Clinical outcomes of pulmonary hypertension in pregnancy among women with congenital heart disease in China

Absrtact Objective Pulmonary arterial hypertension (PAH) increases the risk for perinatal women and newborns, especially in women with congenital heart disease (CHD). We explored the maternal, perinatal, and postneonatal outcomes of PAH in pregnant women with CHD in China. Methods A total of 95 pregnant women with CHD-PAH in Beijing Anzhen Hospital from 2009 to 2013 were included retrospectively. We described their characteristics and examined the associations between the grade of PAH and maternal, perinatal, and postneonatal outcomes. Results The New York Heart Association (NYHA) classification grade, delivery mode, and infant outcomes in CHD-PAH patients were analyzed. Overall 95 patients with CHD-PAH, there were 17 patients in mild group(17.7%), 27 patients in moderate group (28.1%), and 51 patients in severe group (53.1%)。The CHD patients with mild PAH, were mostly NYHA class I–II and CHD patients with severe PAH were NYHA class II–IVs. Cesarean section (67.7%) was the most common method of delivery. The rate of therapeutic abortion in the severe group (76.9%) was obviously higher than that in other groups (11.5% in mild group and moderate group respectively), whereas there was no term delivery in severe group, with 2 cases in mild group and moderated group respectively . The rates of heart failure and therapeutic abortion in pregnant women were positively associated with the severity of PAH. The rate of term delivery was higher in patients whose CHD had been corrected by cardiac surgery (83.3%) before pregnancy. Conclusion Patients with severe PAH have poor cardiac adaptability, poor maternal and fetal outcomes, and are contraindicated during pregnancy. Patients with mild PAH are not absolutely contraindicated during pregnancy, but their heart burden increases significantly in the third trimester. Patients in mid-gestation should preferentially be delivered by cesarean section. When pregnant patients prefer to continue pregnancy, their close monitoring is essential. We provide useful data for guiding management of pregnancy and delivery in patients with CHD in China.


Introduction
Pregnancy is accompanied by physiologic changes that stress the heart; these changes are well-tolerated in healthy women. However, women with underlying heart disease may experience adverse consequences [1]. Congenital heart disease (CHD) is the most common heart disease in pregnant women in China [2,3]. Due to the systemic-pulmonary shunt, some CHD patients experience increased pulmonary arterial pressure, which leads to pulmonary arterial hypertension (PAH) during pregnancy. Many patients have no obvious symptoms before pregnancy and may have a history of repeated respiratory tract infections.
PAH can be idiopathic (IPAH), heritable (HPAH) [4,5], or associated with various diseases (APAH), including CHD (CHD-PAH) [6,7]. In pregnancy, PAH is characterized by elevated pulmonary vascular resistance and secondary right-sided heart failure [8], which gives rise to the reported maternal mortality rates as high as 30-55% [9]. The increased mortality risk results from the poor tolerance of pregnancy-related hemodynamic and physiologic changes that can precipitate right ventricular (RV) failure and arrhythmias. These changes begin in the first trimester and continue for weeks into the post-partum period [10]. Thus, experts recommend that women with PAH at childbearing age should use effective contraception to avoid pregnancy, and early pregnancy termination is recommended in the event of pregnancy [11,12]. However, for such women, the desire to bear children is an important component of their care, so pregnancy counselling and management are important issues for cardiac health providers. In many women with CHD (either unoperated or repaired), pregnancy can be accomplished with minimally increased risks for mother and baby, but an individual approach is needed for each case.
In this study, we retrospectively explored the association between PAH, presence of CHD, cardiac function, delivery mode, and infant outcomes in patients in China so as to enhance pregnancy management strategies and thus improve maternal, perinatal, and postneonatal outcomes of patients with this condition.

Study population
The study sample population was obtained from January 2007 to June 2013 at Anzhen Hospital of Capital Medical University, Beijing. There were 86 primiparous and nine multiparous cases, at 6-41 weeks of gestation. Twelve patients had undergone cardiac corrective surgery before they became pregnant. Approval for human subject research was obtained from the Ethics Committee of the Anzhen Hospital, and the research was carried out in accordance with the approved guidelines.

Ascertainment of pulmonary hypertension
Pregnant women were subject to colour Doppler ultrasound, ECG, 24-h dynamic ECG, examination of myocardial enzymes and troponin, and cardiac function testing. Chest radiographs were also used if necessary. PAH refers to the mean pulmonary artery pressure !25 mm Hg measured by the right cardiac catheter at sea level. In this study, according to the systolic pulmonary artery pressure measured by echocardiography during pregnancy, the patients were divided into the following three groups: 40-49 mm Hg (1 mm Hg ¼ 0.133 kPa), mild PAH; 50-79 mm Hg, moderate PAH; and !80 mm Hg, severe PAH. New York Heart Association (NYHA) classification was used for clinical/functional rating.

