Sickle Cell Disease in Pregnancy

Ali Al-Ibrahim

Mrs. TH, 33 years old lady G3, P2+0. Presented at 16 weeks of gestation. Sickle Cell Disease 1-2 major painful crises per year. On/Off Hydroxyurea Frequent Blood Transfusion. Never admitted to ICU, no Acute Chest Syndrome

 This pregnancy is unplanned Not on Hydroxyurea when she conceived Husband not a carrier of Sickle Cell or other hemoglobinopathies Not on Folic Acid. First pregnancy: 31 weeks IUGR, failed induction, C-Section Second pregnancy: IUFD while admitted at 39 weeks.

 Examination showed:
Well built Jaundice Normal Vital Signs No Spleenomegaly detected Ejection Systolic Murmur Clear Chest

 Investigations:

How do I monitor disease activity? How do I prevent crises? How do I manage crises? How do I counsel the patient? What investigations do I order? What to do for the pregnancy? When to deliver the baby?

Sickle Cell Disease

One of the most common single gene disorders in the world. Certain areas in sub-Saharan Africa 40-60% of population heterozygote 1-4% of babies born have disease. HbS is resistant to P. Falciparum

Inheritance

Is it an autosomal recessive disease? Co-Dominance Phenotypically complex Association with other hemoglobinopathies
Hb SS, Hb SC, Hb SD-Punjab, Hb SO-Arab, Hb SThal, Hb SA

Phenotypes
Sickle Cell Disease is an extremely variable disease. HbSS: Disease severity is variable, HbF key factor. (Benin type HbSS, Indian Type HbSS) The presence of another type of hemoglobin modulates the severity (Sickle-Thal, HbSC, HbSD) HbSA: Heterozygous individuals

Pathophysiology
HbS polymerises on deoxygenation rigidity of erythrocyte, distorts its shape & causes structural damage in red cell membrane. Altered rheologic properties of cell impairs blood flow through microvasculature haemolysis &vaso-occlusive episodes. A Normal RBCs life span is: 120 day. A typical sickle RBCs lifespan is: 10-20 days.

Acute Painful Episodes

Recurrent episodes of severe pain in SCD Caused by microvascular entrapment of RBC & WBC obstruction in blood flow & organ ischaemia Microvascular events episodes of explosive pain & inflammation. May be accompanied by fever & leukocytosis +/- bone marrow necrosis with pulmonary emboli.

Anemia
The anemia of SCA is usually a chronic Reasonably well-compensated hemolytic anemia with an appropriate reticulocytosis. SCD variants are less anemic with an appropriate compensated reticulocytosis Hemolysis is the primary mechanism

Anemia
Factors other than chronic hemolysis can contribute to the anemia. These include:
Inappropriately low serum erythropoietin concentrations, worse in overt renal disease Folate and/or iron deficiency resulting from increased utilization of folate

Acute severe anemia

Splenic sequestration crisis Aplastic crisis Hyperhemolytic crisis

Pulmonary Complications
ACUTE COMPLICATIONS(Triad of Acute Chest Syndrome)

Infection Embolic phenomena due to bone marrow infarction and fat emboli Infarction caused by in-situ thrombosis

A working definition of ACS is the presence of the following signs and symptoms in a patient with sickle cell disease:
Presence of a new pulmonary infiltrate, not due to atelectasis, involving at least one complete lung segment Chest pain Temperature >38.5C Tachypnea, wheezing, or cough

Pulmonary Complications
Sickle cell chronic lung disease Essentially progressive lung fibrosis Alterations in baseline pulmonary function:
Total lung capacity and vital capacity may be reduced. Arterial oxygen saturation (SaO2) is reduced, with steady-state baseline values below 96 percent in an appreciable percent of patients. Even when corrected for anemia, the diffusing capacity for carbon monoxide (DLCO) is abnormally low, particularly in patients with a history of the acute chest syndrome.

Pulmonary Complications
The alveolar-arterial difference is widened both at rest and with exercise, which most likely results from ventilation and perfusion abnormalities. Mild to moderate airflow obstruction may be present, particularly among patients with recurrent episodes of acute chest syndrome Pulmonary Hypertension

Neurologic complications
24% of individuals with sickle cell anemia experienced a clinical overt stroke by age 45 Risk for neurocognitive decline and intracranial hemorrhage Chronic transfusion therapy is the mainstay therapy for patients with overt central nervous system injury

Cerebrovascular events
Transient ischemic attacks Infarctive stroke Intracerebral hemorrhage Spinal cord infarction or compression Vestibular dysfunction Sensory hearing loss Cognitive impairment may occur as a consequence of vascular disease and/or silent cerebral infarcts.

