Authors

• Maja Strozzi — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Darko Anić — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Željko Baričević — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Margarita Brida — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Irena Ivanac Vranešić — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Kristina Marić Bešić — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
• Jadranka Šeparović Hanževački — Medicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska

DOI

Full Text

We recently informed the general cardiologic public in Croatia about the increasing problem of adult patients with congenital heart disease (ACHD) (1, 2). With this thematic issue of the Cardiologia Croatica journal, we hoped to increase the awareness of the problem and present some progress we have achieved over time. In this article, we will focus on one specific aspect of the issue: the problem of pregnancy in women with ACHD, including our experiences with these patients. It is not hard to see why pregnancy is full of risk for patients with ACHD. Pregnancy in any women is associated with significant hemodynamic changes. Due to hormonal changes, there is a very early drop in systemic vascular resistance (SVR), leading to compensatory renin-angiotensin reaction on pre- and afterload drop, with a correspondent rise in blood volume and heart rate. This results in increased cardiac output (CO), which can be almost doubled at the end of the pregnancy. Extra-cardiac anatomy can also have a negative effect on hemodynamics. In patients with already decreased cardiac function, this can have a severe impact (3). Maternal cardiac mortality during pregnancy is very low. Based on data from the British statistical office, it was 2.3 per 100 000 pregnancies in 2011 (4). The good news is that patients with ACHD only make up a small portion of this group, but other problems occur during pregnancy that can influence later mortality and morbidity (5). Pregnancies in patients with ACHD should be managed according to a precise plan that includes: - Evaluation before pregnancy - Avoidance of drugs harmful to the baby - Cardiac and obstetric care prior to delivery - Fetal development care - Cardiac and obstetric care during labor - Post-delivery care - Future contraception - Genetic counseling (if needed) - Antibiotic prophylaxis (if needed) According to this algorithm, the first rule is pre-conception counseling. Our goal is to establish and optimize the future mother’s heart condition, and discuss the following issues: immediate and late effects of pregnancy on the mother’s cardiac condition and risk to the baby. The pre-pregnancy examination includes history and clinical status, ECG, echocardiography (ECHO) to establish ventricular function, valves, vessels (conduits), shunts, and pulmonary pressure. If necessary, alternative imaging or other methods such as nuclear magnetic resonance (MR), exercise capacity testing, and heart catheterization in suspected high pulmonary vascular resistance (PVR), should be performed. In some cases, genetic counseling is advised. Unfortunately, patients sometimes come to our outpatient clinic already pregnant! Pregnancy risk should be determined, which is best done according to **WHO risk stratification during pregnancy** (ESC Guidelines on the management of cardiovascular diseases during pregnancy) (6). All patients with ACHD can be stratify into four groups (I-IV). ## Low who risk stratification group - In patients with surgically corrected atrial septal defect (ASD) and ventricular septal defect (VSD) without complication, a normal pregnancy can be expected (I). - In un-operated ASD and small VSD with good left ventricular function and no pulmonary hypertension (PH), normal pregnancy is expected (II). The left-to-right shunt can decrease because of the fall in SVR. There is a small risk of atrial arrhythmias and a theoretical risk of paradoxical embolization in ASD. (7) - Pulmonary stenosis (PS) with a gradient lower than 60 mmHg is also not a high risk for pregnancy (I). ## Intermediate WHO risk stratification group - It is recommended to treat severe PS before pregnancy (RVP>75 mmHg, P gradient >60 mmHg). Untreated PS caries high risk for right heart failure (II-III). - Repaired Tetralogy of Fallot (TOF) is a moderate risk for pregnancy (II). - Marfan syndrome can cause dissection during pregnancy, but the risk is not so high if the dimensions of the ascending aorta are less than 4.0-4.5 cm (II-III). ## High WHO risk stratification group - Transposition of the great arteries (TGA) after atrial switch (Senning-Mustard procedure); changes in RVEF and systemic valve competence can be permanent! (III). - Mechanical valves carry a great pregnancy risk. There is no consensus on the best anticoagulation regime in pregnancy (risk for pregnancy termination, thrombosis risk, teratogenicity risk for the baby) (III). - Un-operated TOF, rare today, carries a risk of cyanosis (III). - Pregnancy