

Aronow and colleagues said their review of existing literature showed there are significant gaps in data regarding the safety and efficacy of specific PAH therapies. They added that the development of newer therapies, like Winrevair (sotatercept) and gene therapies, offer mechanistic insights into PAH that might help with patient management.

"Ultimately, enhancing our understanding of PAH in the context of pregnancy will lead to better management strategies, reduced morbidity and mortality, and improved quality of life for affected women," the investigators concluded.

Pregnancy Complications And Long-term Risk Of Cardiovascular Events In Women With Structural Heart Disease

Introduction

Improved early surgical and medical treatment of congenital and acquired heart disease increases the possibility of pregnancy in women of childbearing age with structural heart disease (SHD).1 SHD is associated with a risk of both maternal and fetal complications during pregnancy2–4 and clinical recommendations highlight the importance of structured follow-up to prevent adverse outcomes of pregnancy.5

SHD is a heterogeneous group of diseases with varying risks that are dependent on the severity of the underlying condition.5 Maternal mortality is high in pregnant women with pulmonary arterial hypertension (PAH)6 and is associated with an increased risk of preterm birth (PTB), fetal or neonatal death and low birth weight.6 7 Congenital heart disease (CHD) includes simple and complex lesions of varying severity, and the risk of pregnancy complications varies for different conditions and severity of CHD.8 Acquired valvular heart disease (aVHD) is often due to rheumatic heart disease in childbearing age but can also be degenerative5 and is associated with an increased risk of pre-eclampsia (PE), PTB, intrauterine growth restriction and fetal death.9 10 Knowledge of pregnancy complications in women with SHD has improved over the last decades, but recent guidelines address the need for larger cohort studies to evaluate the frequency of pregnancy complications and cardiovascular events in this population.5

Pregnancy complications, including PE, gestational hypertension (gHT), PTB and small for gestational age (SGA), are associated with an increased risk of early asymptomatic coronary artery disease as well as ischaemic heart disease, stroke and peripheral artery disease in the general population.11 12 Whether pregnancy complications have prognostic value for the long-term risk of atherosclerotic cardiovascular disease (CVD) and deterioration of heart function for women with SHD is unknown.5

The objectives were to determine the frequency of pregnancy complications in women with SHD (defined as PAH, CHD and aVHD) and to evaluate the association of these complications for the long-term risk of atherosclerotic CVD and deterioration of heart function in this population.

Methods Study population

In this register-based cohort study among 2 134 239 women with singleton births registered in Sweden's Medical Birth Register (MBR) between 1973 and 2014, 2554 women had SHD (PAH, CHD or aVHD, figures 1–2). The study population has been described in detail elsewhere.12 The study cohort was followed from the date of a woman's first delivery until death or the end of follow-up (31 December 2014). In order to focus on women at risk for an earlier onset of CVD, only women aged 75 years or younger at the end of 2014 or, women who died before the end of 2014, who were younger than 76 at the time of death, were included. Multiple gestation pregnancies and pregnancies with missing delivery dates were excluded. Data in MBR from the included women without SHD (N=2 131 685) were used as a reference group.

Figure 1

Study design. CVD, cardiovascular disease; MBR, Medical Birth Register; SHD, structural heart disease.

Figure 2

Flow chart of the study population with births in Sweden 1973–2014. AVHD, acquired valvular heart disease; CHD, congenital heart disease; PAH, pulmonary arterial hypertension.

Data sources

Baseline characteristics and pregnancy complications exposures were collected from MBR and linked to outcomes of mortality (Cause of Death Registry, CDR) and hospitalisations (National Patient Registry, NPR). Information about comorbidities was collected from both the MBR and NPR. Diagnoses were registered according to International Classification of Diseases (ICD) codes (ICD-8, ICD-9 and ICD-10, online supplemental table S1).12

Women with PAH, CHD and aVHD were identified by the ICD codes (online supplemental table S1) for diagnoses registered in both MBR and NPR, from 1 year before and 5 years after delivery for all registered deliveries. This was based on the assumption that a diagnosis of SHD within this time interval was likely present during pregnancy. If there were several registrations of the same SHD diagnosis in more than one pregnancy, the first registered diagnosis was used. If there were several different diagnoses of SHD, women were divided into groups according to this hierarchical order: PAH, CHD and aVHD.

