Obstetrics and Gynecology

Sickle-cell anemia

Sickle-cell Anemia

1. Clinical Decision Support Digital Program for Obstetrics

Pathophysiology

The sickle hemoglobin molecule is a result of a gene mutation that substitutes a valine for glutamic acid at the sixth position in the hemoglobin beta-subunit rendering the molecule less stable than the Hgb A structure. In the presence of hypoxia, infection, dehydration and other triggers, a structural change occurs in the unstable Hgb S molecule leading to the characteristic sickle shape. These malformed RBCs can subsequently precipitate microvascular occlusion leading ultimately to tissue infarction. The hyperviscosity of pregnancy can exacerbate this process leading to significant maternal-fetal morbidity. The life of the deformed RBC is only 12 days compared to a normal RBC (120 days). This eventually leads to a state of chronic anemia and increased clearance of the malformed cells by the reticuloendothelial system.

Screening

Universal screening of pregnant patients for sickle cell disease is not recommended. However, the disease is more common in certain ethnic groups such as African-Americans and has been observed in Hispanic-Americans. Because of the increased maternal-fetal morbidity associated with this disease process, screening in this group of patients, especially African-Americans, is considered relevant. Anemia and vaso-occlusive episodes are the hallmark of this disease process, but the majority of patients that are afflicted with sickle cell disease will have already had the diagnosis made prior to their reproductive years because of childhood hematologic or vaso-occlusive crises. Screening in those who are potential carriers (carrier prevalence is 1:12 in African-Americans) is warranted due to potential pregnancy complications associated with the carrier status in addition to providing appropriate genetic counseling to patients and their families about their child's risk of sickle cell disease.

Screening Tests

Solubility tests (e.g., Sickledex®) alone are inadequate for the diagnosis of sickle cell disorders because they cannot distinguish between the heterozygous (i.e., carriers) and homozygous (i.e., sickle cell disease) genotypes. Those patients who are considered high risk for being carriers should undergo a hemoglobin electrophoresis. Patients that are anemic and have lower mean corpuscular volumes (<80 fL), should also undergo evaluation for iron deficiency. If sickle cell disease or trait is identified, then the partner should also be tested. If the partner is found to be affected, antenatal diagnosis should be offered which includes fetal DNA testing utilizing either chorionic villus sampling at 10-12 weeks or culturing of amniocytes after 15-16 weeks. Free fetal DNA testing for sickle cell disease is being investigated but is not commercially available in the United States at this time.

Sickle Cell Trait Management and Concerns

A common problem observed in pregnant patients with the sickle cell trait is an increased rate of urinary tract infection. Some observational studies have demonstrated increased rates of stillbirth, spontaneous miscarriage, and intrauterine growth restrictions while other observational studies have shown no difference in baseline risks. Due to the lack of sufficient supporting evidence, our recommendation is routine obstetrical management with routine monthly urinalysis in patients that are sickle cell carriers in addition to partner testing and genetic counseling.

Sickle cell disease: maternal-fetal implications

Women with sickle cell disease are at an increased risk of experiencing both medical complications (e.g., pyelonephritis, thromboembolic events, and stroke) and pregnancy-related complications (e.g., pre-eclampsia, eclampsia, preterm labor, placental abruption, endometritis). Fetal complications are often related to disruptions in placental blood flow due to sickling in the tortuous arcuate uterine vessels, leading to increased rates of miscarriage, intrauterine growth restriction, stillbirth, and low birth weight.

Prenatal management

Many non-pregnant patients take hydroxyurea in an attempt to decrease the frequency of vaso-occlusive crises. Due to the paucity of data that exists with regard to its use during pregnancy, this medication should be discontinued, preferably prior to conception. Also, antiplatelet drugs have shown promise among children and adolescents in reducing painful crises but are not used during pregnancy. Additionally, patients should be seen every 1-2 weeks for prenatal evaluation and should be started on 4 mg of folic acid daily due to high red blood cell turnover. Complete blood counts should be obtained monthly and as deemed necessary. Initial iron studies should be performed (serum iron and ferritin) to determine whether iron supplementation is appropriate due to the risk of iron overload in these patients.