problems are common in Fontan patients (III). ## Case 1 ## MD, 1981, “murmur” known from childhood - Effort intolerance in the last two years, pregnancy planed. - Valvular pulmonary stenosis (PS) diagnosed (gradient 94 mmHg, annulus 21 mm) (**Figure 1**).Figure 1Echo finding of a congenital valvular pulmonary stenosis. - Pre-pregnancy intervention recommended. - PTA successful with two balloons 16+13 mm (**Figure 2**)Figure 2Percutaneous balloon dilatation of stenotic pulmonary valve: A) Pulmonary angiography before dilatation; B) Simultaneous inflation with two balloons; C) Pressure gradient before dilatation; D) After dilatation. - Pregnant, so far without complication, a normal vaginal delivery is expected. **This case is a good example of pre-pregnancy evaluation and optimized pregnancy outcome due to the advised intervention.** ## Case 2 ## JS, 1989, healthy - Mother died at 47 years of age (sudden death from aortic rupture, previous operation of cerebral aneurysm). - 2015: sister successfully operated for ascending aortic aneurysm (9 cm). - Accompanying her sister for postoperative ECHO control, somebody of echo staff she was pregnant (23 weeks) and offered her ECHO control as well. - ECHO revealed 4.5 cm of sinus Valsalva, Cesarean section recommended (**Figure 3**).Figure 3Dilatation of sinus Valsava in pregnant patient with suspected Marfan syndrome. - Birth was uneventful, and the patient is in regular follow-up; small progression of aortic dimension (4.7 cm) after 1.5 years. **The case is an example of the importance of screening. Marfan syndrome with aortic dilatation carries high risk for aortic dissection during pregnancy or delivery!** ## Case 3 ## PH, 1995, transposition of great arteries (TGA) - Senning-Mustard operation was performed at 4 months, in regular pediatric FU. Last pediatric control was 12/2012; **37 months pregnant**. ECHO description: normal tricuspid valve (systemic) function, good systemic right ventricular function. In ECG, a sinus tachycardia 140/min was described. - 3 weeks later, (1/2013) gave normal vaginal birth to a healthy girl. - 3/2013: hospitalization for severe heart failure, referred to our center (5/2013). - Atrial flutter at first presentation, low max oxygen consumption on spiroergometry (20 vol %O2), low EF, and significant systemic valve insufficiency on ECHO found (**Figure 4**).Figure 4Echo finding of patient with systemic right ventricle (transposition of great vessels after Senning Mustard operation): A) Dilatation and systolic function reduction of systemic right ventricle; B) Significant systemic (tricuspid) valve regurgitation. - Electrocardioversion was done, on beta-blocker therapy without without significant arrhythmia, on regular follow-up. Improvement of clinical and ECHO findings (**Figure 5**).Figure 5Improvement of systolic function of systemic right ventricle after pregnancy. **In this case, the question is whether EF deterioration was associated with pregnancy and was arrhythmia unrecognized. After pregnancy and conversion to sinus rhythm, fortunately, improvement of systolic function and reduction of systemic valve regurgitation was observed.** In the literature (8) on patients with TGA after Senning-Mustard operation, RV dilatation progressed in 1/3 of patients and with no recovery in 31%. RV systolic dysfunction progressed in 25% of patients, in the majority with no recovery. Tricuspid regurgitation progressed in 50%, and 1/3 of patients did not recover! The mother should be informed about the risk, and if she is willing to take it, careful follow-up is needed. ## Case 4 ## KS, 1994, congenital mitral valve disease - ×2 mitral valve repair in childhood. - 2009: mechanic valve implantation for severe mitral regurgitation was performed (parents’ decision). - 2015: first pregnancy, miscarriage in the 8th week (fetal death). - Last year: frequent SVT, electrophysiology was scheduled, but in the meantime there was second pregnancy; the patient presented at our center after 6 weeks: warfarin stopped, fractionated heparin introduced, beta blocker continued. - High warfarin dose needed (10.5 mg), so fractionated heparin continued, aspirin 75 mg introduced (from 14 to 32 weeks), regular anti-Xa level control (0.35-0.7 IU/mL). - New onset of SVT 220/min, stopped with verapamil (introduced instead of beta blocker for regular therapy) (**Figure 6**).Figure 612-lead ECG in pregnant patient with mechanical mitral valve; A) Supraventricular tachycardia 194/min; B) Sinus rhythm, after conversion with verapamil. - Ablation was planed after delivery, but for increase in arrhythmia frequency, the procedure was done in the 6-th month of pregnancy, with maximal radiation protection. In regular FU, so far with no complication, Cesarean section planed. **The case is a good example of the need to discuss the treatment strategy with patients (parents). Mechanical valves represent a high risk for future pregnancy, and this should be explained to patients (parents) before surgery!