CONTRACEPTION, PREGNANCY and SICKLE CELL DISEASE

People with sickle cell disease (SCD) who are of childbearing age have many choices regarding family planning. Counseling includes discussion of contraception, complications of pregnancy outcomes, and the importance of maintaining good health habits, including taking folic acid and iron, if needed. Patients should also receive genetic counseling and their partners should be offered testing to determine the presence of a hemoglobinopathy. Both should then be counseled about their chances for having an infant with sickle cell disease.

Table 1. Complications of Pregnancy in Women with Sickle Cell Disease

Maternal	Fetal
Preeclampsia (14%)	Miscarriages (6%)
Eclampsia (1%)	Stillbirth (1%)
Pyelonephritis (<1%)	Small for gestational age, <10th percentile (21%)
Placenta previa (1%)	Premature, <37 weeks at birth (27%)
Rupture of membranes (6%)
Premature labor (9%)
*Acute anemic event (3%)
Maternal mortality (0.45%)
*defined as decrease in hemoglobin levels by 30% of baseline Data are based on study of 445 pregnancies in 297 women (predominantly in women with Hb SS) recorded between 1979 and 1986 in 19 centers participating in the Cooperative Study of Sickle Cell Disease (ref. 1).

In a large multicenter observational study (1), hypertension was the most common complication during pregnancy for women with SCD (see table). One-fifth of the pregnancies produced preterm deliveries and infants that were small for gestational age. No increase in the frequency of pain crises occurred during pregnancy. Ninety-nine percent of the pregnancies carried to 28 weeks gestation produced live deliveries. This study debunked a widely held and unsubstantiated belief that pregnancy is contraindicated for women with SCD. However, prenatal care for women with SCD should be managed by a multi-disciplinary team that includes an obstetrician, nutritionist, primary care physician and hematologist. The team must decide who will be responsible for each aspect of the patient's care. Close monitoring combined with prompt diagnosis and aggressive treatment of complications during the prenatal and neonatal period by a multidisciplinary team will produce better outcomes.

CONTRACEPTION

Oral contraceptives as well as contraceptive agents administered intramuscularly and barrier methods are all acceptable choices for women with SCD. Few studies have evaluated oral contraceptives in this population, but none showed adverse effects (2). Intrauterine devices are not optimal, since they may be associated with uterine bleeding and infection in any user, regardless of the presence of SCD.

CONSULTATION CONCERNING IMPACT OF NEWER TREATMENTS ON PREGNANCY

Hydroxyurea: Women and men who are taking hydroxyurea should use contraceptive methods and discontinue the drug if they plan to conceive a child, since hydroxyurea is in animal models. If conception accidentally occurs when either partner is taking hydroxyurea, the couple should be told that a paucity of information exists on which to determine the effect of hydroxyurea on the fetus. However, in the 14-15 cases in which hydroxyurea was taken throughout pregnancy, no fetal malformations occurred (3,4).

New technologies in preventing or curing sickle cell disease: A few centers are developing a technique known as preimplantation selection (5). In this procedure, eggs from the mother are fertilized in vitro and those that do not contain markers for sickle cell disease are implanted into the mother's uterus. This variation of the commonly available in vitro fertilization technique (IVF) requires great expertise in manipulating the fertilized cells. Other members of the team must be expert in the analysis of minute amounts of DNA, the genetic material that determines whether the child will have sickle cell disease. The need for leading experts in two medical and scientific areas severely limits the availability of this approach to preventing sickle cell disease in the children of couples at risk.

Cord blood transplant is a more widely available option for couples with a child who is severely affected by sickle cell disease (6). Cord blood from subsequent newborns who have normal hemoglobin or sickle cell trait can be used as a source of hematopoietic stem cells. A bone marrow transplantation can cure the child with sickle cell disease. The probability that cord blood from a later sibling will be an HLA match is, of course, only 25%. Although the risks are lower, cord blood transplantation nonetheless runs the risk of significant complications in the recipient including graft-versus-host disease. For some children, however, transplantation is literally a new lease on life. Providers should inform eligible couples of the option early in the pregnancy to allow training and coordination of the obstetrics team by the cord blood donation program. The Chidlren's Hospital of Oakland Research Institute trains the obstetricians, collects and stores the cord blood stem cells without charge for couples with children affected by sickle cell disease or thalassemia.