Statistical analyses
Statistical analysis was performed using SPSS version 12.0 (SPSS Inc, Chicago, IL, USA. Statistical significance was defined as p < 0.05).

Summarizing patients' characteristics
A total of 95 pregnant women with CHD-PAH were identified between 2007 and 2013. Detailed demographic and clinical characteristics of the patients are shown in Table 1 and Figure 1. Fifty-one patients had severe PAH; 27 patients had moderate PAH; and 17 patients had mild PAH. The underlying diseases in these patients are shown in Table 2 and Figure 2. In this study, CHD-PAH was divided into the following four types: Eisenmenger syndrome (ES), CHD-PAH associated with left-to-right shunt, postoperative CHD-PAH, and small defect CHD-PAH. The most common  (Table 1). NYHA Class I patients were found significantly more commonly in the mild group than in the severe group (p < 0.001). Likewise, patients with NYHA Class IV were significantly less common in the mild group than in the severe group (p < 0.01). These data showed that pregnant women with severe PAH tended to have high NYHA Class.

Delivery and maternal outcomes
Sixty-three out of 93 patients (excluding one death and one discharge against medical advice) underwent cesarean section ( L R PAH( P n=60) Repaired PA P AH (   Figure 1. Workflow of the study participant. ES-PAH, pulmonary hypertension in Eisenmenger syndrome, PAH, pulmonary arterial hypertension, CHD-PAH, pulmonary arterial hypertension associated with congenital heart disease, PH, pulmonary hypertension, L-R-PAH, left to right shunt pulmonary arterial hypertension.  these patients terminated pregnancy by induced abortion on the advice of a cardiac surgeon early in pregnancy, and one patient died before delivery of multiple organ failure at 38 weeks of gestation. Seven patients underwent cesarean section at 32-39 weeks of gestation when cardiac function deteriorated into NYHA Class IV. One patient whose cardiac function deteriorated heavily was discharged against medical advice at 28 weeks of gestation. Six patients in the severe group (11.7%) developed heart failure during pregnancy, while none in the mild group (0%) and two in the moderate group (7.4%). And there is no significant difference in the risk of preeclampsia, gestational diabetes, gestational hypertension, anemia and arrhythmia in patients with different groups during pregnancy.
A total of 12 patients who underwent cardiac corrective surgery before pregnancy appeared to better tolerate pregnancy-induced hemodynamic changes. The heart function was maintained in NYHA Class I-III, and pulmonary artery pressure was lower in the surgically treated group than in the untreated group (p < .05). In the surgically treated group, 10 CS were performed at 35-40 weeks of gestation (83.3%), which was higher compared with the untreated group (30.5%, p < .001). Two of these patients had a therapeutic abortion early in pregnancy, which was lower than in the surgically untreated group (25/82 patients; p < .001) ( Table 4). These data showed that early surgical repair of CHD before pregnancy is helpful for women with CHD-PAH. All patients delivered by CS were given epidural anesthesia, except three cases, who received general anesthesia.
During delivery, a blood volume of approximately 500 ml is shifted from the uterus to the venous system. In this study, three patients with severe PAH developed acute decompensated heart failure. One case terminated the pregnancy by induced abortion; one case improved under combined therapy directed by the cardiac surgeon and obstetrician in the Surgery Intensive Care Unit after CS; and one death occurred from multiple organ failure after CS.

Infant outcomes
Among 44 term births, 12 cases were born to mothers in the mild PAH group, 17 in the moderate group, and 15 in the severe group, with a significant difference, found between the mild and the severe groups (p < .05). Among 22 cases of preterm births, two cases (35 weeks) occurred in the mild group (one infant birth weight below 2500 g), five cases (28-36 weeks) in the moderate group, and 15 cases (28-36 weeks) in the severe group (all infants' birth weight below 2500 g), with a significant difference between the mild and the severe groups (p < .05). With the severity of PAH, the incidence of premature birth increased. Among 27 cases of iatrogenic abortion, three cases were performed in the mild group, four in the moderate group, and 20 in the severe group ( Table 5). The average birth weight was 3016 ± 103 g in the mild group, 2562 ± 143 g in the moderate group, and 2865 ± 123 g in the severe group, with significant   Data are presented as the number of subjects; 1 woman death before delivery in the moderate group, 1 woman check out from the hospital against medical advice in the severe group, Ã : Therapeutic abortion including vacuum aspiration, mid-trimester pregnancy medicinal abortion, abdominal hysterectomy.
differences identified between the mild and the moderate groups, and between the mild and the severe groups (p < .001) ( Figure 3). Furthermore, the average birth weight was higher in the surgically treated group than in the untreated group (p < .05) (Figure 3).