Ensure that the patient has received the pneumococcal and meningococcal vaccines in the past 5 years due to the patient's susceptibility to encapsulated bacteria as a result of autosplenectomy (a common finding in sickle cell patients). Neither vaccine is contraindicated during pregnancy. Additionally, we routinely collect a 24-hour urine assessment of protein and creatinine early in the pregnancy due to the risk for underlying microvascular disease leading to an increased risk for the development of preeclampsia.

Currently, the only cure for sickle cell disease is a bone marrow transplant. Because sibling donor cord blood can be used for marrow transplants without undergoing painful marrow harvesting, the option of cord blood banking should be discussed early in pregnancy. Families should be advised that cord blood banking is available at no cost, even with private cord blood banks, if a family history of a transplant treatable disease (e.g., sickle cell disease) is present.

In 2012 the American College of Chest Physicians’ Evidence-Based Clinical Practice Guidelines recommended that pregnant sickle cell patients that are hospitalized for any reason should receive medical thromboprophylaxis with Lovenox® 40 mg daily or heparin 5,000-10,000 units subcutaneously twice daily, if they are not actively bleeding. Mechanical prophylaxis (e.g., sequential compression devices) is advised in those hospitalized patients who are actively bleeding.

Antepartum testing

Weekly fetal assessments in the form of non-stress testing or biophysical profile should be initiated at 32-34 weeks. Please note that antenatal testing performed during a sickle cell pain crisis can by complicated by the use of opiates which can transiently affect the interpretation of these tests. Caution must be used when evaluating these tests, because they may not be predictive of increased perinatal morbidity and mortality in the absence of other findings. These non-reassuring events are often self-limited and resolve with routine intrauterine resuscitative efforts.

A baseline ultrasound at 18-20 weeks should be obtained, followed by repeat sonography targeting interval fetal growth at 24-26 weeks and then every 3-4 weeks until delivery. The addition of umbilical artery Doppler assessment during growth evaluation is prudent due to the increased risk for placental dysfunction.

Intrapartum management

Patients with sickle cell disease can anticipate a routine term delivery in the absence of other obstetrical or medical factors that would dictate otherwise. Adequate IV hydration, laboring in the left lateral recumbent position, supplemental oxygen via nasal cannula at 2-4 L/min with continuous pulse oximetry and cautious monitoring of the patient's temperature with measures taken to avoid her core temperature from dropping below 96 degrees Fahrenheit, are all actions that will reduce the risk of a crisis from occurring during this time. Regarding anesthetic care, it appears that regional anesthesia is superior in controlling a pain crisis during labor and likely decreases rates of exacerbation in the postpartum period. In contrast, general anesthesia can result in significant increases in postpartum sickling complications.

We recommend collection of cord blood at birth to establish if the newborn has evidence of a hemoglobinopathy and additional consideration should be given for cord blood banking if the parents have been counseled appropriately and wish to proceed with this process.

Postpartum management

Adequate intrapartum management decreases the likelihood of postpartum crises. Cautious observation for postpartum urinary tract infections and endometritis is warranted. These patients are at an increased risk for pulmonary edema (microvascular damage from sickling) and thromboembolic events. Thromboprophylaxis with Lovenox® 40 mg subcutaneously daily should be considered in all patients until they are ambulatory and discharged.

Contraception

The Centers for Disease Control modified the World Health Organization recommendations for medical eligibility criteria for contraceptive use in 2010. The use of contraceptive options such as progestin only pills, depot medroxyprogesterone acetate, and levonorgestrel-releasing implants/intrauterine devices should be considered safe and used without restriction in sickle cell patients. Additionally, the use of combined oral, transdermal, or vaginal ring hormonal contraception or those utilizing the copper intrauterine device should be considered methods that generally outweigh the theoretical or proven risks.

Chronic pain

Many health care providers caring for pregnant women with sickle cell disease are not familiar with the chronic, severe pain that is associated with long standing disease. Permanent damage to the microcirculation secondary to years of recurrent sickling is the likely etiology of this affliction. Fibrosis and scarring of cartilage and bone can lead to permanent damage and in some instances, avascular necrosis. In addition to analgesic medications, cognitive/behavioral therapy should be considered in order to enhance coping strategies. Caregivers must recognize that the use of opioids for acute pain attacks is appropriate and that withholding this treatment due to the fear of addiction can lead to inadequate treatment and is unwarranted. The patient also needs to be counseled about the increased risks for neonatal abstinence syndrome. Some information in the literature would suggest that the risks for neonatal abstinence syndrome increase linearly as maternal opioid doses are increased.