MANAGEMENT OF PREGNANCY

PRENATAL CARE

The prenatal assessment visit allows counseling and an outline of care for the duration of the pregnancy. The primary focus is to identify maternal risks for low birth weight, pre-term delivery and genetic risks for fetal abnormalities. The physician reviews and discusses the behavior and social patterns that place the patient at risk for sexually transmitted diseases, illicit drug use, alcohol and tobacco use, and physical abuse. The prenatal assessment also allows the couple to voice questions and concerns.

The correlation of placenta previa with prior uterine surgery makes a history of previous cesarean section or uterine curettage key items in the prenatal evaluation. Adequate nutritional assessment and avoidance of factors that precipitate painful events should emphasized with each visit. The patient's pre-pregnant weight, height, and optimal weight gain in pregnancy should be recorded. Physical exam should also include determination of splenic size.

The initial comprehensive laboratory studies should include a complete blood count with a reticulocyte index, hemoglobin electrophoresis, serum iron, total iron binding capacity (TIBC), ferritin levels, liver function tests, measurement of antibodies to hepatitis A, B, and C, as well as HIV, urine examination and culture, electrolytes, blood urea nitrogen (BUN), creatinine, blood type and group, and red cell antibody screen. Rubella antibody titre, tuberculin skin test, pap smear, cervical smear, and gonococcus culture and screening for sexually transmitted diseases as well as bacterial vaginosis should also be performed.

A baseline hemoglobin concentration of 6-8 g/dL is typical for patients with sickle cell disease along with a high reticulocyte count and sickle cells on the peripheral smear. Microcytosis often reflects associated thalassemia and/or Iron deficiency. Women who are doubly heterozygous for hemoglobin SC  or sickle ß(+)-thalassemia often have higher hemoglobin levels that range between 9-12 g/dL. A low reticulocyte count can reflect inflammation, infection, or deficiencies of folate or iron which can suppress the bone marrow response. The rate of hemolysis can be gauged by the bilirubin levels, LDH values and reticulocyte count.

Abnormal liver function tests can reflect chronic hepatitis, acute cholecystitis, cholelithiasis or other causes of liver toxicity. Screening for red cell antigens that commonly cause alloimmunization (Rh C and E as well as Kell antigens) will allow the blood bank to provide phenotypically matched units if transfusions are needed.

Hepatitis vaccine should be administered when appropriate for hepatitis B negative patients. If asymptomatic bacteruria is found, the patient should receive antibiotics in order to prevent urinary tract infection and pyelonephritis.

Return visits are recommended two weeks after the initial visit. Low risk patients are scheduled for monthly visits until the 2^nd trimester when they should be seen every two weeks and in the 3^rd trimester every week. Maternal serum should be obtained between 15 and 18 weeks to assess alpha fetoprotein levels to determine risk of neural tube defect. The concentration of human chorionic gonadotrophin and estriol should also be measured in order to assess the risk of trisomy 21 or 18 in the fetus.

Uterine growth is usually assessed by measuring fundal height. Ultrasound should be performed for specific obstetric indications. Examination of the cervix, clinically or by vaginal ultrasound, is done in the 2^nd and 3^rd trimester to determine risk for pre-term labor.

Recognition of Pregnancy-Induced Hypertension and Diabetes

For women with SCD, preeclampsia and severe anemia have been identified as risk factors for delivering infants that are small for their gestational age (1). In the study described in the table, the incidence of preeclampsia (defined as BP>140/90 mmHg, proteinuria of >300 mg/24 hours, and pathological edema), and eclampsia (seizures in addition to features of preeclampsia) in pregnant women with sickle cell disease was 15% (1). The precise reason for the high incidence of hypertension in this patient population is unclear. Multiple factors such as placental ischemia and endothelial injury have been implicated, however. Other known risk factors for preeclampsia, even in women without sickle cell disease, are nulliparity, a history of renal disease or hypertension, multiple gestation, and diabetes (7).

