Pregnancy in pulmonary arterial hypertension: Midterm outcomes of mothers and offspring

Before the turn of the century, pregnancy in women with pulmonary arterial hypertension (PAH) was associated with maternal mortality rates of 30% and neonatal mortality rates of 11%.1Weiss BM Zemp L Seifert B Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996.J Am Coll Cardiol. 1998; 31: 1650-1657Crossref PubMed Scopus (444) Google Scholar In more recent series, despite improved management of PAH, pregnancy-associated maternal mortality remained high, ranging from 11% to 25%.2Luo J Shi H Xu L Su W Li J. Pregnancy outcomes in patients with pulmonary arterial hypertension: a retrospective study.Medicine (Baltimore). 2020; 99: e20285Crossref PubMed Scopus (5) Google Scholar, 3Duarte AG Thomas S Safdar Z et al.Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience.Chest. 2013; 143: 1330-1336Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 4Jaïs X Olsson KM Barbera JA et al.Pregnancy outcomes in pulmonary arterial hypertension in the modern management era.Eur Respir J. 2012; 40: 881-885Crossref PubMed Scopus (151) Google Scholar, 5Bédard E Dimopoulos K Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension?.Eur Heart J. 2009; 30: 256-265Crossref PubMed Scopus (359) Google Scholar, 6Kiely DG Condliffe R Webster V et al.Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach.BJOG. 2010; 117: 565-574Crossref PubMed Scopus (116) Google Scholar As of today, there is no cure for PAH, and case reports have suggested that pregnancy may accelerate disease progression.7Bostock S Sheares K Cannon J Taboada D Pepke-Zaba J Toshner M. The potential effects of pregnancy in a patient with idiopathic pulmonary arterial hypertension responding to calcium channel blockade.Eur Respir J. 2017; 501701141Crossref PubMed Scopus (3) Google Scholar Hence, current pulmonary hypertension guidelines continue to recommend that all patients with PAH avoid pregnancy.8Galiè N Humbert M Vachiery JL et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1516) Google Scholar However, with recent therapeutic advances, an increasing number of young women with PAH have well-controlled disease and are able to lead a near-normal life.9Hjalmarsson C Rådegran G Kylhammar D et al.Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension.Eur Respir J. 2018; 511702310Crossref PubMed Scopus (32) Google Scholar This is particularly true for women who are responders to calcium channel blockers but also for women who respond well to other PAH treatments. Despite the known risks of becoming pregnant with PAH, some women are willing to accept these risks and actively plan pregnancy. At our institution, since 2007, we have been offering individualized advice to women with PAH who consider becoming pregnant. As a basic rule, we never encourage patients to become pregnant. However, in patients with well-controlled disease indicated by a low-risk profile and a pulmonary vascular resistance < 500 dyn × s × cm–5 on therapy, we take a neutral position, share our experience together with published data, and indicate that we support any decision made by the patient and their families. In patients with less well-controlled disease, we strongly advise against pregnancy but still signal our full support in case the patient decides to become pregnant. In addition, in 2007, we initiated prospective documentation of pregnancies in patients with PAH and formed a multidisciplinary team consisting of pulmonary hypertension specialists, obstetricians, anesthesiologists, and cardiothoracic surgeons for standardized management of these patients. Our strategy includes planned delivery by cesarean section under peridural or spinal anesthesia during the 38th gestational week with post-partum intensive care monitoring. Extracorporeal membrane oxygenation (ECMO) standby is ascertained in patients considered at high risk of developing post-partum right heart failure. PAH medications are maintained during pregnancy except for endothelin receptor antagonists, which are discontinued when pregnancy is detected and reintroduced after delivery (all patients are discouraged from breastfeeding). A more detailed description of our management of pregnant patients with PAH can be found in the Supplementary Material available online at ww.jhltonline.org. All patients of the present series were regularly followed after pregnancy. Their offspring underwent the legally required regular infant checks. Between August 2020 and October 2020, we reviewed the reports of these checks and performed a standardized developmental questionnaire for infants and adolescents (Child Behavior Checklist 1.5–5 or 6–18R).10Chen WJ Faraone SV Biederman J Tsuang MT. Diagnostic accuracy of the Child Behavior Checklist scales for attention-deficit hyperactivity disorder: a receiver-operating characteristic analysis.J Consult Clin Psychol. 