PREGNANCY & HEART DISEASE

This is a debated subject and physicians often have to take decisions considering the patients condition and the status of pregnancy which are in variance with book teachings or published periodic guidelines. Every physician is bound by an oath. A healthy outcome for the recovering mother and a thriving neonate is the desired goal. As long as the mother is living, however disfigured she might be with a growing and viable fetus in the womb, the primary responsibility of the physician is with the woman patient who has not still given a live birth. Even so he, bound by the oath, would not do or advise anything detrimental to the growth, evolution and development of the living fetus inside the mother's womb. In their case of intrauterine fetal death (IUFD) the mother is the sole patient and her wellbeing is a priority and in such situations an early evacuation along with other measures are planned.

Anatomically and physiologically there are changes in the different human sexes in accordance to specific to specific gender and societal roles. For convenience the duration a normal pregnancy is divided into three equal periods, or trimesters. It is proven by various studies that organogenesis occur and is completed in the first trimester. Evolution, increase in size and maturation if the organs happen within the mother's body till term.

Termination of pregnancy is mainly vaginal, spontaneous or assisted, and operative by Caesarian section. Many changes occur to a conceived female body during the term period and, though there may be overlaps, the principle ones are summarized as follows:--

1. Visible physical changes.

2. Psychological changes.

3. Hormonal changes

4. Modifications in the circulatory pattern.

The first indication of pregnancy in case of an adult woman is missing her periods Corroboration is done by pregnancy and other blood tests. Soon she is overwhelmed by a battery of specific symptoms, better and colloquially called "Morning sickness", though it can happen at any time. Typically there :--

1. is an increased tendency to retching and vomiting,

2.  partiality to certain types of food while developing a distaste for some other types,

3. easy fatigability,

4. cramped leg muscles and restless legs on lying down,

5.  increased frequency of urination,

6.  dyspepsia and a sense of bloating, and indigestion,

7. frequent genital itchy sensations with an higher incidence of vaginal candidiasis,

8.  altered bowel habit with more bouts of constipation.

Physical changes, which is more visible, include the following:--

1. gradual increase in size, especially the abdominal girth, with the development of stretch marks (striae gravidarum),

2. increase in size of the nipples and areolae,

3. increased pigmentation of the darkened patches,

4. new appearance of varicosities of the lower limbs indicating pressure by the gravid uterus on pelvic veins dampening venous return from lower limbs.

5. newly developed hemorrhoids (piles).

Now that a fetus is developing and growing inside the enlarging womb, some circulatory changes must occur in the circulation to meet the fetal nutritional needs. The growing fetus is oxygenated by the intricate chorionic villi of the placenta which make deep inroads into the uterine endometrium. The umbilical arteries on two sides arise from the anterior division of the internal iliac arteries and in the adults, having little function, these taper and ultimately obliterate. In the intra-uterine life, the umbilical arteries remain patent and after passing through the umbilicus of the baby entwine the, umbilical vein in a paired fashion. The umbilical vein is single and unlike other veins, transport oxygenated blood from the placenta; the umbilical arteries, on the other hand, carry mixed blood due to the patency of ductus arteriosus in intrauterine life. The umbilical cord consists of one umbilical vein intimately encircled by two umbilical arteries, embedded in Wharton's jelly and encased by a layer of amnion. The umbilical vein carrying oxygenated blood from the placenta is directed towards the liver via the falciform ligament and courses further ahead along the

left branch of the portal vein in the substance of the liver ultimately to drain in the inferior vena cava (IVC). more or less creating a straight and direct path trough the substance of the liver. On reaching the IVC, this oxygenated blood mixes with the returning venous blood and proceeds to the right atrium (RA). Blood flow inside the fetal heart differs considerably from that is in the adult heart ---- there is differential flow of blood with oxygen contents in the upper and lower chambers of the right atrium. Head-neck and upper limbs extract more oxygen and hence the venous blood returning via the SVC to the upper RA. Deoxygenated blood from the lower extremities mix with the oxygenated umbilical venous blood. Preferentially this mixed blood flows through a patent foramen ovale in the inter-atrial septum from the right atrium to left atrium and ultimately reaches the left ventricle. The left ventricle is the main pump squeezing oxygenated blood to the systemic circuit. The right ventricle, on the other hand, pumped deoxygenated venous blood, with lower oxygen saturation, into the pulmonary circulation. However, in the intrauterine fetal life, the lungs are not functional and require little blood and the majority of the flow in the main pulmonary artery is diverted to the systemic circulation via the ductus arteriosus, another shunt of variable size between the pulmonary circuit and post-subclavian descending aorta. This model also explains lower oxygen saturation of fetal blood in general while ensuring the supply of blood with highest oxygen content to the brain.