The blood pressures in non-pregnant individuals with SCD tend to be in a lower range than that of women without hemoglobinopathy (90/50 to 110/70). Pregnant women with SCD should be observed closely if blood pressure rises above 125/75, or if the systolic BP increases by 30mm Hg, or the diastolic by 15mm Hg, in association with edema and proteinuria in the second trimester. Preeclampsia, which requires frequent monitoring, can be treated with bed-rest at home or in hospital, if needed. If preeclampsia is worsening, delivery of the fetus may be required if the gestational age is greater than 32 weeks. Expedited delivery is recommended for uncontrolled hypertension.

Women generally should be screened for diabetes at 26 weeks gestation with a 50 gram oral glucose challenge. If the blood glucose remains over 140mg/dL after one hour, further evaluation is necessary.

Indications for Blood Transfusion During Pregnancy

The role of prophylactic transfusions in pregnancy is controversial. One randomized trial (8) and a retrospective study (9) concluded that routine prophylactic transfusions from the onset of pregnancy do not alter the outcome for the fetus or mother. However, one additional study, also retrospective in nature, concluded that prophylactic transfusions, if initiated at about 20 weeks, may be beneficial (10). A realistic approach is to avoid routine prophylactic transfusions for uncomplicated pregnancies but to consider transfusions for women who have complications such as preeclampsia, severe anemia, or increasing frequency of pain crisis (11). Women who have had previous pregnancy losses or who have multiple gestation may benefit from the early use of transfusions to maintain the hemoglobin level, above 9 g/dL (11).

Women should receive leuko-reduced packed red blood cells that have been phenotyped for major and minor antigens as discussed above. If the primary goal of transfusions is to reduce the percent of hemoglobin S and the hemoglobin level is high, one approach is to remove 500 ml of whole blood and transfuse 2 units of packed red blood cells. This procedure can be done manually or by automated methods to obtain a post transfusion hemoglobin level ranging between 10 and 11 g/dL and to reduce the percentage of hemoglobin S to 30-40% of the total hemoglobin concentration.

SICKLE CELL RELATED EVENTS DURING PREGNANCY

The clinical problems of SCD, such as chronic hemolytic anemia, vasoocclusion, ischemic injury and organ damage also need to be addressed during pregnancy.

Painful Crisis

The frequency of previous acute vasoocclusive painful crisis episodes is usually predictive of the anticipated events during pregnancy, although some patients may experience more frequent pain crises (12,13). Pregnant women with a painful crisis should be evaluated and treated in the same fashion as nonpregnant women. Patients with a chronic pain syndrome often benefit from an individualized care plan. The obstetricians and the neonatologists must communicate clearly on the issue of prenatal opiod pain control. Opiods do not harm the fetus. The newborn will require an opiod-taper program t oavoid withdrawl complications, however.

Seizure Disorder

Patients with sickle cell disease have a high frequency of neurological events. Thrombotic strokes are most common in childhood. A careful history can ferret out the details of a past stroke that left few clinical sequelae by which could predispose the mother to seizures. New onset seizures can be induced by either thrombosis, hemorrhage, hypoxia, excessive use of meperidine and/or complications of hypertension. If a sickle cell-related central nervous system complication is diagnosed, the patient should receive transfusion therapy with the goal of reducing the hemoglobin S level to less than 30% and maintaining a hemoglobin level of 10-11 g/dL during the remainder of pregnancy.

Hepatopathy

Acute and chronic events involving the right upper quadrant have been collectively referred to as sickle hepatopathy. The diagnosis and management are similar to that for nonpregnant individuals.

Acute Anemia and Splenic Sequestration

If the patient suddenly develops severe anemia, the differential diagnosis includes external blood loss, suppression of the bone marrow by infection, inflammation, deficiency of iron, folic acid or B12, red cell aplasia or aplastic crisis due to parvovirus B19, hyperhemolysis, and sequestration syndrome. Acute splenic sequestion is manifested by abdominal pain, a rapidly enlarging spleen and a dramatic decrease in the hemoglobin level by 30% or more from the baseline values. In this situation transfusion can be lifesaving.

Acute Chest Syndrome

This complication usually presents with fever, cough, pleuritic chest pain, pulmonary infiltrates, leukocytosis and occasionally severe hypoxemia. The pregnant patient should be evaluated and treated in the same fashion as the nonpregnant patient.

