Andra H. James, MD, MPH

) is a devastating blood disorder with particular implications for women. In the 1970s, the life expectancy for a person with SCD in the United States was approximately 10 years.

 Now, the life expectancy is approximately 50 years.

 Girls born with SCD in this century can expect to live to and through their childbearing years. Their blood disorder, however, presents unique challenges at every life stage that ob/gyns need to know how to manage.  

SCD is an autosomal-recessive disease characterized by presence of sickled red blood cells (RBCs). Sickled RBCs form in an individual who is homozygous for the sickle hemoglobin (HbS) gene (SS genotype) or is heterozygous for HbS and has another abnormal hemoglobin such as hemoglobin C (SC genotype), beta thalassemia (S-beta thal+ or S-beta thal

 genotype), or some other rare hemoglobin. HbS has a single amino acid substitution of valine for a glutamic acid in the beta chain of the hemoglobin molecule, which prevents hemoglobin from forming neat tetramers. Instead the hemoglobin forms long, fibrous polymers that distort RBC membranes. These distorted RBCs are readily destroyed by the reticuloendothelial system. The normal life span of sickled RBCs is approximately 15 days compared to the 120 days of normal RBCs.

 Consequently, individuals with SCD suffer from moderate to severe anemia. Table 1 lists the prevalence of various genotypes derived from California newborn screening data

 and the severity of the various genotypes.

 The SS genotype (which accounts for more than half of the affected individuals in the United States) and the S-beta thal

 genotype generally result in a more severe phenotype described as “sickle cell anemia.” The other genotypes do not usually result in severe disease.  

Anemia is not the only mechanism of the disease. Lysed RBCs release free hemoglobin, which consumes nitric oxide and leads to endothelial damage and possibly thrombosis. Membrane receptors become rearranged on the distorted RBC surface, altering its adhesive properties. These altered RBCs interact with the endothelium, white blood cells, and platelets, and contribute to intravascular congestion, thrombosis, and downstream ischemia, resulting in both acute and chronic tissue damage.  

SCD affects approximately 1 million individuals worldwide, two-thirds of whom live in West Africa. Unfortunately, mortality for children with SCD in low- and middle-income countries is 50% to 90%. In the United States, approximately 100,000 Americans are affected with SCD, mostly individuals of African descent, but also Mediterranean, Middle Eastern, and Indian descent.

 Forty years ago, 50% of children in the United States born with SCD also died before adulthood and 30% died before their fifth birthday,

 but since the 1970s, newborn screening programs, institution of penicillin prophylaxis, vaccinations against encapsulated organisms, and disease-modifying therapy with hydroxyurea have led to  a dramatic decline in childhood mortality. SCD is no longer a life-threatening disease of childhood, but now a chronic disease of adults.

SCD affects almost every organ and organ system, as shown in Table 2. Acute complications of the disease are listed in Table 3.

 The cost of care, estimated from a study of Florida Medicaid claims from 2001-2005, averaged $1389 per month per patient.

Of particular concern to ob/gyns are the maternal and fetal consequences of SCD. Pregnancy complications are summarized in Table 4. During normal pregnancy, there is a demand for increased erythropoiesis. Because women with SCD are already anemic, 30% to 40% require transfusion during pregnancy.

 During normal pregnancy, women have an increased susceptibility to certain infections. The risk of infection is compounded in women with SCD. Compared to women without SCD, infectious morbidity is increased 2- to 13-fold. During normal pregnancy, women have an increase in glomerular filtration. Pregnancy has the potential to further impair renal function in women with sickle cell nephropathy. Normal pregnancy results in an increase in cardiac output. In a woman with SCD, the increased cardiopulmonary demands of pregnancy are potentially life-threatening, especially in women with SCD-induced pulmonary hypertension. Pregnancy results in an increased risk of thrombosis. In women with SCD who are already at high risk of VTE and stroke, pregnancy increases the risk of thrombosis 2- to 5-fold compared to women without the disease. Preeclampsia is increased 6- to 8-fold in women with SCD and maternal mortality is increased 6-fold, compared to women without SCD.

Fetal growth appears to start out normally, then lags after 25 weeks’ gestation.

 Fetal consequences of SCD include a 2-fold increased risk of preterm birth,

 a 3-fold risk of small-for-gestational age,

 and a 4-fold increased risk of stillbirth.

Diagnosis of SCD within the first 3 months of life allows for early treatment. Since 2006, every state in the United States has had a newborn screening program for the disease. A study conducted in California found that overall mortality for children who were diagnosed after they presented with symptoms was 8%, compared to 1.8% after early identification of SCD through screening and accompanying education of providers.

Treatment for SCD consists of preventing complications, managing pain, modifying the disease, or attempting a cure. Prevention of complications includes prophylactic penicillin for children to prevent sepsis and meningitis from encapsulated bacteria, and vaccinations against 

 Individuals with SCD are particularly vulnerable to these encapsulated bacteria due to functional or surgical asplenia. Children with SCD are also particularly vulnerable to stroke. Children with abnormal transcranial Doppler velocities are prescribed long-term transfusion therapy, which has been shown to dramatically reduce incidence of stroke.