 Heart disease in pregnancy may be of the following types:--

1. Pregnancy in a woman with existing heart disease,

2. Heart disease occurring during pregnancy. .

A female subject able to conceive is almost a young adult with somewhat altered hemodynamics. The symptoms & signs are often exaggerated and early. Recognition of whether the condition is congenital, acquired or developed de novo is necessary early for appropriate management.

The usual conditions affecting a carrying female are:--

1. Congenital heart defects which escape detection in early childhood,

2. Irreparable complex congenital defects with high pulmonary artery pressure where symptoms abate temporarily during the period of equalization of pressure progressing to ultimate reversal,

3. Childhood rheumatic heart disease with damaged valves at an asymptomatic state in the normal person. As an example, the diameter of the mitral valve orifice in a healthy person is about 4 to 6 cm square and a patient becomes symptomatic only when the diameter narrows down to >than 2.5 cm square in stenotic disease and leaflets, or some portions of it, are flail leading to regurgitation of varying degrees. The compromised heart has now to bear the onslaught of an increased blood volume in a milieu of increased blood volume and the symptoms of heart failure appear early.

4. Dyslipidemia, advanced age and ischemic heart conditions are gradually increasing in number, especially among the 'so-called' educated urban populace. Delaying pregnancy with consequent advancement of age has become fashionable now and the mushrooming of in vitro fertilization and surrogacy clinics have added fodder to fire.

The physiological changes occurring in the pregnant state that may alter the symptomatology profoundly. These are:--

a). Blood volume -- During pregnancy, the total blood volume increases by about 1.5 liters, mainly to supply the demands of the new vascular bed and to compensate for blood loss occurring at delivery. Actually there is 10 to 15% increase in the plasma volume. Morphologic cellular changes, especially of the RBC, may occur but has little significance. The increase in the circulatory volume leads to a physiological anemia that, in its turn, alters the clinical hemodynamic effects within controllable limits.

b). Cardiac output -- Evidence throughout the world suggest a generalized increase in CO during the entire duration of pregnancy. The maximal rise is seen in the 24th week and cardiac echo and MRI both indicate suggest increase in left ventricular mass and end-diastolic volume. Paradoxically there is no effect on contractility or ejection fraction and changes in the myocardial mass is considered temporary remodeling.

c). Heart rate -- The heart rate of a pregnant woman is significantly high (around 20-30%) presumably as an effort at maintaining the circulation of the additional developing intrauterine conceptus.

d). Blood pressure -- In general the blood pressure in early pregnancy falls by about 10 to 20 mm of Hg, both systolic and diastolic. This state of low blood pressure continues till the early 3rd trimester and from then on there is an upward trend reaching normal levels at term.

e). Coagulability -- Hypercoagulability is a known phenomenon in pregnancy and retrospective literature search shows a higher incidence of venous thromboembolic events. There is a quantitative increase in clotting factors that may contribute. This is considered as a protective mechanism to limit blood-loss during childbirth and factors like increased of inactivity, obesity, pregnancy induced lower-limb varicosity, relatively sluggish venous flow from the lower limbs, etc., are the main reasons for the higher incidence of venous thrombo-embolic events, like deep vein thrombosis of the lower limbs and pulmonary embolism. If in addition, the red cell mass and the hemoglobin is high in the conceived subject the arterial flow is also sluggish raising the risk of miscarriages and thrombo-embolic events. Hence a "physiologic" anemia and a Hb% of 11 gm/dl is considered acceptable in pregnancy.