Multiorgan failure
Potentially fatal acute multiorgan failure syndrome is most often seen during severe pain episodes in patients with SCD Aggressive exchange transfusion therapy

Infection
The patient is susceptible to overwhelming infection by encapsulated organisms, especially Streptococcus pneumoniae and Haemophilus influenzae. Dysfunctional IgG and IgM antibody responses Defects in alternative pathway fixation of complement, and opsono-phagocytic dysfunction may also play a role in the predisposition to invasive infection

Bone Complications
Bone infarction and necrosis Osteonecrosis Pulmonary fat embolism is a complication of bone marrow infarction Orbital compression syndrome Osteomyelitis

Cardiac complications
Common, often unrecognized No specific cardiomyopathy in Sickle Cell Disease Chronic Anemia leads to increased cardiac output and enlarged chambers Myocardial infarction without coronary disease

Hepatobiliary complications
Acute hepatic ischemia Benign cholestasis Hepatic sequestration crisis Transfusional iron overload Acute and chronic cholelithiasis secondary to pigmented gallstones Acute and chronic liver disease secondary to hepatitis C virus infection (HCV) complicating blood transfusion Drug toxicity (eg, deferasirox, hydroxyurea)

Renal complications
Enuresis secondary to hyposthenuria Painless hematuria due to papillary infarcts Proteinuria and hypertension Renal infarction, papillary necrosis, and renal colic Nephrogenic diabetes insipidus that can lead to polyuria Focal segmental glomerulosclerosis that can lead to end-stage renal disease Renal medullary carcinoma is a malignancy found almost exclusively in black patients with HbSC disease or sickle cell trait.

Other complications
Retinopathy: proliferative retinopathy, retinal artery occlusion, and retinal detachment and hemorrhage Priapism Leg ulcers Meningitis specifically in Children Growth failure and delayed puberty Psychosocial issues

Pregnancy and Sickle Cell Disease

Pre-conceptional Counseling is of paramount importance. Combined clinic ideal Partner testing/PND discussion Pattern and frequency of crises Previous CVA, infarction, VTE Analgesic dependency Transfusion history Echocardiography

More Counseling
Immunization status Antibiotics prophylaxis Renal and hepatic status Cardiopulmonary status Eye status High dose folic acid Past Obstetric history Individualized care plan

If the patient is on Hydroxyurea

The safety of Hydroxyura in pregnancy is unclear. Very large doses in animals are teratogenic, but no teratogenicity ever reported in humans Follow up of children inadvertently exposed to HU shows no major anomalies or complications Avoid pregnancy while on HU If pregnant while on HU, Stop and termination

Suitability of PGD
If infertile, it would be ideal If the patient can not have a termination of pregnancy Not suitable for majority of couples Stressful, time-consuming, requiring high level of commitment Only 15-20% of PGD cycles result in babies Reduces risk rather than eliminates - roughly 5% failure rate, due to limitation of single-cell analysis

Problems with CVS/Amnio

What happens after the diagnosis? Dependent on the population and health practices National Programs proved VERY successful

Non-invasive Fetal Diagnosis

Isolation of fetal DNA from maternal blood
small amounts of free fetal DNA present in maternal plasma technically easy to concentrate and analyse by PCR limited application - dominant diseases, screening for paternal contributions to compound heterozygous states currently being developed at Kings College Hospital for HbSC and HbSS

Maternal Complications

 The maternal mortality rate was 72 deaths per 100,000 in SCD compared with 12.7 deaths per 100,000

Fetal Complications
Fetal complications are usually related to compromised placental blood flow and include the following:
Spontaneous abortion Intrauterine growth restriction Increased rate of fetal death in utero Low birthweight Preterm delivery

Goals of Antenatal Care

To give appropriate care to ensure healthy mother and baby Avoidance and early treatment of crises Low threshold for admission if unwell Screening of partner and offer prenatal diagnosis where indicated Multidisciplinary Care

Dating scan to reduce postmaturity Uterine artery doppler (Placental Ultrasound) Growth Scan and BPP Delivery between 38-40 weeks if not indicated earlier for obstetric reasons Prevent dehydration High incidence of alloimmunization

 Maternal crises are usually treated as in nonpregnant women, with some exceptions:
Medications such as nonsteroidal anti-inflammatory drugs and hydroxyureacan be teratogenic and are contraindicated during pregnancy. Iron chelation therapy should be stopped once pregnancy is recognized. Urinary tract and pulmonary infections should be diagnosed promptly and treated with appropriate antibiotics. Close monitoring of blood pressure and hemoglobin throughout the pregnancy is necessary.

Iron and Folate

Sickle Cell Disease patients require folate supplementation No Iron supplementation without Iron studies (Ferritin, Transferrin and TIBC)

Prophylactic Transfusion
Pregnancy in sickle cell disease in the UK: results of a multicentre survey of the effect of prophylactic blood transfusion on maternal and fetal outcome. Howard RJ, Tuck SM, Pearson TC. Br J Obstet Gynaecol. 1995;102(12):947 A randomized, controlled trial in 72 patients found no significant difference in perinatal outcome between the offspring of mothers with SCD treated with prophylactic transfusions and those who were not

Prophylactic Transfusion
Prophylactic transfusion significantly reduced the incidence of painful crises. This advantage must be weighed against the associated increases in cost, number of hospitalizations, and risk of alloimmunization.

When painful crises strike

Hydrate, hydrate, hydrate, hydrate, hydrate Proper analgesia Low threshold for admission Low threshold to start antibiotics Painful crises in pregnancy are seldom solitary, monitor for hemolysis and acute chest syndrome When in doubt, give blood MgSO4 Dont miss HELLP Syndrome