1994; 62: 1017-1025Crossref PubMed Scopus (242) Google Scholar These studies were approved by the local institutional review board, and all patients as well as all children aged ≥6 years provided written informed consent. In this report, we present the outcomes of all women with PAH whom we attended to during pregnancy between January 2007 and November 2019. Follow-up ended in October 2020. As summarized in Figure 1, there were 25 pregnancies in 16 patients. The characteristics of these patients at the time of pregnancy are depicted in Table 1. A total of 5 patients had a total of 5 spontaneous abortions and 3 terminations of pregnancies. This included 1 patient (Number 9 in the tables) who became pregnant during an accelerated phase of PAH progression. On gestational Week 10, she developed hyperemesis and subsequent right heart failure. She required awake ECMO support during which pregnancy was terminated. After 17 days on ECMO, bilateral lung transplantation was performed. She did well for some time after transplantation but died 2.5 years later from chronic lung allograft dysfunction.Table 1Characteristics of Patients at the Onset of Their Respective PregnanciesPt numberAge (years)TypeFC6MWDNT-pro BNP (ng/liter)RAP (mm Hg)mPAP (mm Hg)CI (liter/ min/m2)PVR (dyn)SvO2 (%)PAH medication11staHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.2nd2132IPAHVRT‒224014954219010480382.32.71,5013797574SIL‒ BOSbEndothelin receptor antagonists were discontinued when pregnancy was detected.SIL + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.229IPAH, VRT+1379793232.436665NIF31staHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.2nd3rd263134IPAH, VRT+32336354747073661532340182.03.67101737181AMLOAMLOAMLO432IPAH, VRT+25891475373.330778NIF51st2nd3rd4th28293031IPAH, VRT+2112520600587129771383313.129173AMLOAMLOAMLOAMLO + TAD632IPAH VRT‒33668479413.142072TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.7 1staHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant. 2nd2530IPAH, VRT+2251452854610855262.52.37833057369NIFNIF8 1st 2nd3439APAH (SLE) VRT‒21492600309499634362.72.94934005769TADTAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.9 1st 2nd2526HPAHVRT‒3352343229814481238573.52.25397636564TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected. + IV TRE10aHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.28APAH (SLE) VRT‒154216619601.41,59834TADMACbEndothelin receptor antagonists were discontinued when pregnancy was detected.1132IPAH VRT‒1657742313.830377TAD + AMBbEndothelin receptor antagonists were discontinued when pregnancy was detected.12aHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.37IPAH, VRT+27201032563.762179DIL + TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.1329IPAH VRT‒1624966474.238475TAD + AMBbEndothelin receptor antagonists were discontinued when pregnancy was detected.14aHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.27APAH(CHD) VRT‒2NA784101022.81,82995TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.15aHemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.32APAH VRT‒25861045753.21,056NATAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.1625APAH (CHD) VRT‒33361426484.249782TAD + MACbEndothelin receptor antagonists were discontinued when pregnancy was detected.Abbreviations: 6MWD, 6-minute walking distance; AMB, ambrisentan; AMLO, amlodipine; APAH, associated pulmonary arterial hypertension; BOS, bosentan; CHD, congenital heart disease; CI, cardiac index; DIL, diltiazem; FC, World Health Organization functional class; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; MAC, macitentan; mPAP, mean pulmonary arterial pressure; NIF, nifedipine; NT-proBNP, N-terminal fragment of probrain natriuretic peptide; PAH, pulmonary arterial hypertension; Pt, patient; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SIL, sildenafil; SLE, systemic lupus erythematosus; SvO2, mixed venous oxygen saturation; TAD, tadalafil; TRE, treprostinil; VRT, vasoreactivity test.Data are from the respective last measurement before pregnancy.a Hemodynamics were obtained while on treatment except for measurements marked, which represent hemodynamics at the time of the PAH diagnosis. In these patients, no follow-up hemodynamics were available before they became pregnant.b Endothelin receptor antagonists were discontinued when pregnancy was detected. Open table in a new tab Abbreviations: 6MWD, 6-minute walking distance; AMB, ambrisentan; AMLO, amlodipine; APAH, associated pulmonary arterial hypertension; BOS, bosentan; CHD, congenital heart disease; CI, cardiac index; DIL, diltiazem; FC, World Health Organization functional class; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; MAC, macitentan; mPAP, mean pulmonary arterial pressure; NIF, nifedipine; NT-proBNP, N-terminal fragment of probrain natriuretic peptide; PAH, pulmonary arterial hypertension; Pt, patient; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SIL, sildenafil; SLE, systemic lupus erythematosus; SvO2, mixed venous oxygen saturation; TAD, tadalafil; TRE, treprostinil; VRT, vasoreactivity test. Data are from the respective last measurement before pregnancy. A total of 13 patients had a total of 17 successful pregnancies—1 with twins—and delivered 18 newborns who all were healthy at the time of birth. The clinical courses are shown in Table 2. During pregnancy, all patients remained stable except 1. This patient (Number 1 in the tables) initially had an uneventful course of her pregnancy. However, at gestational Week 36, she developed a febrile respiratory