f). Major hormonal changes -- Estrogen and progesterone are the main hormones responsible for the maintenance and continuance of a normal pregnancy up to term. In the early stages, both are liberated by the corpus luteum and later the placenta, after proper development and anchorage, takes up the major and sole responsibility. Serum levels of both hormones quantitively increase through the trimesters and play pivotal roles in the growth and development of the fetus till term. There may be some variations in the serum estrogen levels, especially during the 1st trimester, and the early surge during the initial stages of conception is essential for endometrial proliferation and anchorage of the fertilized conceptus. Morning sickness is also attributed to this sudden estrogen surge. Progesterone is the other important sex hormone having a profound effect on the female sex. The effects are different in pregnancy where in conjunction with estrogen it is primarily responsible for decidual maintenance and growth. Progesterone primarily allow implantation of the fertilized ovum in the receptive endometrium under the influence of estrogen, and the vasogenic effect of progesterone promotes capillary endothelial growth and encroachment into the decidua that gradually encircles and nourishes the developing conceptus. The vasogenic progesterone also ensures vascularization of the growing uterus and keeps the enlarging irritable organ calm till the time is ripe. There are other hormones secreted in maternal circulation at various times of pregnancy in response to different and specific stimuli. These in short include --

a). Human chorionic gonadotropin (HCG) -- the beta subunit is commonly detected in pregnancy. This hormone is exclusively of placental origin and produced early.

b). Human placental lactogen -- as the name suggests, this is also of placental origin and is responsible for preparing the breasts for milk production after birth.

. c). Luteinizing hormone (LH) and follicle stimulating hormone (FSH) -- Primarily these hormones are involved in the maintenance of a monthly menstrual cycle in the normal human females, but their activity is also detected and a normal value is important in the maturation of the growing intra-uterine fetus.

g). Enhanced sympathetic activity.

h). Psychological changes -- sudden mood swings

i). Aldosterone-Renin-Angiotensin system -- During normal conception enhanced activation of the Aldosterone-Renin-Angiotensin system commensurate with the stages. This is a complex interactive process that helps in maintaining the fine balance of the 'hyponatremic' oncotic pressure, vasodilatation, and a developing circulatory system. Retrospective studies also suggest 40% increase in atrial natriuretic peptide levels. Intravascular nitric oxide levels are also raised, but the significance is still not clear.

As said before, heart disease in pregnancy can be of various types and awareness is necessary for guiding a conceived female subject uneventfully to a successful outcome, both for the mother and the just born baby.

When the mother herself has a congenital heart defect, even-if clinically innocuous, genetic counselling is mandatory because the probability of birth of a fetus with congenital anomaly is very high. Large, prospective, worldwide projects like the Registry Of Pregnancy And Cardiac disease (ROPAC) collect data on maternal and fetal outcomes, risk assessment, management strategies, and the efficacy of interventions to improve care for pregnant women with heart conditions.

In our country, the State of Tamil Nadu takes this issue seriously and an all-out effort is made to register every female conceived subject in the state. This appears to be a model worth following universally, Tamil Nadu Registrar of Pregnancy and Rheumatic Heart Disease (TNPHDR).

Nowadays the American College of Cardiologists (ACC)/American Heart Association (AHA) issue periodic guidelines that are accepted and followed universally. The first guideline was published in 1987 and thereafter whenever a new evidence or scientifically proven knowledge is published in a peer reviewed journal, alterations and additions are made by the authors accordingly. Specific procedural techniques or each situation is in the guideline and following the same helps a positive outcome in most cases.

In pregnancy, a 'physiologic' anemia, with a Hb% of 11 gm/dl, is preferred because a high Hb% and increased red cell content in the circulation leads to a sluggish flow that in its turn may result in a higher incidence of venous thromboembolic events (like DVT of lower limbs), lower limb varicosities, periodic morbid embolic episodes (mainly PE), etc. The chances of a miscarriage is also increased. Even though erythropoietin is produced in the mother in greater amounts, clinical polycythemia never occur. A throbbing headache may occur due to the sluggish cerebral flow.

Conceived female subjects with a correctable complex heart defect in utero should be delivered near a centre equipped with facility for neonatal cardiac surgery. In some cases like the hypoplastic left heart syndrome (HLHS) or an anomalous left coronary artery arising from pulmonary artery (ALCAPA), etc., surgery has to be initiated almost immediately.

