|Year : 2021 | Volume
| Issue : 2 | Page : 89-96
Outcome of pulmonary hypertension in pregnancy in contemporary era: A case-based narrative review
Mohsin Raj Mantoo, Nayani Makkar, J Mahidhar, Uma Devi Karuru, Devesh Kumar, Sandeep Seth
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||13-Jul-2021|
|Date of Decision||13-Jul-2021|
|Date of Acceptance||13-Jul-2021|
|Date of Web Publication||31-Aug-2021|
Mohsin Raj Mantoo
Department of Cardiology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
A 35-year-old female presented to us with a history of exertional dyspnea from the last 20 years and low oxygen saturation noticed from last 1 month during her COVID-19-related illness. The patient did not seek medical attention over these years as the degree of limitation of physical activity was modest. She had a bad obstetric history: five second trimester pregnancy losses and one early neonatal death. Her symptoms were worse during pregnancy and improved thereafter. Physical examination was notable of cyanosis and features of pulmonary hypertension (PH). Echocardiography was suggestive of double outlet right ventricle, large subaortic ventricular septal defect with bidirectional shunt, and severe PH. This case highlights a variable clinical outcome of Eisenmenger syndrome in pregnancy. We did a literature review for studies reporting the outcomes of PH in pregnancy. The overall mortality rates seem to have declined dramatically from as high as 56% reported in studies in the 1990s to < 5% in more contemporary studies. The common adverse obstetric outcomes include prematurity and growth restriction.
Keywords: Eisenmenger syndrome, pregnancy, pulmonary hypertension
|How to cite this article:|
Mantoo MR, Makkar N, Mahidhar J, Karuru UD, Kumar D, Seth S. Outcome of pulmonary hypertension in pregnancy in contemporary era: A case-based narrative review. J Pract Cardiovasc Sci 2021;7:89-96
|How to cite this URL:|
Mantoo MR, Makkar N, Mahidhar J, Karuru UD, Kumar D, Seth S. Outcome of pulmonary hypertension in pregnancy in contemporary era: A case-based narrative review. J Pract Cardiovasc Sci [serial online] 2021 [cited 2023 Jan 31];7:89-96. Available from: https://www.j-pcs.org/text.asp?2021/7/2/89/325231
| Introduction|| |
Adults currently represent about two-third of the overall congenital heart disease (CHD) population. Hence, more women with various forms of CHDs are surviving till pregnancy. Various acquired cardiac pathologies can complicate pregnancies as well, like cardiomyopathies and rheumatic heart disease. Pulmonary hypertension (PH), in particular, has been linked to an extremely poor prognosis in pregnancy, with maternal mortality as high as 50% reported in past literature.
In this review, we highlight the various pathophysiologic mechanisms of hemodynamic impairment in pregnant patients with PH and the decrease in overall maternal mortality in this patient population in the more contemporary data.
| Methodology|| |
We did a comprehensive search of Medline database and included original studies and systematic reviews/metanalyses reporting the key outcomes of pregnancies in patients with PH. We selected studies reporting outcomes on at least 15 patients with pregnancies complicated by PH. Studies included in the more recent systematic reviews were not tabulated individually [Figure 1] and [Table 1].
|Table 1: Summary of the included studies reporting outcomes of pregnancies complicated by pulmonary hypertension|
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| Clinical Case|| |
Mrs. M, a 35-year-old female, presented first time to our facility with a history of exertional dyspnea from last 20 years and low oxygen saturation noticed from 1 month. The patient had New York Heart Association (NYHA) class I dyspnea from 15 years of age but did not seek medical attention as it did not progress to hamper her day-to-day activities. She had worsening of her dyspnea during pregnancies, but she again reverted back to prepregnancy state after few weeks postpartum. She never noticed any bluish discoloration of her lips or nail beds. One month back, she was hospitalized for fever and cough, diagnosed as COVID-19 based on reverse transcriptase–polymerase chain reaction, and was noticed to have low oxygen saturation (80%). She was suspected to have a cyanotic heart disease and referred to our center. She did not have any history of cyanotic spells in childhood nor did she have any history of frequent lower respiratory tract infections (LRTIs). There was no history of body swelling, syncope, or chest pain. She had a total of eight pregnancies: five abortions (during second trimester), one early neonatal death, and two living issues.