Baseline characteristics

Baseline characteristics considered in each pregnancy were maternal age, body mass index (BMI), smoking and civil status. Parity was calculated from the total number of deliveries registered in MBR. Comorbidities (diabetes mellitus, hypertension, chronic kidney disease and venous thromboembolism) from two time points were considered: both those in association with each pregnancy (diagnoses registered in MBR and NPR dating from 1 year before delivery date to 6 months postpartum), and at hospitalisation(s) (main and secondary diagnoses registered in NPR).

Pregnancy complications

Three pregnancy complications were studied: PE or gHT, PTB and SGA. PE/gHT was defined based on corresponding ICD codes collected from MBR and NPR (registered from 1 year prior to delivery to 6 months postpartum) (online supplemental table S1). PTB was defined as a gestational age of less than 37 weeks, both iatrogenic and spontaneous. SGA was defined as a birth weight for gestational age and sex less than 2 SDs for weight below the Swedish reference curve. Pregnancy complications were studied separately for all registered pregnancies.

Cardiovascular outcomes Mortality

Mortality was classified according to the underlying cause of death and included all-cause mortality and cardiovascular mortality due to ischaemic heart disease or ischaemic stroke.

Hospitalisation for CVDs

Hospitalisation for CVD was defined as a first-time hospital admission based on a main diagnosis of atherosclerotic CVD (ischaemic heart disease/ischaemic stroke/transient ischaemic attack/peripheral artery disease), heart failure or arrhythmia (both supraventricular and ventricular). Hospitalisations for the same main diagnosis with less than 24 hours between discharge and the next admission were treated as one hospital admission and the main diagnosis of the first hospitalisation was defined as the outcome. Heart failure in association with pregnancy was defined as hospitalisation or a diagnosis registered in MBR (between 1 year before delivery and 6 months post partum) for each registered pregnancy. The women were followed until the first registered hospitalisation for atherosclerotic CVD, heart failure or arrhythmia, separately. The ICD codes for outcomes of mortality and hospitalisations are described in online supplemental table S1. Women with outcome events before the date of the first delivery were excluded, separately for each outcome (24 with atherosclerotic CVD, 63 with heart failure and 170 with arrythmia).

Confounders

Potential confounders were identified by direct acyclic graphs described in online supplemental figure S1. Maternal age, BMI, smoking, civil status, parity and comorbidities in pregnancy or in hospitalisations (ie, diabetes mellitus, hypertension, chronic kidney disease or venous thrombosis registered in MBR, or any of these registered as a main or secondary diagnosis in NPR) were considered as potential confounders. BMI and maternal smoking were registered from 1982 onward. BMI was categorised as below 18.5 (underweight), 18–24.9 (normal weight), 25–29.9 (overweight) or above 30 kg/m2 (obese) in the description of the baseline characteristics. Smoking was categorised as non-smoker or smoker. Civil status was categorised as cohabitation/married or single parent/previously married/unmarried/other. To adjust for societal and medical changes over time, we adjusted for decades.

Statistics

Categorical variables were described as frequencies and percentages, and continuous variables were categorised or presented as means with SD. Simon-Makuch's modified Kaplan-Meier curves describe the cardiovascular outcomes in women with and without pregnancy complications. All reported p values were two sided. All Simon-Makuch curves were started at age 20 to avoid instabilities. Associations between pregnancy complications and adverse cardiovascular outcomes were studied by Cox regression models and reported as HR with 95% CI with age as the time scale. We studied all registered pregnancies with exposures of pregnancy complications fixed to each pregnancy and with time-dependent confounding. Robust SEs were used to handle multiple pregnancies. Adjustments were performed for the identified potential confounders: BMI at pregnancy, smoking (smoker/non-smoker), civil status (cohabitation/married and single parent/previously married/unmarried/other), parity, decade and comorbidities (described above). Comorbidities were assumed to persist for all the remaining time after the first registration. Multiple imputation was performed for missing variables (BMI, civil status and smoking), using confounders and outcomes as predictors. Descriptive statistics and data processing were performed with SPSS Statistics V.28, Python (used for data management) and R (V.4.2.1). The Cox regression models and Simon-Makuch curves were performed in R.