Termination of pregnancy within 24 weeks is a legal option if on anti-natal echo-cardiac screening a complex congenital defect is detected and the quality of life even after all possible corrections will remain poor. Law permits pregnancy termination in hopeless situations with court order later as well.

Pregnancy in subjects with high pulmonary artery pressure or Eisenmengerization is risky because the already compromised heart is not able to cope with the pregnancy induced increase in blood volume and cardiac output. Right heart failure is common and even unexplained sudden death may occur.

Rheumatic heart diseases are insidious and cause pan carditis. At first they are silent and become symptomatic only when the altered hemodynamics lead to changes of certain features stretched beyond tolerable limits. Pregnancy induced circulatory changes causes the symptoms to appear earlier. Women can conceive with a pre-existing disease which was not detected earlier, or afflicted later and became pregnant with the condition. In majority of such situations the left heart valves are affected and both mitral and aortic stenosis are less well tolerated than early mild to moderate regurgitant lesions. This is primarily because of the reflex reduction of the systemic afterload in response to the regurgitant heart valve lesions. Symptoms, mainly of heart failure and cerebral hypoxia, appear later when the myocardium starts failing. In mitral and aortic stenoses the situations are different --

a). in mitral stenosis, the left ventricle chronically remains underfilled because the stenosed mitral valve between the left atrium and left ventricle prevents adequate priming of the left ventricle before each contraction, and

b). in aortic stenosis, the narrowed semilunar valve at the ventricular outflow to the systemic circulation leads to the real outflow obstruction.

This ultimate obstruction to the systemic circulation causes a state of inadequate blood-flow to organs and the early symptoms.

In regurgitant rheumatic left heart valvular lesions, the regurgitant volume, within physiological limits, is accommodated by the heart. There is a compensatory myocyte hyperplasia that allow the extra stretching required. Decompensation occur thereafter. and so the symptoms appear late.

Normal vaginal delivery at term is always preferred and a multidisciplinary team with a specialist who can calmly manage heart-related complications, like failure, arrhythmia, etc., should be present during delivery.

Anti-coagulation changes the scenario in conception and decision making becomes challenging. The various situations are --

1. A patient visits a clinician with the complaint of recurrent early abortions with resultant infertility. Investigations revealed anti-platelet antigens (APLAS) to be the cause. Such a condition mandates the use of low molecular weight heparin to prevent micro-clot formation and miscarriages.

2. Acetyl salicylic acid (commonly known as aspirin) in low doses (not more than 150 mg/dl) is routinely used in pre-eclampsia/eclampsia (suspected or when diagnosed) and similar conditions where intravascular clot formation is a probability.

3. Anticoagulation in pregnancy in prosthetic heart valve replacement subjects is a difficult advice. First it has to be determined whether the subject is aware of her heart condition and the additional risk with a pregnancy running full-term. Awareness of the partner and immediate family members/care giver is important. In fact, both partners are made aware of such a dangerous situation at the outset and the male partner should not only understand the gravity of the condition, but also agree to bear responsibility of related untoward scenarios. Prosthetic valves may be --

i). mechanical ---- durable, but requires life-long steady anti-coagulation.

ii). bio-prosthetic ---- better hemodynamics, but patient and party will have to be aware of the reality of re-replacements when needed. As anticoagulation is no longer needed after the housing and sutures have been neo-reendothelized, bioprosthetic valves (ideally homograft valves) are always recommended for young women who desire to have a family.

Meticulous planning is necessary if a mechanical prosthetic valve has been implanted. Stuck-valve situations are dangerous and may be fatal. Prevention of clot formation by timed daily oral anticoagulants and monthly prothrombin time (P-time)/International Normalized Ratio (INR) is absolute for such women. Because intra-endothelial clot formation can be devastating certain facts should be known:--

1. The novel (new) or direct oral anticoagulants (NOACS/DOACS), anti-platelet agents like aspirin, clopidogrel, etc., direct thrombin inhibitors like argotroban, monoclonal antibodies like abciximab, and direct inhibitors of factor Xa like rivaroxaban, apixaban, etc., have all been used for the prevention of DVTs, embolic PEs, embolization of intra-cardiac clots in atrial fibrillation or a myocardial infarction, risk reduction of thromboembolic cerebrovascular events, etc. Not one of the large cohort studies could exhibit a confident result that a single intra-vascular micro-clot shall not be formed while the medicine is being used.