Based on history, differential diagnoses kept included Tetralogy of Fallot (TOF) physiology, Ebstein anomaly, and Eisenmenger syndrome.
On examination, the heart rate was 120 bpm, central cyanosis was present along with pandigital clubbing [Figure 2]. Saturations in room air were 78% in the right upper limb and lower limb. She had a low body mass index (17.3 kg/m2). Jugular venous pressure was elevated (5 cm above the sternal angle) with a prominent “a” wave. Left lower parasternal pulsations were visible and palpable. There was a grade I parasternal heave. The second heart sound was loud (Loud S2). There was a grade 2/6 early diastolic murmur at the left upper sternal border. This was interpreted by many of the clinical fellows as a systolic murmur and is a mistake common with very fast heart rates. There was no hepatomegaly or pedal edema. The rest of the systemic examination was unremarkable.
Electrocardiography (ECG) had right ventricular (RV) hypertrophy with RV strain pattern.
On echocardiography [Figure 3], diagnosis of double outlet right ventricle, large subaortic ventricular septal defect with bidirectional shunt, and severe PH was made. The diagnosis of PH was made based on echocardiographic and clinical impression alone and cardiac catheterization was deferred for a later date in view of the ongoing COVID-19 pandemic.
|Figure 3: Echocardiography showing DORV, large subaortic ventricular septal defect with bidirectional shunt, and severe pulmonary hypertension.|
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| Discussion|| |
Based on the above history, what is your differential diagnosis and in what order?
The differential diagnosis in this 35-year-old lady with dyspnea and cyanosis includes
- Eisenmenger syndrome
- TOF physiology (TOF; double outlet right ventricle + VSD + PS; single ventricle + PS)
- Ebstein's anomaly
- Idiopathic pulmonary artery hypertension (IPAH).
How is the onset of cyanosis different in the above differential diagnoses considered?
Patients with TOF are either cyanotic at birth or invariably develop cyanosis in the 1st year of life. Single ventricle with pulmonic stenosis patients are cyanotic right from birth due to admixture physiology. Patients with Eisenmenger syndrome typically have features of increased pulmonary blood flow in infancy like congestive heart failure (CHF) and frequent LRTIs, and they develop cyanosis later in life after the shunt reverses its direction from right to left.
What are points in history against a diagnosis of Eisenmenger syndrome?
There was no history of features of increased pulmonary blood flow like CHF or frequent LRTIs. In addition, the patient had two successful pregnancies in past which again casted a doubt in the diagnosis of Eisenmenger syndrome. We, therefore, did a comprehensive search of literature on this issue (presented below) and conclude that the previously described mortality and adverse event rates of Eisenmenger syndrome may not be the same in the contemporary era.
What is the difference between hypoxia caused by COVID-19 and hypoxia due to cyanotic congenital heart diseases?
The causes of hypoxia in cyanotic CHDs (CCHD) include decreased pulmonary blood flow (TOF physiology), mixing of the venous and oxygenated blood in the heart (admixture physiology), or transposition of great vessels (TGA physiology). These defects cannot be reversed by simply administering oxygen to the patient. In contrast, in pure pulmonary pathologies including COVID-19, the hypoxia is caused by ventilation–perfusion mismatch. Administering 100% oxygen for instance will increase partial pressure of arterial oxygen (PaO2) to >100 mmHg in pulmonary pathologies in contrast to CCHD (hyperoxia test).
What are the causes of dyspnea in pulmonary arterial hypertension?
