Predictors of Maternal and Neonatal Complications in Patients With Severe Valve Heart Disease During Pregnancy

Background: The severe valve disease especially stenosis is a contraindication to conception according to WHO. This situation is still encountered in countries with a high rheumatic fever prevalence. The objective of this study was to determine the predictors of maternal cardiac, obstetric and neonatal complications. Methods: This is an observationnal study of all pregnant women with severe valvulopathy, delivered between 2010 and 2017. Results: We included 60 pregnancies in 54 women. Cardiac complications occurred in 37 patients (61%). In multivariate analysis, the predictors for these complications were parity (OR = 2.41, p = 0.023), revelation of valvulopathy by pregnancy (OR = 6.34, p = 0.025), severe mitral stenosis (OR = 6.84, p = 0.035) and systolic pulmonary arterial pressure (OR = 1.08, p = 0.01). Obstetrical complications were noted in 19 women (31.8%). The predictive factors for these complications were primiparity (OR = 5.22, p = 0.032), multiple valve disease (OR = 5.26, p = 0.028), systolic pulmonary arterial pressure (OR = 1.04, p = 0.04) and treatment with vitamin K antagonist (OR = 8.71, p = 0.04). Neonatal complications were noted in 39% of new-borns. The predictive factors for these complications were the occurrence of obstetric complications (OR = 15.48, p = 0.001) and the revelation of valvulopathy by pregnancy (OR = 6.95, p = 0.017). Conclusions: The revelation of valve disease by pregnancy is predictor of not only cardiac complication but also neonatal complications, thus valve disease screening during pre-conceptional counselling is crucial.


Background
Pregnancy is associated with several hemodynamic modi cations which could disturb the function of cardiac pump, especially in woman with cardiac disease. In fact, the prevalence of heart disease in pregnant woman is estimated between 1 and 4% (1,2) . According to the largest multicentre registry of heart diseases in pregnant women " ROPAC", the most prevalent cardiac diseases are acquired valvular pathology in emerging countries and congenital heart disease in developed countries (3,4). The World Health Organisation considers severe stenotic valve heart disease as a contraindication to conception (WHO IV category) (5). Giving that rheumatic heart disease remains prevalent in our country (6), managing pregnant woman such conditions is still encountered in our daily practice and is a challenging situation for obstetricians, cardiologists and anaesthesiologists. We have to deal in this situation with two main challenges; rst should we advise to stop the pregnancy taking in consideration the maternal and foetal risk. And second what is the appropriate mode of delivery in case of currying on the pregnancy.
Thus, this study aims assessing both maternal and neonatal prognosis in pregnant women with at least one severe cardiac valve disease and to identify those at high risk of complications.

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Methods Population This is a transversal retrospective study that includes a cohort of all consecutive pregnant women with at least one severe organic valve disease during the period between January 2010 and December 2017. We excluded pregnancies in patients with cardiac valve prothesis, as well as pregnancies in women who underwent termination or had a spontaneous abortion or a miscarriage. Baseline clinical, electrocardiographic, and echocardiographic variables were collected from the medical les and included maternal age, educational level, parity, gravidity, cardiac lesions, prior cardiac interventions, New York Heart Association (NYHA) functional class, cardiac rhythm, ventricular systolic function, valvular function and pulmonary arterial systolic pressure. The severity of valve lesions was assessed according to the criteria of the guidelines of the European Society of Cardiology (7).
The included women were contacted to get information about both the contraception use after delivery and the eventual new pregnancies before treating the valve disease.
Women who refused to give their verbally consent were excluded from the study. The study was approved by the ethic committee of the hospital " Committee of person protection SUD: CPP SUD", the reference of the study was 0245/2020.