2. Warfarin embryopathy is a recognized phenomenon and other than the hitherto

known non-teratogenic drugs, all agents are prohibited during the period of organogenesis.

3. Low molecular weight heparin (LMWH) is an interesting alternative but selection of the safe agent, the cost, and the uncomfortable thought of daily injection are against its widespread use. Also knowing whether the agent is effective or not requires assay of factor Xa that is not available everywhere and beyond the reach of most people. Furthermore, still no studies universally proclaim that LMWH can prevent clot formation on mechanical valve discs.

4. In planned pregnancy in mothers with a mechanical valve, the logical choice will be --

Stopping warfarin/other dicoumarol vitamin k antagonists as soon as the plan is confirmed-> P-time/INR estimation -> injection heparin (unfractionated), preferably s/c and multiple doses with activated clotting time (ACT) estimation and p-time/INR measurement ensuring an ACT > 400 seconds at all times and p-time/INR one and half times above the normal value (dose titration may be required). This has to be continued till the end of the period of organogenesis and evolution (if the pregnancy is confirmed).This heparin anticoagulation regime is a must for the first trimester with a spill-over to the 2nd, as confirmed by an anomaly USG scan. Thereafter, i.e. from the 2nd semester till planned termination, the usual dicoumarol regime and weaning of from injection of unfractionated heparin. The usual dicoumarol regime may continue till sometime before a planned termination of the pregnancy when injectable unfractionated heparin is restarted. The usual mode of termination in a planned pregnancy in a woman with a mechanical prosthetic valve is a Caesarian section. Obstetric monitoring always be complemented by the presence of a cardiologist. Pre-conception genetic counselling is mandatory and a 2nd counselling may be necessary after the first anomaly scan and tests for Down's syndrome.

Prospective studies currently is of the opinion that conception in a consenting female subject with appropriate care is a viable probability and Caesarian section in a heparinized mother leads to little extra blood loss. Transfusible blood of the mother's group is kept in reserve for safety and mental peace.

The half-life of UFH is not long, varying from 60 to 90 minutes, and a mandatory wait for 6 to 8 hours is needed for washing out the effects of heparin. Anticoagulation with warfarin/acenocoumalone can again be started in the post-operative period of these patients in the usual manner and no harm happens to the new-born as negligible amounts of these dicoumarols are expressed in breast milk.

If the conception is discovered suddenly, the anticoagulation regime as described, with modification in accordance with the situation, should start immediately. Then a genetic counselling should follow making the parents aware of the possible embryopathies and other defects not detectable in routine antenatal investigations and anomaly scans. The decision whether to proceed to term with the pregnancy has to be decided by the parents.

The question of anticoagulation in pregnant females with a prosthetic mechanical valve is contentious. A physician is bound by oath and cannot risk any procedure which has the chance of creating endovascular clots thereby leading to a stuck valve. A number of unrelated reports and claims using alternative anticoagulation protocol in such conditions have been published in journals These are sporadic and not unanimous. The preference for a normal vaginal delivery is preferred in most situations but pregnancy in a woman with a prosthetic mechanical heart valve is a unique situation where both the lives are precious. The practical approach is leaving nothing to chance and surgical termination at the earliest ensuring adequate lung maturation.

Bleeding during surgery is more possible in cases where myocardial ischemia or arrhythmias are treated with anti-platelet and other agents that are more effective in keeping revascularization stents and conduits open. Same is the case with LMWH, which is used in the APLA syndrome. A couple of units of platelet concentrate are needed to minimize the bleeding.

Heart disease in the pregnant female sex is rare and conception to term in a woman with a prosthetic mechanical valve even rarer. It may be a lifetime experience for a clinicians engaged in obstetrics and a knowhow of the present cardiovascular attitude towards heart disease in pregnancy may be helpful.