Even though the pathophysiology of PAH is well described, it is not absolutely clear as to how it produces dyspnea on exertion. There may be multiple involved mechanisms including:
- Inability to augment cardiac output during exercise due to increased RV afterload. This, in turn, leads to impaired LV filling and decreased cardiac output
- Skeletal muscle dysfunction
- Chronic deconditioning
- The combination of decreased cardiac output and skeletal muscle dysfunction leads to anaerobic metabolism and increased CO2 production, hence an increased ventilatory drive
- Respiratory muscle dysfunction
- Psychological and emotional status.
What are the differentiating features of Eisenmenger syndrome complicating atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA)?
This is explained in [Table 2].
What is the second heart sound in TOF like?
There is a single loud second heart sound due to inaudible P2 component.
What are the causes of tachycardia in this case?
The patient had sinus tachycardia on multiple ECGs done during hospital stay. The causes may have been relative anemia (hemoglobin 16 g/dl), or a side effect of vasodilator therapy (sildenafil).
Can COVID-19 be the cause of tachycardia in this case?
Post-COVID-19 syndrome may also produce sinus tachycardia (inappropriate sinus tachycardia or postural orthostatic tachycardia). COVID-19 can produce atrial and ventricular arrhythmias because of multiple mechanisms including autonomic dysfunction, systemic inflammation, or direct damage to myocardium or specialized conduction system of heart.
Discussion on pulmonary hypertension in pregnancy
Pulmonary hypertension definition
PH is a heterogeneous group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) to >20 mmHg as measured by right heart catheterization in the supine position at rest. Pulmonary vascular resistance index (PVRI) is further used to characterize PH into precapillary and postcapillary forms of the disease. Precapillary PH is defined as mPAP >20 mmHg, PVRI ≥3 wood units (WU), and pulmonary artery wedge pressure (PAWP) 15 mmHg. Isolated postcapillary PH is when mPAP >20 mmHg, PVRI <3 WU, and PAWP >15 mmHg. Combined pre- and postcapillary PH has when mPAP >20 mmHg, PVRI ≥3 WU, and PAWP 15 mmHg.
PAH is a subgroup (Group 1) of PH patients and is characterized by adverse pulmonary vascular remodeling and increased PVR leading to right heart failure and death.
Pulmonary hypertension classification
This has recently been updated in the 6th World Symposium on PH. A new addition to Group 1 PH is PAH long-term responders to calcium channel blockers (CCBs) and PAH with overt features of capillary/venous involvement. The details of classification are not mentioned in this manuscript.
Pulmonary hypertension pathology
PH involves structural and functional alterations in pulmonary vasculature. This includes the stiffening of larger main pulmonary artery and its branches, medial hypertrophy/hyperplasia, and intimal/adventitial fibrosis of small muscular arterioles in addition to the classic plexiform lesions. PH also involves perivascular inflammatory cell infiltrate and intraluminal microthrombi.
Hemodynamics during normal pregnancy
Normal pregnancy involves various physiologic changes in maternal hemodynamics to meet increased maternal metabolic demands and uteroplacental circulation., Red blood cell mass and blood volume increase; the greater increase in the latter leads to so-called physiologic anemia of pregnancy. There is a decline in systemic vascular resistance as a result of vasodilation as early as the first trimester of pregnancy, reaching a nadir in the second trimester. Cardiac output increases starting from the first trimester and peaks around the end of 2nd trimester. Blood pressure (BP) drops with diastolic and mean pressures dropping more than systolic BP.
Labor and delivery involve even more hemodynamic stressors to maternal circulation. During labor and delivery, there is a maximal increase in cardiac output as a result of increased circulating blood volume, heart rate, and elevated catecholamines. As much as 500 ml of blood is pushed into the maternal circulation during each uterine contraction. BP changes are more varied: BP may increase as a result of increased cardiac output and catecholamine levels or may even decrease as a result of blood loss during delivery or vasovagal event.
Spinal anesthesia commonly used during cesarian section also decreases systemic vascular resistance and BP, with a concomitant increase in heart rate.