tract infection followed by rapidly progressive right heart failure. She underwent an emergency cesarean section but required ECMO support within a few hours after delivery. No recovery was seen despite maximized medical therapy, including IV treprostinil, and she underwent lung transplantation 31 days after delivery. Both mother and offspring were alive and well at the last follow-up, which was 2 years after transplantation.Table 2Pregnancy Outcome and Clinical Course After PregnancyPt numberPregnancy outcomeFollow-up durationaFollow-up duration from first abortion or first delivery. (years)FC last visit6MWD last visitClinical worseningPAH medication at last visitLuTxStatus (alive/dead)12 pregnancies;(1) TOP at Week 5;(2) C-section11(1) (after Tx)NAYes, right after deliveryNA (after LuTx)yesAlive2C-section, full-term inf;122446noNIFnoAlive33 pregnancies;(1) C-section(2) C-section(3) C-section82457noAMLOnoAlive4C-section111611Yes,12 months after deliveryNIF + SIL + MACnoAlive54 pregnancies; (1) spont. abortion at Week 7(2) C-section(3) spont. abortion at Week 8;(4) C-section92566Yes, 21 months after the 4th pregnancyAMLO + TAD + MACnoAlive6C-section72NAYes, 17 months after pregnancyTAD + MAC + IV TREnoAlive72 pregnancies;(1) C-section(2) C-section63486Yes, 13 months after 2nd pregnancyNIF + TAD + MACnoAlive82 pregnancies;(1) intrauterine fetal death at Week 20(2) spont abortion at Week 862541noTAD + MACnoAlive92 pregnancies;(1) spont abortion at Week 6;(2) TOP at Week 10;13442Yes, right after 2nd abortionTAD + IV TRE + ECMOyesDead (2.5 years after Tx)10C-section61609noTAD + MACnoAlive11C-section41660noTAD + AMBnoAlive12C-section11716Yes, 22 months after deliveryDIL + RIO + MACnoAlive13C-section11604Yes, 9 months after deliveryTAD + AMB + IV TREnoAlive14C-section12545noTAD + MACnoAlive15C-section12NAnoTAD + MACnoAlive16TOP at Week 1512451noTAD + MACnoAliveAbbreviations: 6MWD, 6-minute walking distance; AMB, ambrisentan; AMLO, amlodipine; C-section, cesarean section; DIL, diltiazem; ECMO, extracorporeal membrane oxygenation; FC, World Health Organization functional class; Inf, infusion; LuTx, lung transplantation; MAC, macitentan; NA, not applicable; NIF, nifedipine; PAH, pulmonary arterial hypertension; Pt, patient; RIO, riociguat; SIL, sildenafil; spont, spontaneous; TAD, tadalafil; TOP, termination of pregnancy; TRE, treprostinil; Tx, transplantation.a Follow-up duration from first abortion or first delivery. Open table in a new tab Abbreviations: 6MWD, 6-minute walking distance; AMB, ambrisentan; AMLO, amlodipine; C-section, cesarean section; DIL, diltiazem; ECMO, extracorporeal membrane oxygenation; FC, World Health Organization functional class; Inf, infusion; LuTx, lung transplantation; MAC, macitentan; NA, not applicable; NIF, nifedipine; PAH, pulmonary arterial hypertension; Pt, patient; RIO, riociguat; SIL, sildenafil; spont, spontaneous; TAD, tadalafil; TOP, termination of pregnancy; TRE, treprostinil; Tx, transplantation. The post-partum follow-up of the remaining patients ranged from 1 to 12 years (median, 6 years). A total of 6 patients (Numbers 4, 5, 6, 7, 12, and 13 in the tables) showed signs of clinical worsening within 9 to 22 months after delivery. All of these patients responded favorably to treatment escalation and were alive at the end of the observation period. At the last follow-up, all but 1 patient presented in the World Health Organization Functional Class I or II, and 6-minute walking distances ranging from 442 m to 716 m. The offspring of our patients (age ranging from 1 to 12 years) were invariably doing well at the end of the observation period. All of them had normal findings at the legally required infant checks, and all children aged ≥18 months had normal results on the Child Behavior Checklist tests. Taken together, our data reinforce the notion that pregnancy in patients with PAH is a risky and complex undertaking. Still, our data suggest that good midterm outcomes are achievable, especially in patients with well-controlled disease when treated by a multiprofessional team experienced in the management of PAH and pregnancy. In this series, all mothers who delivered a baby were alive at the end of the observation period, and their infants were healthy and normally developed. During follow-up, several patients showed signs of clinical worsening, but the relatively long intervals between delivery and clinical worsening did not suggest that pregnancy was a triggering factor. Although our data are limited by the small number of patients, we believe that today, an individualized risk-based approach with shared decision making may be a more appropriate approach to pregnancy in PAH than the current guideline recommendation to avoid pregnancy in all of these patients. L.W. has received fees for lectures from Servier, outside the present work. M.M.H. has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, and Pfizer, all outside the present work. K.M.O. has received fees for lectures and/or consultations from Actelion, Bayer, United Therapeutics, GlaxoSmithKline, and Pfizer, all outside the present work. The remaining authors have no conflicts of interest to disclose. 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