Managing the acute and chronic pain of SCD is challenging. The mainstay of pain management has been opioids, but nonsteroidal anti-inflammatory drugs (NSAIDs) have also been used. Particularly for management of chronic pain, amitriptyline, gabapentin, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and complementary therapies have also been helpful. Disease-modifying therapy includes hydroxyurea, which raises fetal hemoglobin levels and reduces incidence of vaso-occlusive crises and episodes of acute chest syndrome. Hydroxyurea has been found to cause birth defects in animals, but has not been found to increase risk of birth defects in humans.

 Nonetheless, hydroxyurea has generally been avoided during pregnancy. L-glutamine has recently been approved for prevention of vaso-occlusive crises, but there is little experience with this medication.

 Other disease-modifying therapies are currently in development, but have not been approved for use.

Cures of SCD have been accomplished with hematopoietic stem cell transplantation (HSCT) and now with gene therapy.

 For HSCT, the donor may be related (e.g. a sibling) or unrelated. Related donors can be human leukocyte antigen (HLA) histocompatibility-matched (typically at
	8/8 HLA loci) or haploidentical (matched at half of HLA loci). Originally only matched donors were considered, but now successful transplants have occurred with haploidentical donors as well. In preparation for HSCT, recipients receive chemotherapy or radiation. HCST offers a cure, but can result in death, graft rejection, graft versus host disease, and sterility.

 After HSCT, a high proportion of young women do become amenorrheic and are presumed infertile.  Gene therapy for SCD

 is still experimental but there are three clinical trials underway.  Subjects receive their own genetically modified hematopoietic stem cells. In preparation, however, they still require gonadotoxic chemotherapy with the same potential risks to fertility as those with HSCT.  

 Menstruation and contraception in young women with SCD

Typical case: A 16-year-old gravida 0 with SCD is referred by her pediatric hematologist because of heavy, painful periods since she started having periods 1 year ago. She reports that the menstrual pain is distinct from the pain of vaso-occlusive crises. Her disease is otherwise adequately managed. She has no history of stroke or venous thromboembolism (VTE). Her Hb is 9 g/dL. A transabdominal ultrasound of the pelvis was normal.

Delay in menarche is not uncommon in girls with SCD. Several studies have reported on delayed menarche among girls with the disease.

 A longitudinal cohort study of girls from infancy to young adulthood in Jamaica found that compared to controls, girls with SC genotype had a delay in mean age at menarche of 0.5 years and girls with SS genotype had a delay in mean age at menarche of 2.4.

 This patient’s ability to distinguish menstrual pain from the pain with vaso-occlusive crises is also not uncommon. Women with SCD do report distinct differences in the pain of menstruation compared to the pain with vaso-occlusive crises.

Management of primary dysmenorrhea includes hormonal contraceptives and NSAIDs. In SCD, NSAIDs may increase vascular, bleeding, and renal risks, which may be compounded in patients with end-organ co-morbidities. For patients with SCD without a contraindication, however, NSAIDs are acceptable.

 Hormonal therapy can reduce blood loss and pain with periods (a potential benefit in SCD), but combined hormonal contraceptives increase risk of VTE and stroke

 (a potential hazard in SCD). Depot medroxyprogesterone acetate (DMPA) injections have also been shown to increase risk of VTE,

 but other progestin-only contraceptives do not.

 In women with SCD, a systematic review of four studies showed no increased risk of VTE among those who used hormonal contraceptives, but there were only 118 total subjects.

 Obviously, no combined hormonal contraceptives should be prescribed to a young woman with a history of stroke or VTE. Common sense further dictates progestin-only contraceptives be prescribed to a woman with SCD over combined hormonal contraceptives whenever possible.

 of a young woman referred for HSCT describes a scenario that has become more frequent. This patient was a 19-year-old young gravida 0 with SS genotype. She had a history of multiple episodes of vaso-occlusive pain crises and acute chest syndrome. Fortunately, her sister was an HLA match. She was referred to a reproductive endocrinologist who counseled her and her family regarding the options for cryopreservation of:

embryos (created with donor sperm), which allows for preimplantation genetic testing (PGT)

ovarian tissue – still experimental, but the only option for pre-pubescent girls.

A low-dose ovarian stimulation protocol was used. Enoxaparin 30 mg subcutaneous every 12 hours was administered during stimulation and held 24 hours before egg retrieval. Eight mature oocytes were vitrified (rapidly cooled to prevent formation of crystals). No reports exist about whether this patient has pursued a pregnancy successfully, but thousands of women without SCD have had successful pregnancies after oocyte preservation.

 Also, while ovarian tissue preservation is considered experimental, more than 87 subsequent pregnancies have been reported, including two in women with SCD (one using her own ovarian tissue and another using her sister’s).