Pathophysiology of pulmonary hypertension in pregnancy
In normal pregnancy, pulmonary vasculature also dilates just like systemic vasculature, leading to a decrease in PVR. The increased cardiac output and decreased PVR lead to a relatively unchanged mPAP. This way a normal pulmonary vasculature accommodates increased cardiac output during pregnancy. The same is not possible in a patient with pulmonary vascular remodeling, resulting in worsening of PH, right heart overload, and hemodynamic decompensation.
In a patient with pulmonary vascular disease, decreased pulmonary vasodilatory capacity in the setting of increased cardiac output leads to a marked increase in mPAP. This increases RV afterload which results in RV failure. This is accompanied by systemic hypotension and hypoxia (including myocardial ischemia as well), resulting in further deterioration of ventricular function. This explains the risk of RV failure, systemic hypotension, hypoxia, and arrhythmias in a pregnant patient with PH [Figure 4]. The risk of decompensation is highest in the peripartum period and late second trimester as the increase in pregnancy-related cardiac output is maximum during this period. Maximum mortalities are reported around the time of labor/delivery and postpartum period which represents the state maximum fluctuations in hemodynamics., In addition, thromboembolic phenomena may also account for adverse outcomes during pregnancy and peripartum period.
|Figure 4: Pathophysiology of pulmonary artery hypertension in pregnancy.|
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In patients with Eisenmenger syndrome, there is an increased right to left shunting of deoxygenated blood as a result of decreased systemic vascular resistance during pregnancy. This leads to worsening hypoxia and pulmonary vasoconstriction.
Pulmonary hypertension and pregnancy: Outcomes
The adverse outcomes associated with PH in pregnancy are well known, with prohibitive maternal mortality. Weiss et al. reported data (between years 1978–1996) on pregnancy outcomes in 125 patients with PH, including Eisenmenger syndrome (n = 73), primary PH (n = 27), and secondary vascular PH (n = 25). Maternal mortality was highest in the secondary vascular group (56%) followed by Eisenmenger syndrome (36%) and was least in primary PH (30%). Most deaths occurred in postpartum period. Late diagnosis and late hospital admission were associated with increased mortality. The reported causes of death in patients with Eisenmenger syndrome were PAH crisis with refractory heart failure, sudden death, pulmonary thromboembolism, and stroke. The fetal/neonatal mortality rate reported was 13%.
However, after the introduction of PAH-specific therapies, maternal mortality rates have declined, though still high and prohibitive. Be' dard et al., in a systematic review published in 2008, studied 73 cases of pregnant women with PH, including idiopathic PAH (n = 29), PAH associated with CHDs (n = 29), and other causes (n = 15). The overall mortality rate was 25% (17% in IPAH group, 28% in CHD group, and 33% in PH due to other causes). Most deaths occurred in the 1st month postpartum and mortality was highest in primigravida and those who received general anesthesia. In another multicenter retrospective study from the United States, Duarte et al. reported outcomes of 18 pregnant PAH patients (12 continued pregnancy; 6 underwent first-trimester termination). Half of the patients had PAH associated with CHD. About 75% of patients were receiving PAH-specific therapy (sildenafil, IV prostanoids, or combination) at the time of delivery. Cesarian section was done in all cases at 34 weeks' gestation, with one inhospital death and 1 death at 2 months postpartum, with an overall mortality rate of 16.7%.
In a study from our own hospital (retrospective data between 2006 and 2012), Subbaiah et al. report data on 30 pregnant PH patients (not all cases had undergone right heart catheterization to diagnose PH). There was one maternal mortality in a case of PDA Eisenmenger on postoperative day 4 due to refractory heart failure. Patients who had severe PAH at baseline experienced worsening of functional class during pregnancy. Another study from a tertiary care center in South India by Keepanasseril et al. included 81 pregnancies in 73 women with PH, majority (81%) being PAH associated with CHD. Only 25 patients (31.3%) were on PAH-specific therapy. Overall maternal mortality was 4.9% (n = 4). The other complications included heart failure (6.3%), preeclampsia (8.9%), and fetal growth restriction (26.3%).