** In meta-analysis of studies (9) examining the best anticoagulation strategy in pregnant women with mechanical valves, different anticoagulation regimes had different impacts on maternal death, thromboembolism risk, valve failure, but also fetal spontaneous abortion, death, and congenital defects. Warfarin is the best drug for the prevention of valve thrombosis (only 5% risk for the mother) but has a high impact on congenital defect incidence in the fetus (up to 45%). There is also a risk of fetal hemorrhage (the drug is crossing placental membrane). Low-dose warfarin (if it is sufficient for good coagulation control) carries a much smaller risk. It should be avoided in the first trimester. Heparin carries approximately 15% risk for the child but also for the mother as well. Fractionated heparin is easier to use. The following combination can be recommended in some patients: fractionated heparin in the first 3 and last 2 months with warfarin in between; however, there is no a perfect anticoagulation regime for pregnancy! ## Case 5 ## MI, 1973, AV canal (large VSD and single atrium), severe PS - Cyanotic from childhood, rejected for reconstruction due to complexity. - 1998: Kawashima operation at 25 years of age (Fontan circulation). - 2000: normal pregnancy, gave birth to a small but healthy girl by vaginal delivery. - 2003 and 2006: pulmonary AV fistula closure. - Last 2 years: ascites, moderate reduction of EF, no systemic valve regurgitation, no conduits stenosis, no evidence of PLE, chronic hepatic lesion, suspect ovarian disease (Meigs syndrome?); adnexectomy 7/2017, ascites still present, but clinical status is stable. **This case represents the only Fontan patients with a successful pregnancy in our ACHD registry. The uncomplicated pregnancy may be result of late initial operation (at 25 years of age). The majority of our Fontan patients, are burdened with the usual complications occurring 20 years after the operation, when they reach the age for pregnancy.** Pregnancy after Fontan operation is associated with a high miscarriage rate. Older (10) and more recent (11) studies all reached the same conclusions: miscarriage occurs in 1/3 pregnancies in Fontan patients, and 70% pregnancies end with premature delivery, which has an impact on infant mortality and morbidity. Cardiac events are rare, and maternal mortality was not recorded. Group of patients with ACDH strongly discouraged from pregnancy (WHO IV) 1. Eisenmenger syndrome (50% maternal mortality). 2. Marfan’s syndrome with dilated aortic root (>4.5cm). 3. Severe aortic stenosis/coarctation. 4. Systemic ventricular ejection fraction <35%. 5. Severe pulmonary hypertension. The risks for the baby in pregnant women with ACHD includes: - Fetal growth restriction (Fontan circulation, cyanosis, beta-blockers users). - Preterm delivery (spontaneous, sometimes iatrogenic). - Teratogenicity (drugs). - Recurrence of congenital heart disease is rare (3-5%, including paternal disease). Medication during pregnancy is of great concern. There are **safe drugs** (digoxin, Ca-channel blockers, beta-blockers, thiazide and furosemide, heparin, sildenafil, low dose aspirin). Some of these drugs should be given with caution in the first trimester, some can reduce fetal growth, and for some, drug concentration monitoring is recommended. Some drugs are **not safe drugs** or at least not proven to be safe (ACE and ARB inhibitors, warfarin in the first trimester, spironolactone, bosentan, amiodarone, etc.). In peripartal care, the emphasis is on delivery planning and timing (and careful induction if necessary). In intermediate and high-risk patients, delivery should take place in a tertiary center, and the mode of delivery should be discussed with the obstetrician. In general, vaginal delivery is recommended. The birth position, analgesia, and time control must be considered. Antibiotic prophylaxis is not recommended in vaginal delivery. Cesarean section should be chosen for obstetric indications and selective cardiac states: Marfan syndrome, heart failure, mechanical valves. Complications in post-partal care can be expected, such as hemodynamic changes (heart failure and pulmonary edema, hypertension, shunting changes, and cyanosis), hemorrhagic complication (careful anticoagulation therapy monitoring); thromboembolic incidents are possible (pulmonary, systemic in patients with shunts), and incidence of infection is higher after section. ## Conclusion - The number of patients with ACHD is growing; more pregnancies in these patients are expected. - Pregnancy is possible in most women with ACHD, but there is an increased risk for the mother and fetus. - Strategy, potential risks, and therapy choices if necessary, should be discussed with the patient. - The risk can be diminished with proper care in a specialized ACHD center, with a multidisciplinary team available. - In our experience, the most vulnerable period is the transition from pediatric to adult care.

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