Acute pain crisis

Episodes can affect any area of the body with the back, chest, extremities, and abdomen being most commonly affected. The duration of these episodes is variable, ranging from 2-7 days and the intensity can range from minimal to severe. Objective complaints of fever, nausea, emesis, swelling, focal tenderness to palpation, and shortness of breath often accompany these episodes. Initial medical assessment should focus on detection of the following medical complications requiring specific therapy: infection, dehydration, acute chest syndrome (fever, tachypnea, chest pain, hypoxia, radiologic chest infiltrates), severe anemia, cholecystitis, abdominal crisis, and neurologic events (cerebral infarct/hemorrhage, TIA). However, the majority of these episodes will have no identifiable cause. There are no laboratory tests to diagnose an occlusive pain crisis. We typically order a CBC, peripheral smear, and hemoglobin electrophoresis to help guide therapy if transfusion is warranted. An arterial blood gas should be obtained if hypoxemia is suspected.

Pain crisis treatment

If the patient is not in labor and is remote from term, bed rest with vigorous hydration and pain management is standard. In the absence of cardiopulmonary disease, infusion of a liter of lactated Ringer's solution during the first 2-hour period with continued replacement at 125 mL/hour should be undertaken. Oxygen should be administered at 3-6 liters/minute by tight face mask or nasal cannula. Opiates are considered superior when managing acute crises but as the pain improves, non-opiate analgesics (e.g., acetaminophen) are preferred. If the vasoocclusive crisis is refractory, exchange transfusions maybe helpful. If an infection is suspected, then administration of a broad-spectrum antibiotic (e.g., ceftriaxone; clindamycin if patient has penicillin/cephalosporin allergy) should be initiated after appropriate cultures are obtained. However, if the cultures are negative and other sources of infection are ruled out, then the antibiotics should be discontinued promptly.

Acute anemic crisis

Acute anemic crises are rare in the pregnant patient and can most likely be attributed to splenic sequestration (unlikely in adulthood), aplastic crisis, and delayed transfusion reaction. Aplastic crises are more common in childhood and are often associated with the parvovirus or other infectious etiologies. It commonly presents with abrupt anemia with reductions in red cell precursors including reticulocytes (reticulocyte count <1%). Delayed transfusion reactions (i.e., occurs days to weeks after transfusion) present with a falling hematocrit, low-grade fever, and increased serum unconjugated bilirubin and spherocytosis on peripheral smear. No treatment is required in most situations, other than replacement of RBCs, if indicated.

Transfusion

Prophylactic transfusions have been shown to decrease the risk for painful crises and severe anemia and in recent systematic reviews have suggested a positive effect on pregnancy outcomes. Additionally, transfusions come with the risk for blood borne infections, iron overload, and alloimmunization (18-36% of sickle cell patients are alloimmunized). We consider exchange or simple transfusions in patients with clinical complications such as worsening anemia, recent intra-partum hemorrhage, septicemia, refractory pain crises, acute chest syndrome, and those requiring cesarean delivery. We utilize exchange transfusions via erythrocytaphoresis (automatic or manual) in patients remote from term and who are not considered to have an imminent threat for delivery. In those patients where delivery is considered imminent, direct (simple) transfusion is used, as it is more readily available.

Transfusion goals

When an exchange transfusion is clinically indicated, the objective is to lower the percentage of Hgb S (measured via electrophoresis) to <40% while simultaneously raising the hemoglobin concentration to 9-12 g/dL. Generally, 6 units of donor leukoreduced, CMV negative, Hgb A-containing packed red blood cells that have been typed and matched for major and minor antibodies, are given while irreversibly sickled cells are removed from the opposite arm. The use of blood from family members or friends matched for recipient and donor red cell antigens is clinically helpful in reducing the number of post transfusion crises.