Ladouceur et al. did a multicenter study from France on pregnant PAH patients. They present 28 pregnancies in 20 women with CHD-associated PAH (retrospective data from 1997 to 2015), with 18 completed pregnancies, 8 abortions, and 2 miscarriages. Severe heart failure and hypoxemia occurred in 6 (33%) patients who continued pregnancy, with one maternal death (mortality rate 5%). There was no neonatal death, although prematurity (78%) and growth restriction (39%) were common.
Sliwa et al. presented their experience on 151 pregnant PH patients from Europe. Group 1 PH (PAH) was present in 39 (25.9%) patients, where 112 (74.1%) patients had Group 2 PH (due to left heart disease). Therapeutic abortion was done in six patients. Nine patients received PAH-specific therapies during pregnancy. Maternal mortality reported in this study was 5.9%, with five deaths occurring in 1st week postpartum and another two deaths within 6 months postpartum. The most common cause of death was severe heart failure. The highest mortality was observed in IPAH group (43%). Heart failure occurred in 27% of cases during pregnancy. Obstetric complications included miscarriage (5.6%), fetal mortality (2%), preterm delivery (21.7%), low birth weight (19%), and neonatal mortality (0.7%).
In another recent study, Zhao et al. report their experience from China on 249 pregnancies with PH including IPAH (n = 25), PAH associated with CHD (n = 185), and Group 2 PH (n = 35). Overall, 63.8% of cases were NYHA I/II and 36.2% were NYHA III/IV. A total of 70 (28%) PH patients had adverse cardiac outcomes as a result of pregnancy, with 7 deaths (2.8% mortality rate). Adverse events included arrhythmias, heart failure, PH crisis, deterioration of cardiac function, and infective endocarditis. In the seven cases of mortality, most deaths (71%) occurred in the 1st week postpartum. The risk factors for cardiac complications included rapid symptom progression, BNP >300 pg/ml, severe PAH (PAP >80 mmHg), WHO functional class III/IV, and delivery at ≥28 weeks gestation. Luo et al. in another retrospective study from China report the maternal and fetal outcomes in 79 consecutive pregnant PAH patients who presented between 2004 and 2016. Pregnancy was terminated in 22 patients, while 57 women continued their pregnancy. Overall, 9 patients (who had severe PAH at baseline) died within 3 months of labor, with a maternal mortality rate of 15.8%. The obstetric complications in the patients who continued pregnancy included premature delivery (35.6%), cesarian delivery (96.5%), and fetal demise (12%).
In a multinational prospective study, Jaïs et al. reported data on 26 pregnancies in PAH patients from 13 participating sites over a 3-year period. Overall, 16 (62%) pregnancies were successful and there were 8 abortions (6 induced and 2 spontaneous abortions). Both patients who had spontaneous abortion died. Three women succumbed to severe right heart failure in the early postpartum period, whereas one patient required urgent heart–lung transplantation. Patients who had successful deliveries had well-controlled PAH (PVR: 500 ± 352 dyn-s/cm5), whereas patients with poorly controlled PAH (PVR: 1,667 ± 209 dyn-s/cm5) had poor outcomes (died or required transplantation). Half of the patients who had successful pregnancies (8/16) were long-term responders to CCBs.
Thomas et al. did a large retrospective analysis of PH-pregnant patients from the US to characterize the risk factors of major adverse cardiac events (MACE) in this high-risk population. The authors present data on 1519 pregnant PH patients including isolated PH (59.6%), PH + CHD (10.7%), PH + valvular heart disease (VHD) (18.1%), PH + CHD + VHD (3%), PH + cardiomyopathy (6.6%), and PH + cardiomyopathy + VHD (1.9%). As compared to patients with no heart disease/PH, those with PH were more likely to experience MACE (24.8% vs. 0.4%), most commonly heart failure and arrhythmias. Overall, the mortality rate in this cohort of pregnant PH patients was low (0.8%). Respiratory failure and acute kidney injury were also more common in PH group. Pregnant patients with PH + cardiomyopathy + VHD and PH + cardiomyopathy experienced highest MACE rates (62.1% and 59.4%, respectively), while MACE rates were lowest in PH-CHD group (15.3%). Heart failure and arrhythmias were the most common complications. Women with PH were also more likely to have obstetric complications including preeclampsia/eclampsia syndromes, obstetric bleeding, cesarean deliveries, fetal demise, and preterm delivery. Eisenmenger syndrome, the most severe form of PAH in CHD patients, was only present in 3% of the cohort.