INTERRUPTION OF PREGNANCY

If interruption of pregnancy is considered at less than 13 weeks, analgesia rather than anesthesia is usually all that is required for suction curretage. Beyond 13 weeks hypertonic urea solutions are injected into the uterus and contractions are stimulated with prostaglandin F2. Hypertonic sodium chloride should not be injected because it can cause sickling. Rh-negative women should receive Rh immunoglobulin after therapeutic or spontaneous abortion. Newer methods for medical termination of pregnancy are available but their use has not been extensively described in women with SCD (14).

LABOR, DELIVERY, POSTPARTUM CARE AND COUNSELING

Cardiac function can be compromised because of chronic hypoxemia and anemia, and oxygen therapy may be helpful. During labor, fetal monitoring is useful to detect fetal distress, which can require prompt delivery by cesarean section. If surgery appears imminent, simple transfusion or rapid exchange transfusion can be beneficial depending on the baseline hemoglobin levels. The postpartum patient may require transfusion if she has undergone extensive blood loss during partuition. Venous thromboembolism can also complicate the postpartum course. Early ambulation lowers the risk of venous thrombosis.

Counseling is also an important component of postpartum care. Results of the screen for sickle cell disease in the infant should be made available to the mother and father as well as to the pediatrician. Contraception and plans for future pregnancies should also be discussed. If a woman is considering not undergoing future pregnancies, she can receive preliminary counseling about tubal ligation for permanent birth control. Couples who contemplate future pregnancies should be informed of the option of cord blood storage. Cord blood from a child with sickle cell trait or normal hemoglobin can be banked against the risk of a future sibling afflicted with sickle cell disease. Therefore, cord blood storage should be considered by couples at risk for children with sickle cell disease even if they have not had an affected child.

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REFERENCES

1. Smith JA, Espeland M, Bellevue R, Bonds D, Brown AK, Koshy M. Pregnancy in sickle cell disease: experience of the cooperative study of sickle cell disease. Obstet Gynecol 1996; 87: 199-203.
2. Freie HMP. Sickle cell disease and hormonal contraception. Acta Obstet Gynecol Scand 1983; 62:211-17.
3. Diav-Citrin O, Hunnisett L, Sher GD, et al. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am J Hematol 1999; 60: 148-150.
4. Byrd DC, Pitts SR, Alexander CK. Hydroxyurea in two pregnant women with sickle cell anemia. Pharmacotherapy 1999; 19:1459-1462.
5. Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation diagnosis for sickle cell anemia. JAMA 1999;281:1701-1706.
6. Reed WF, Trachtenberg E, Walters MC et al. Comprehensive sibling donor cord blood banking for children with malignant and non-malignant disease. Blood 2000;96:452a.
7. Repke JT. Intrapartum preeclampsia and hypertension. In. Intrapartum Ostetrics, ed Repke JT, Churchill Livingston, 1996.
8. Koshy M, Burd L, Wallace D, Moawad A, Baron J. Prophylactic red cell transfusion in pregnant patients with sickle cell disease. A randomized cooperative study. N Engl J Med 1988; 319:1447-1452.
9. Tuck SM, James CE, Brewster EM, Pearson TC, Studd JW. Prophylactic blood transfusion in maternal sickle cell syndromes. Br J Obstet Gynaecol 1987;94:121-125.
10. Morrison JC, Morrison FS, Floyd RC, et al. Use of continuous flow erythrocytapheresis in pregnant patients with sickle cell disease. J Clin Apher 1991; 6:224-229.
11. Koshy M, Chisum D, Burd L, et al. Management of sickle cell anemia and pregnancy. J Clin Apher 1991; 6:230-233.
12. Koshy M, Burd L, Dorn L, Huff G. Frequency of pain crisis during pregnancy. Prog Clin Biol Res 1987; 240:305-311.
13. Koshy M, Leikin J, Dorn L, Lebby T, Talischy N, Telfer MC. Evaluation and management of sickle cell disease in the emergency department (an 18-year experience): 1974-1992. Am J Therap 1994; 1:309-320.
14. Christin-Maitre S, Bouchard P, Spitz I. Medical termination of pregnancy. N Engl J Med 2000;342:946-956.

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