Endpoints
Maternal cardiac complications were de ned as maternal cardiac death, new episode of arrhythmia requiring treatment, heart failure, thromboembolic events, clinical overdose with the anticoagulants, endocarditis and hospitalization for cardiac reason during pregnancy and up to 1week postpartum.
Obstetrical complications were de ned as maternal non-cardiac death up to 1 week postpartum, gestational diabetes, pre-eclampsia, premature delivery threats, premature rupture of membranes and per partum haemorrhagic complications (increased blood loss, >500 mL after vaginal delivery or >1000 mL after caesarean delivery, up until 24 hours postpartum).
Neonatal complications were de ned as premature birth <37 weeks, small-for-gesta tional-age (<10th centile), hospitalization in neonatology department and neonatal death up to 1 week after delivery.

Statistical Analysis
Categorical variables are presented as frequencies and percent ages and differences between groups were assessed using χ2 tests. Continuous variables are presented as mean and standard deviation , or as median and rst and third quartiles as appropriate, and differ ences were assessed using Student's t-test or Mann-Whitney U tests depending on the data distribution. Univariate analysis to identify predictors of adverse events was performed using chi-square, Fisher exact, or Student's t-tests as appropriate.
Univariate predictors of adverse events with p values <0.2 were entered into a multivariate logistic regression model using backward elimination with a level of signi cance of 0.05.

Results
Our cohort included 60 pregnancies in 54 women with at least one severe valve disease. It was about 59 spontaneous singleton pregnancies and one assisted twin pregnancy. In fact during the study period, 80624 deliveries were ensured in our hospital. Six hundred thirty nine cardiac ultrasound exams were performed in pregnant woman or during the rst week after delivery. The prevalence of valve heart disease was 0.49%. The prevalence of severe lesions was 0.074% (about 7 patients among 10000 deliveries).
The mean age of our cohort was 32.55±5.6 years. More than half of the patients were symptomatic of at least stage II dyspnea during the rst trimester of pregnancy, however 60% of women showed also anaemia on their biological analysis. Baseline characteristics are shown in Table 1.
Pregnancy had revealed the valve disease in 31 patients (52%) and the mean term of diagnosis was 27± 6.7 weeks of amenorrhea (range: 12-38 weeks) in the others patients.
The median term of delivery was 38 weeks of amenorrhea (range: 30-42 weeks); preterm delivery occurred in 12 patients (20%) and only one case of exceeding the term. The latter patient was not aware of her valvulopathy which was discovered following an acute pulmonary oedema occurred during labour.
The revelation mode of the valve disease was pulmonary oedema in most cases (21 patients, 68%). Nearly, half of our patients didn't plan the current pregnancy. In this group, only 13 women (43.3%) used a contraceptive method at the time of conception (micro-progestative in 5 cases, intra-uterin device in one patient and periodic continence in 7 patients). The most prevalent valve disease was mitral stenosis (43 patients, 67%). Eight patients underwent percutaneous mitral commissurotomy during pregnancy; the procedure was not performed in 24 women either because of contraindications or because of anatomically unfavourable valve. However, 11 patients were deprived of this procedure despite the theoretical feasibility, either because they refused the intervention or because the valvulopathy was diagnosed late (in peripartum). Among the 8 women who received mitral comissurotomy, a vaginal delivery was achieved in 7 patients; the indication for caesarean section in the last patient was obstetrical.
Most of our patients (68%) had delivered by caesarean section. In three patients an assisted delivery with oxytocin was performed as the valvulopathy was discovered late, in post-partum. The indication for caesarean section was in most cases cardiac (73%) and performed on a scheduled basis (88%).
As far as new borns are concerned, we notice that the median birth weight was 3000 g (range: 1500 g -3750 g) .The median Apgar score on the rst minute was 9 (range: 3-9). All new-borns had an Apgar score ≥7 on the 5th minute, except for one neonate, born from twin pregnancy, who had a score = 3 at birth, he had been hospitalized in neonatology for 17 days because of respiratory distress, the evolution was favourable.
In our population, 44 cardiac events occurred in 37 pregnancies (61.6%). The most cardiac events (95%) occurred during the antepartum period, while the other events occurred during labour and delivery or in the postpartum week following discharge (5%) ( Table 2 and 3). The most common cardiac complications were heart failure (36 patients) and arrhythmias. Only one case of cardiac arrest happened in one patient with twin pregnancy because of ventricle arrhythmia, this event occurred two hours after a mitral commisurotomy, a severe hypokalaemia was noted. The woman was transferred to reanimation department, the evolution was favourable. A foetal extraction was achieved at 30 gestational weeks.
Twenty three obstetrical events occurred in 19 pregnancies (31.8%) ( Table 4 and 5) and 27 foetal events occurred in 24 new born (40%) ( Table 6 and 7). Overall, no cases of maternal or neonatal death were observed. Three patients showed preeclampsia and were in fact treated with intravenous diuretic because of pulmonary oedema.
The rate of preterm delivery was 20% in our series (12 deliveries). It was about two cases of spontaneous prematurity and 10 cases of iatrogenic prematurity. Nine patients (75%) among those with preterm delivery had a severe mitral stenosis. Pulmonary arterial pressure was signi cantly higher in the preterm delivery patients (60.08 ± 16.81 versus 48.08 ± 15.94mmHg, p = 0.04). After one year of the current pregnancy, only 31 women used contraception (51.7%). And among the other women, 6 patients had a new pregnancy even before treating the severe valve heart disease.