Discussion

In this nationwide cohort of 2554 women with SHD and 5568 singleton pregnancies with a median follow-up time of 22 years, we can confirm that pregnancy complications are more common in women with SHD than in women without. Furthermore, PE/gHT and PTB in women with SHD were associated with an increased risk of future atherosclerotic disease. These findings support that pregnancy complications, both maternal and fetal, should be monitored during pregnancy and considered in the cardiovascular risk evaluation of women with SHD.

The mechanisms behind the increased risk of pregnancy complications in women with SHD are not fully elucidated, but pre-existing suboptimal cardiac performance has been described to be associated with poor placentation, a mechanism involved in pregnancy complications.13 We found a high prevalence of PE/gHT in women with SHD. We found the numbers of PE/gHT to be higher in women with CHD and aVHD compared with what has been published elsewhere.14 Hypertensive disorders of pregnancy have been reported to be more common in CHD,15 although a systematic review and meta-analysis did not find an increased incidence of PE above the expected baseline risk in women with CHD, except for women with aortic stenosis.16 In a recent Registry of Pregnancy and Cardiac Disease (ROPAC) study, the prevalence of PE was as high as 11.1% in women with PAH, and an association was found between PE and maternal mortality in pregnancy in these women.14 ROPAC is based on data reported from selected centres, in contrast to our study, which is based on nationwide data that includes all pregnancies and women with simple and complex heart disease, and this might explain the lower proportion in women with PAH in our study. More studies are needed to elucidate the risk in specific diagnoses of SHD. The incidences of PTB and SGA in our study were lower than previously shown in the literature17 but in accordance with other Swedish findings for women with CHD18 and another study that included PTB in women with CHD.2 PE/gHT and PTB were most common in women with aVHD in our study, as well as in a recent cohort study based on a more selected group of subjects.19 This finding might be explained by the higher age in this group of patients, but possibly also by aortic valve disease, which has been reported to be associated with PE.20

Several of the pregnancy complications studied were associated with an increased long-term risk of cardiovascular mortality and first-time hospitalisations for atherosclerotic CVD. Placental anomalies have been described to be common in women with SHD, especially uteroplacental insufficiency that leads to growth restriction in the infant, although inflammatory mechanisms also seem involved.21 Endothelial dysfunction is an early mechanism of atherosclerosis involved in both CVD22 and the pregnancy complications studied.23 Increased carotid intima–media thickness as an early sign of atherosclerosis has been found in young women with CHD,24 and increased intima–media thickness has been associated with pregnancy complications.25 26

A recent study on a Danish registry-based cohort of women with CHD also found an association between PE/gHT and increased risk of long-term cardiovascular morbidity.27 In our study, PTB and SGA were more clearly associated with mortality and hospitalisations than PE/gHT. A possible explanation for this might be a change in how women with SHD are treated during as opposed to after a pregnancy, complicated by increased blood pressure, which can be symptomatic in these women. During the time span of the study, blood pressure has been structurally monitored in the Swedish antenatal care. Whether pregnancy in women with SHD contributes to a higher long-term risk of CVD including heart failure and arrhythmias is not fully explored and since there is great variation in disease severity among these women, findings depend on the cohort included.28 Hypertensive disorders of pregnancy have been described to be associated with an increased risk of heart failure,29 but this could not be corroborated in our study. In the present study, the fetal complications seem important in the prediction of long-term risk of heart failure as well as arrhythmias and, within the group of women with SHD, pregnancy complications might help to identify those with the highest risk for complications such as heart failure and arrhythmias but these findings need to be studied further.27

Primary prevention of CVD is important in women with SHD, and pregnancy complications may be useful in identifying women at increased risk. Further studies are needed to evaluate whether the long-term risk of cardiovascular events can be reduced by enhanced cardiovascular prevention in SHD after pregnancy complications. Fetal complications could help to identify women with SHD at increased risk for heart failure and arrhythmias.