Transfusion alternatives

We have occasionally experienced situations where transfusion was felt to be necessary for maternal-fetal benefit but the transfusion was not possible due to religious beliefs or due to the presence of multiple blood antibodies and the lack of appropriately cross-matched blood. In these situations, success with fluid resuscitation and administration of epoetin alfa, 40,000-60,000 units 2-3 times per week until hemoglobin concentrations reached values >8 g/dL yielded positive results. Adverse fetal effects in an animal model have been reported including growth restriction and delayed ossification but other studies suggest that epoetin does not cross the human placenta and it is likely the benefits outweigh the potential risks.

Adverse fetal effects in an animal model have been reported, including growth restriction and delayed ossification, but other studies suggest that epoetin does not cross the human placenta and it is likely that the benefits of using this medication in this special subset of pregnant patients would outweigh the potential risks.

These non-reassuring events are often self-limited and resolve with routine intrauterine resuscitative efforts (i.e., positional changes, IV fluids, maternal oxygen administration). A baseline ultrasound at 18-20 weeks should be obtained followed by repeat sonography targeting appropriate fetal growth at 24-26 weeks and then every 3-4 weeks until delivery. The addition of umbilical artery Doppler assessment during growth evaluation is prudent due to the increased risk for placental dysfunction.

Complications

Women with sickle cell disease are at increased risk to experience both medical complications (e.g., pyelonephritis, thromboembolic events and stroke) and pregnancy related complications (e.g., pre-eclampsia, eclampsia, preterm labor, placental abruption, endometritis). Fetal complications are often related to disruptions in placental blood flow due to sickling in the tortuous arcuate uterine vessels, which leads to increased rates of miscarriage, intrauterine growth restriction, stillbirth and low birth weight.

What is the evidence for specific management and treatment recommendations

"ACOG Practice Bulletin No. 78: Hemoglobinopathies in pregnancy". Obstet Gynecol. vol. 109. 2007 Jan. pp. 229-237.

"NHLBI. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014". pp. 24. http://www.nhlbi.nih.gov/guidelines.

Villers, MS, Jamison, MG, De Castro, LM, James, AH. "Morbidity associated with sickle cell disease in pregnancy". AM J Obstet Gynecol. vol. 199. 2008. pp. 125.e1-5.

Koshy, M, Burd, L, Wallace, D. "Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study". N Engl J Med. vol. 319. 1988. pp. 1447-1452.

Okusanya, BO, Oladapo, OT. "Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy". The Cochrane database of systematic reviews. vol. 12. 2013. pp. CD010378.

Malinowski, AK, Shehata, N, D'Souza, R, Kuo, KH. "Prophylactic transfusion for pregnant women with sickle cell disease: a systematic review and meta-analysis". Blood. vol. 126. 2015 Nov 19. pp. 2424-35.

Asma, S, Kozanoglu, I, Tarım, E, Sarıturk, C. "Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy". Transfusion. vol. 55. 2015. pp. 36.

Martí-Carvajal, AJ, Peña-Martí, GE, Comnián-Carrasco, G, Martí-Peña, AJ. "Interventions for treating painful sickle cell crisis during pregnancy". Cochrane Database Syst Rev. 2009.

Little, JA, McGowan, VR, Kato, GH, Partovi, KS. "Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review". Haematologica. vol. 91. 2006. pp. 1076-1083.

"U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. Adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use". MMWR. 2010. pp. 59. www.cdc.gov/mmwr/preview/mmwrhtml/rr59e0528a1.htm.

Zempsky, WT. "Treatment of sickle cell pain: fostering trust and justice". JAMA. vol. 302. 2009. pp. 2479.

Shirel, T, Hubler, CP, Shah, R, Mager, AB. "Maternal opioid dose is associated with neonatal abstinence syndrome in children born to women with sickle cell disease". American journal of hematology. vol. 91. 2016 Jun. pp. 416-9.

Bates, SM, Greer, IA, Middeldorp, S. "VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. vol. 141. 2012 Feb. pp. e691S.

"Committee on Obstetric Practice; Committee on Genetics. ACOG committee opinion number 399, February 2008: umbilical cord blood banking". Obstet Gynecol. vol. 111. 2008. pp. 475.

Heeney, MM, Hoppe, CC, Abboud, MR, Inusa, B. "A Multinational Trail of Prasugrel for Sickle Cell Vaso-Occlusive Events". N Engl J Med. vol. 374. February 18, 2016. pp. 625-635.

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