Discussion
Cardiovascular diseases are the most common causes of maternal death during pregnancy(8). Knowledge of the risks associated with such conditions in pregnant women and their management is of pivotal importance. However, the number of published cases is limited and most recommendations are class C even in the most recent guidelines (9). The tolerance of valvular heart disease during pregnancy is little recognized since the prevalence of rheumatoid arthritis is decreasing. However, nowadays there is an increase in the age at which women are becoming pregnant; thus the prevalence of pregnant woman with severe cardiac valve disease remains unchanged. The current study, was carried to evaluate our maternofoetal outcomes in pregnant women with severe valve lesions. The recently published Global Rheumatic Heart Disease Registry (REMEDY) included 3343 patients with rheumatic heart disease in 12 African countries, India and Yemen; the median age was 28 years (10). The majority (63.9%) had moderate to severe valvulopathy complicated by congestive heart failure in 33.4%, pulmonary hypertension in 28.8%, atrial brillation in 21.8%, stroke in 7.1%, and infectious endocarditis in 4% and major bleeding in 2.7%. In 1,825 women of reproductive age (aged 12-51), only 3.6% used contraception.
In a Tunisian study analysing the epidemiological pro le of cardiac women who gave birth in a Tunis maternity center between January 2010 and December 2012, out of 19655 deliveries studied, the prevalence of heart disease was 1 in 351 deliveries (0.285%). The mean age was 30.89±5.3 years (ranges between 21 and 42 years). Out of the 56 cases of cardiac women, 35 patients (62.5%) had valvulopathy , which means a prevalence of 0.17% (11). In our cohort, the mean age was 32.5±5.6 years and the prevalence of heart valve disease was about 0.49% and of severe disease was estimated at 0.074%.