Strengths and limitations

Almost all childbearing women in Sweden are included in the MBR, which enabled us to identify a large number of women with SHD, with a long follow-up. Information about all registered pregnancies has been taken into account as well as time-dependent confounding factors. To reduce missing diagnoses, we included information on exposures and comorbidities from both the MBR and NPR. As with all registry studies, registration quality may vary and there is a potential for missing data. Overall, however, the quality of the MBR, NPR and CDR registries is high. With the use of historical ICD codes, there is also a potential for misclassification and diagnostic overlap. Since the study is based on registries there is no information on the severity of the SHD, results of previous surgery procedures, or functional status during pregnancy. Because the study spans over five decades and definitions of PE and gHT have changed over the study period, they were, therefore, analysed as a combined variable. Another limitation is that data on comorbidities at outpatient visits were not accessible. We had limited diagnostic and risk-factor profile details on the women with SHD. We were, however, able to adjust for major confounding, including BMI, smoking and comorbidities. BMI and smoking were only included in the MBR from 1982 onward, so we performed multiple imputations for these variables, with its limitations. For women with SHD, information about smoking was missing for 31.0%, civil status for 8.5%, weight for 42.3% and height for 33.4%, at first pregnancy. Data on the amount of smoking were missing, and more detailed sociodemographic variables, such as education and income. However, in this patient group, individual characteristics have been suggested to explain the differences in outcomes between centres and countries to a greater extent than socioeconomic factors.30 Information on race and ethnicity was limited and the diversity of the study population could, therefore, not be described.

'I Was Diagnosed With Pulmonary Arterial Hypertension At 25—This Was The First Unexpected Symptom I Experienced'

Katrina Berry was 24 years old when she first started experiencing symptoms of pulmonary arterial hypertension (PAH), a progressive health condition that leads to reduced cardiac output and right heart failure.

PAH affects between 500 and 1,000 Americans each year. It's rare, but it's fatal. Here, Berry shares what her initial symptoms were and the long road to finding the current treatment that has changed her life.

Related: The 1 Strange Thing That Can Help With Heart Attack Risk, According to Cardiologists

The Initial Symptoms of Pulmonary Arterial Hypertension

As a healthy 24-year-old, Berry, who is now 29, was surprised when she started finding herself winded after activities she was used to doing effortlessly. "I was always the fastest walker in any group and would run up a flight of stairs," she says. Suddenly, she couldn't do that anymore. She couldn't understand it. She had a healthy diet, having been vegan for the last 10 years, and didn't have a history of health problems. What was going on?

"I had significant shortness of breath, my resting heart rate was 125, stabbing chest pain and was coughing up blood," she says of her initial symptoms. Doctors—and she consulted several—told her she had asthma and gave her an inhaler.

"No one believed me when I told them I was sick. I knew there was something wrong with me," Berry says. Despite her worrisome symptoms, Berry, by now 25, decided to head to Greece for six weeks to volunteer at a public pediatric hospital. One morning three weeks into her trip, she started experiencing nausea and became unable to breathe, gasping for breath. She truly felt like she was going to die. "At that moment, I knew I was having a heart attack and was completely alone," Berry says.

Fortunately, her symptoms subsided and when she was able, she called her mom who arranged for Berry to fly home the next day.