In a recent systematic review, Jha et al. analyzed data from 20 observational studies including a total of 589 women with 610 pregnancies. About 60% of patients had PAH associated with CHD. The pooled maternal mortality rate and pregnancy loss (including therapeutic abortions) were 11.5% and 22.8%, respectively. Majority (81.6%) of maternal deaths occurred in postpartum period. Heart failure and deterioration of NYHA class occurred in 179 pregnancies (29.3%). The rates of preterm delivery and small for gestational age were 51.7% and 29.3%, respectively. The pooled estimates of cesarean delivery and the need for general anesthesia were high, 72.1% and 40.1%, respectively. The authors, therefore, highlight the improved fetomaternal outcomes in pregnant PAH patients in the era of PAH targeted therapies.
Low et al. did a systematic review of studies published between 2008 and 2018 (modern era of PAH specific therapies) including a total of 272 pregnancies in 258 patients with PAH. A total of 214 pregnancies advanced beyond 20 weeks' gestation. Common causes of PAH were PAH associated with CHD (64%), IPAH (22%), and other causes (15%). About 30% of patients in the CHD group had Eisenmenger syndrome. Only 48% of patients were receiving PAH targeted therapies including prostacyclin analogs, phosphodiesterase V inhibitors, and CCBs. Therapeutic anticoagulation was given in half of the patients and prophylactic anticoagulation in another quarter of them. The overall maternal mortality rate was 12%, being highest in IPAH group (20%). Nearly 60% of maternal deaths occurred in the first 4 days postpartum and the reported causes of death were right heart failure, cardiac arrest, PAH crisis, preeclampsia, and sepsis. Obstetric complications were prematurity (58%), cesarean deliveries (76%), stillbirths (3%), and neonatal mortality (1%).
Summing up the evidence, maternal mortality rates in pregnant PAH patients have declined from as high as 36%–56% from 1996 data to around 12% in contemporary systematic reviews. Heart failure and arrhythmias are the most common cardiac morbidities. The risk of adverse events is maximum in the early postpartum period. The risk of perinatal mortality is around 5%, while the rates of prematurity and small for gestational age are quite high.
| Conclusions/Learning Points|| |
- During normal pregnancy, under hormonal influences, there is vasodilation of systemic and pulmonary vessels, leading to a decrease in systemic and pulmonary vascular resistance. The increase in cardiac output with a decrease in PVR results in a relatively unchanged mPAP
- In presence of pulmonary vascular remodeling in PAH patients, the pulmonary circuit is not able to accommodate the increased cardiac output, resulting in a steep rise in mPAP. The ensuing RV pressure overload leads to right heart failure and eventually, left heart underfilling, hypotension, ischemia, and arrhythmias
- The initial data on pregnancies in PAH patients from the 1980s to 90s reveal a very high maternal mortality of 36%–56%. Fetal/neonatal mortality of around 13%, prematurity, and growth restriction further complicate these pregnancies
- Most deaths occur in the early postpartum period, usually due to refractory heart failure, cardiac arrhythmias, sudden death, or thromboembolism
- With the introduction of PAH-specific therapies, the overall maternal mortality rates have decreased significantly; about 25% in studies published around 2005 and below 5% in some studies published in the contemporary era. Two recently published systematic reviews report a pooled maternal mortality of around 12%, which is still prohibitive
- Heart failure and deterioration of NYHA class occur in about 30% of pregnancies
- The published literature has certain limitations, for example, retrospective nature, small samples sizes, and publication bias
- The risks associated with PAH in pregnancy are substantial; hence, avoidance of pregnancy and early termination (in case pregnancy occurs) is recommended.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]