Cardiac adverse events
Cardiac complications are frequent in pregnant women with cardiac valve diseases and varied between 13% and 35,6% according to previous studies (12-16) ( Table 8) . Certainly the rate of complications will be higher in women with severe lesions, especially when the condition is discovered only during pregnancy. In the CAPREG II study, the overall maternal cardiac event rate during pregnancy for mWHO I, mWHO II, mWHO III, and mWHO IV was 3.1%, 12.8%, 21.1%, and 35.6%, respectively. In our cohort two patients from three showed cardiac events. Pulmonary oedema seems to be the most prevalent complications; the advancement of therapeutic strategies improved the prognosis. Maternal cardiac death or cardiac arrest becomes rare, in the recent CAPREG II study it occurred in 11 pregnancies (0.6%) (13); besides the experience of a tertiary care center including women with pulmonary hypertension, no cardiac death occurred (17). In our series no maternal death was noted; only one case of cardiac arrest occurred because of dyskaliemia and the recovery was obtained. However, cardiac mortality remains much higher than that in the general obstetric population (18-21).
Several studies tried to determine predictors of cardiac events and to conclude the scores relying on theses predictors.
The multicenteric CARPREG (Cardiac Disease in Pregnancy Study) including patients both with congenital and acquired diseases, was the rst to develop such risk index. Predictors of cardiac events were left heart obstruction, cyanosis or dyspnea before pregnancy, cardiac antecedents and systolic LV dysfunction (15,22). In the European Registry of Pregnancy and Heart Disease (ROPAC), including 2966 women, valve heart disease account for 25% of pregnant women with cardiovascular disease. Mitral diseases, both stenosis and regurgitation, were the most common valvular lesions (63%), followed by aortic valve disease (23%) ( Table 8). In this registry, signs of heart failure before pregnancy, atrial brillation and no previous cardiac intervention were strong predictors of cardiac events. In our cohort, cardiac complications occurred especially in stenotic lesions; regurgitant lesions were well tolerated and didn't impose the termination of pregnancy. In stenotic lesions, increased cardiac output causes a rise in transvalvular gradient of 50%, mainly between the rst and second trimesters, (23). That's why congestive heart failure more commonly occurred in the third trimester or early postpartum, whereas most arrhythmias occurred in the antenatal period.
Mitral stenosis was the most untolerated valve disease and was found as independent predictor of cardiac complications. In fact during pregnancy there will be an increase of cardiac output brought by increased heart rate and stroke volume, and oppositely a decrease of peripheral resistance by a peripheral vasodilatation. The drop of vascular resistance explains the tolerance of regurgitant lesions (6,24-26).
Pregnancy outcomes in two large centers in the United States reported a risk of pulmonary oedema occurrence in pregnant women with mild, moderate and severe mitral stenosis, respectively between 11% and 24%, 34% and 61%, and 56% and 78%. The rate of occurrence of atrial brillation varied between 0 and 7% in case of mild stenosis, 10 and 22% in the case of moderate stenosis and between 22 and 33% in case of severe lesions(16,27).
Percutaneous mitral dilation seems to improve remarkably the hemodynamic condition of these patients, then allow even a vaginal delivery in most cases. According to the recent ESC guidelines, Intervention should be considered before pregnancy in patients with MS and valve area <1.5 cm² and should be considered in pregnant patients with severe symptoms or systolic pulmonary artery pressure >50 mmHg despite medical therapy (9).
In our study, the revelation of cardiac valve disease by pregnancy was also found as strong predictor not only of cardiac complications but also neonatal complications, this result accord with other predictors found in the ROPAC registry or the CAPREG II study which is the lack of intervention before pregnancy as well as the delayed pregnancy assessment. Therefore, it is strong recommended to assess pre-pregnancy risk and to counsel all women with known or suspected congenital or acquired cardiovascular and aortic disease (28). It is also recommended to perform risk assessment in all women with cardiac diseases of childbearing age before and after conception, using the mWHO classi cation of maternal risk(28).
Generally, women who receive late pregnancy assessment had more frequent adverse cardiac outcomes during pregnancy, which may be attributed to delayed access to appropriate risk strati cation, follow-up, and management plan.
But we noted that in our practice, despite the fact that the rate of illiteracy among women was low (3%), the use of contraception is infrequent, as is the evidence of new pregnancies in cardiac women who had already cardiac complications during pregnancy before treating their heart disease. The cardiologist plays a pivotal role in the therapeutic education of these women and the prescription of an adequate contraception while discussing with the gynecologist.