Related: If You Want to Lower Your Heart Attack Risk, Cardiologists Say You Should Do This One Thing Every Day

Finally Getting a Diagnosis

When Berry arrived Stateside, her mom took her directly to the hospital. Her oxygen had dropped to 82% and the doctors were extremely concerned. A CT scan showed dozens of blood clots in her lungs causing very severe heart damage. "The cardiologist said I should not have survived that flight with dozens of blood clots in my lungs and that my level of heart damage wasn't typically found until autopsy," Berry says.

Berry was put on blood thinners and underwent a highly specialized open heart surgery called pulmonary thromboendarterectomy (PTE) to remove the blood clots from her lungs. "When they opened me up, they didn't find the clot burden they were expecting. Instead, my arteries were collapsed. They also found a hole in my heart," Berry says. This is when doctors finally realized she had pulmonary arterial hypertension, a far cry from the prior misdiagnosis of asthma.

While in surgery, she went into cardiac arrest and was placed on ECMO, the most advanced form of life support. During this time, the doctors still could not close up her chest, which was packed with medical-grade stuffing and wrapped in a material similar to Saran Wrap. After five days, they were able to take Berry off ECMO and close her chest. She woke up a week later not knowing what had happened.

Katrina's first time walking after her ECMO procedure.

Katrina Berry

It was a month before Berry was discharged from the hospital. There is no cure for PAH, but there are treatments that reduce symptoms. Though stable enough to go home, she was given an oxygen tank, which she had to be connected to and bring with her everywhere, told she would have to be on it the rest of her life. She also had to stay connected to an IV medication that threaded directly into her heart, pumping the medication there directly. "If anything happened to this med pump, I had about three hours to get to the hospital before the situation became fatal," Berry says. She also continued the blood thinners, which she said had horrible side effects.

Her calendar was full of doctor's appointments, including seeing a pulmonologist weekly (and eventually every other week) as well as physical therapy since she had lost much of her muscle mass in the hospital. "I had to teach my muscles how to walk again," Berry says.

Related: This Is the #1 Sign of a Healthy Heart, According to Cardiologists

The Clinical Trial That Changed Her Life

Though she was home and had machines and medication to help manage her symptoms, Berry was not getting better. "I could feel my body become weaker. I was truly dying," she says. With nothing to lose, she enrolled in a clinical trial for a new experimental drug for people with PAH called sotatercept. The drug works by inhibiting proteins called activins that cause blood vessel walls to thicken, which then causes the heart to work harder. The medication helps blood vessels relax so this doesn't happen.

After a couple of months of receiving the injection medication every three weeks, Berry's body was remarkably stronger. "I was still hooked up to oxygen, but I could go on walks and some very minor hikes," she says, adding that before starting the medication, it was difficult for her to even put her laundry away.

Nine months after starting the medication, Berry was able to come off the IV medication and switch to an oral form of it. "That completely changed my life and was the first step toward me getting my life back," she says. She was also able to come off the oxygen machine, no longer having to bring it with her everywhere she went. (Though she says she still needs it from time to time, such as if she's doing a strenuous hike.)

It's been more than two years now and Berry says she's back to solo traveling, having gone back to Greece and even zip-lining in Pakistan. Berry still has PAH and says it impacts her every day. Before starting sotatercept, Berry was only given a few years to live. While the medication is not a cure, it has extended her life and greatly improved her quality of life.

Sotatercept became FDA-approved earlier this year under the brand name Winrevair, produced by Merck. Berry is a patient consultant for Merck but has not received any compensation for sharing her story here, or other places. Besides Berry, 322 other people participated in the clinical trial, either receiving sotatercept or a placebo. After six months, 5% of people taking the medication had died or their PAH had worsened. In the placebo group, 26% of people had died or their condition had worsened.

Berry knew something was seriously wrong with her long before doctors did, serving as an important reminder of how important it is to be your own health advocate. It bears repeating that PAH is rare, but because it's so serious, it's important to know what its initial symptoms are (fatigue, shortness of breath, chest pressure or pain, dizziness or rapid heartbeat) so if you are experiencing them, you can seek medical care ASAP. Remember, no one will ever know your body better than you.

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Sources

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