Discussion
In this study, we retrospectively evaluated maternal, perinatal, and postneonatal outcomes of 95 CHD-PAH women in China. We demonstrated that the prognosis of mother and baby in CHD patients with mild and moderate PAH was relatively good, while the rate of heart failure and therapeutic fetal loss gradually increased with the severity of PAH. The rate of term delivery was higher in patients whose CHD had been corrected by cardiac surgery before pregnancy. The cardiac output during pregnancy increases significantly compared with that in non-pregnancy state, reaching the peak at 32-34 weeks of pregnancy, which could increase by 40%-50% [13]. The increase in blood volume causes an increase in pulmonary artery resistance. Pregnancy in CHD-PAH patients is poorly tolerated and presents a serious risk to them, especially at 32-34 weeks of gestation, at delivery, and at 3 days postpartum [14]. (ES) is the most serious manifestation of CHD-PAH. Congenital cardiac malformations such as ASD and VSD result in a progressive increase of pulmonary vascular resistance, which leads to right-sided heart overload, cardiac dysfunction, the subsequent reduction in pulmonary blood flow with reversed or bidirectional shunt, and finally right-sided heart failure or total heart failure [8,15,16]. Maternal mortality in patients with PAH is high, and most deaths occur postpartum, based on data from earlier studies [9,14]. With the advances in PAH therapies, there has been a decrease in maternal mortality [17]. In this study, all 18 patients with ES were in the severe group, with NYHA grades III-IV. The cardiac function of nine patients was evaluated by a cardiac surgeon in the early pregnancy, and therapeutic abortion was performed to terminate the pregnancy. Seven patients underwent CS in the second and third trimesters, and one out of 18 patients with ES, which is the most severe form of CHD-PAH, died before delivery. The blood volume increases to 40%-100% above normal during pregnancy between 28 and 34 weeks of gestation, and a blood volume of nearly 500 ml is shifted to maternal circulation with the uterus contraction during delivery. Pregnancy is associated with increased plasma volume and cardiac output, which may result in right ventricular failure. In this study, three patients with severe PAH developed right ventricular failure. One case terminated the pregnancy by induced abortion; one case improved under combined therapy directed by the cardiac surgeon and obstetrician in the Surgery Intensive Care Unit after CS; and one death occurred from multiple organ failure after CS. Cardiac corrective surgery in advance of pregnancy appeared to improve the tolerance of pregnancyinduced hemodynamic changes in the present study, given that the patients' heart function was better and their pulmonary artery pressure was lower. The early surgical repair of CHD before pregnancy is helpful for women with CHD-PAH.
During delivery, the patients might endure pain and may be exposed to hypoxia and rapid fluid change [17]. Therefore, timing and mode of delivery should be planned well in advance. Early delivery should optimally be planned between 32 and 36 weeks of gestation [9]. In this study, the rate of term delivery was 70.6% in the mild PAH group; birth weight was reasonable (3016 ± 103 g); and none of the fetuses died. The pregnancy outcome was good in patients with mild PAH complicating maternal CHD. On the other hand, the rate of iatrogenic fetal loss in the severe PAH group was higher than that in the other groups, while the rate of term delivery was lower.
The necessity of termination of gestation should be based on patient's cardiac function, pulmonary artery pressure, and gestation week [18]. For normal women, vaginal delivery is the first and safe choice. Patients with mild PAH could deliver vaginally or undergo CS if cardiac function is acceptable. Patients with severe PAH should not risk pregnancy, and early termination may be wise. However, patients insisting to continue with pregnancy should be monitored monthly. Induced abortion is performed under anesthesia early in pregnancy. Anesthesia could reduce the influence of pain stimulation on the heart, and monitoring of the heart function can assist in assuring the safety of the operation. Cardiac output increases nearly 80% above the normal condition at the time of vaginal delivery [19,20]. Delivery can be completed within a short time by CS, which would reduce the hemodynamic changes caused by prolonged uterine contraction and oxygen consumption. Thus, CS appears to be a much safer option for patients at a late phase of pregnancy, and epidural anaesthesia is used mostly because of its smaller effects on blood pressure and heart rate in CS compared with vaginal delivery. Bed rest with ECG monitoring may prevent heart failure caused by increased venous return and right-heart overload, especially at 1-3 days after delivery. All three deaths postpartum in our study were caused by hemodynamic changes in cases delivered by CS.
In summary, patients with CHD-PAH should be advised by obstetricians and cardiologists before pregnancy and contraception should be urged, especially in cases with moderate and severe PAH. Patients with unplanned pregnancies should consider an induced abortion under anaesthesia as soon as possible. Patients in mid-gestation should preferentially be delivered by cesarean section. When patients prefer to continue the pregnancy, their close monitoring is essential. Obstetricians and cardiologists should follow-up closely and take effective measures according to the patients' condition.