Obstetrical adverse events
The obstetrical risk remains poorly described in the literature. The main parameter to be evaluated is the mode of delivery, which depends, in this context, on the maternal tolerance of pushing efforts, a trigger and the possibility of epidural analgesia. According to the recent guidelines a delivery plan should be made between 20-30 weeks of pregnancy detailing induction, management of labour, delivery, and postpartum following up; moreover the Induction of labour should be considered at 40 weeks of gestation in all women with cardiac disease (9). Obstetric complications were 3 to 4 times more common in our population compared to the ROPAC and CAPREG studies (Table 8). The low parity (nulliparous or primiparous) is a predictor of obstetrical events in many studies, especially it increases the risk of preeclampsia (29) (Table 8).
In our cohort premature labour threat was the most common complication. This is mainly due to both uterine muscle hypoxia as well as to acute heart failure, commonly occurred in our patients Pre-eclampsia was more common in women with aortic valve disease and left ventricle dysfunction because of low cardiac output and, as expected, in nulliparous women and those with pre-existing hypertension. In our series, all the cases of preeclampsia occurred in women treated with intravenous diuretic because of acute heart failure. This is a di cult situation encountered in the daily practice, diuretic results in a placenta hypoperfusion which is the main mechanism of preeclampsia and normally diuretic should be avoided in such patients. The anticoagulant use is also a strong predictor of obstetrical complications mainly haemorrhage. In our cohort this factor increases 8 times the risk of obstetrical events, the association between haemorrhage and anaemia frequently diagnosed in our patients will worsen the prognosis and result in heart decompensation. That's why it is recommended to anticipate the timing of delivery to ensure safe and effective peripartum anticoagulation.

Neonatal complications
The neonatal prognosis is closely correlated with maternal prognosis. Anyway, in our series we have noted the occurrence of obstetric complications (OR = 15.48, p = 0.001) and the revelation of valvulopathy by pregnancy (OR = 6.95, p = 0.017)as strong predictors of neonatal complications. In fact, the delayed discovery of valvulopathy may expose the foetus to a longer duration of hemodynamic stress, especially with a risk of placental hypoperfusion, hypotrophy and prematurity. The immunological status of these new-borns will also be precarious with a higher risk of hospitalization in neonatology. In the ROPAC registry, the rate of foetal complications among women with WHO IV heart disease was 31%, a rate comparable to our series that was 40%. Predictors of these complications in ROPAC were multigestity, treatment with anticoagulant, diabetes, and life in developing countries (table 8).
Symptomatic women (NYHA class III-IV), and oral anticoagulants, were the main reasons for induced preterm delivery. In case of spontaneous prematurity both in ammatory processes, and utero-placental ischemia can initiate preterm labour (30). Certainly, maternal hypoxia increases cytokines and oxygen free radicals, which may cause abnormal placentation; these conditions mostly occurred in woman with congenital heart disease (31). In our cohort most cases of premature delivery were induced, that's why pulmonary systolic pressure were signi cantly higher in mothers of preterm babies. In a Japanese cohort including 857 women with cardiac disease, ischemic cardiac disease followed by valve heart disease were related to the highest risk of induced prematurity , respectively 48.3% and 44.3%; the rate of caesarean section was respectively 81.7% and 68.8%. In our series, we noted only 20% of prematurity; previous studies showed that both induced and spontaneous preterm birth were less common in developing countries than in developed countries. This was explained by the advanced age with uterine dysfunction for the spontaneous prematurity and a quicker access to obstetric care facilities in developed countries.

Study limitations
The main limitations of our study involve the retrospective design from one hand and the small sample size from the other hand. These two limits could be explained by the low prevalence of severe valve disease among pregnant women; as it contra-indicates the conception. Moreover, we included only term pregnancies since abortions and stopped pregnancies are multifactorial, and so we are unable to conclude that there is a relationship between these obstetric events and the severity of valvulopathies.

Conclusions
To conclude, our cohort demonstrates that women with severe heart valve diseases should be counselled about the pregnancy risks and foetal problems. It is crucial to early detect such cardiac lesions during premarital consultation, through a meticulous interrogation on functional tolerance to the effort and an attentive cardiac auscultation.
Since mitral stenosis is the most commonly encountered lesion, the percutaneous treatment should be attempted whenever possible and performed by experimented operator; it improves the hemodynamic conditions and offers more chance of vaginal delivery.
As for the obstetricians, they should give priority to vaginal delivery with triggering as much as possible, use epidural analgesia widely and shorten delivery as much as possible especially in women treated with anticoagulants.
Finally, in developing countries, much more efforts should be given to the organisation of contraception in cardiac women, which necessitates a close collaboration between both the cardiologist and the gynaecologist. The ethic committee approved a verbally consent as patients will be contacted by phone.