A typical case: A 28-year-old gravida 0 with SCD with SS genotype is referred by her hematologist because she will be married soon and is planning a pregnancy. She is currently taking hydroxyurea. Her partner does not think he has sickle trait or beta thalassemia minor, but he is not certain. 

This patient’s partner should be referred for testing. If he has abnormal Hb, the couple should be referred for genetic counseling and they should be aware of the option of PGT with in vitro fertilization. A type and screen should be reviewed or obtained. If antibodies are present that are known to cause hemolytic disease, the partner should be tested for the corresponding antigen(s). The patient should be counseled regarding the maternal and fetal risks of SCD in pregnancy. Although the risk of maternal mortality is increased, the absolute risk of maternal mortality is about 1%,

 which does not discourage most women and their families from pursuing a pregnancy. The patient’s medications should be reviewed and before a prenatal vitamin is prescribed, her ferritin should be checked. If the level is elevated, which is very likely if the patient has received transfusions, she should receive a prenatal vitamin WITHOUT iron (such as prenatal gummies). In addition, the American College of Obstetricians and Gynecologists recommends 4 mg of folate per day for women with SCD.

 With respect to hydroxyurea, the patient should have a consultation with a maternal-fetal medicine specialist. After consultation with that specialist and a hematologist regarding risks and benefits, some patients may elect to continue hydroxyurea during pregnancy or at least until conception, stop for the duration of pregnancy, or stop it temporarily and restart it after the first trimester.  

A typical case: A 32-year-old gravida 3 para 1011 (one term pregnancy and one miscarriage) with SCD (SS genotype) at
	36 weeks’ gestation has worsening fetal growth restriction (FGR), which is now at the fourth percentile. Amniotic fluid volume is low normal and the umbilical artery Doppler S/D ratio is normal. The patient has been hospitalized almost monthly since conception for vaso-occlusive crises and was recently discharged from the medical intensive care unit after an admission for acute chest syndrome. She has received multiple transfusions in the past. Her antibody screen was positive for anti-C antibodies in this pregnancy, but her titer never exceeded 4. She took hydroxyurea in the past but stopped prior to her first pregnancy. The patient’s family history is significant for a sister who also had SCD with SS genotype and died in the second trimester of her first pregnancy. Her partner’s sickle cell status is unknown. The patient’s current medications include prenatal gummies, low-dose aspirin for preeclampsia prevention, and oxycodone for pain. Her only complaint is near constant, severe pain in her bones. Her vital signs are normal, and her exam is unremarkable. Her Hb is 7.6 g/dL, hemoglobin 22%, creatinine 0.6, and lactate dehydrogenase is normal.  

Once pregnancy is established, a patient with SCD should be cared for with the help of specialists in maternal-fetal medicine and hematology who have expertise in SCD. In early pregnancy, this patient’s partner should have been offered testing. If he had abnormal Hb, the couple should have been referred for genetic counseling and made aware of the options for prenatal diagnosis. He also could have been tested for the C red cell antigen. Anti-C antibodies are a rare but documented cause of hemolytic disease of the newborn.

 If the partner were negative, the fetus would not have been at any risk for alloimmunization. 

Because of the increased risk of preeclampsia, low-dose aspirin was started at 12 weeks’ gestation. Because of the increased risk of infection, monthly urine cultures were ordered. The patient’s hemoglobin was monitored. A Hb of 8 g/dL was targeted and a Hb of
	> 7 g/dL was maintained for most of the pregnancy. There is no good-quality evidence that a strategy of prophylactic blood transfusion does or does not benefit the mother or fetus when compared to selective transfusion.

 Whatever the transfusion strategy, the benefits of transfusion need to be balanced against the risks of alloimmunization and delayed hemolytic transfusion reactions, which can be life-threatening.

Because of the high risk of FGR, fetal growth was monitored with serial ultrasounds.

 Our practice is to start at 24 to 28 weeks’ gestation. Due to the increased risk of stillbirth, a plan for fetal surveillance was also in place. Our practice is to start antepartum testing at 32 weeks’ gestation. If all is going well, we plan to deliver women with sickle cell anemia (SS and S-beta thal

 genotypes) at 37 weeks’ gestation and women with other genotypes at 39 weeks. For the patient on opioid medication, the nursery needs to be prepared for neonatal withdrawal syndrome. During hospitalization, there should be a plan for VTE prophylaxis. It is our practice to prescribe prophylactic doses of low-molecular-weight heparin for 6 weeks postpartum.  

This patient was transfused with 2 units of RBCs prior to induction of labor. She delivered a 2400-g infant vaginally. Postpartum, she received thromboprophylaxis with enoxaparin. She planned to use a long-acting reversible contraceptive and restart hydroxyurea postpartum.

For a variety of reasons, women with SCD may be at risk of early menopause or even premature ovarian failure, but there are essentially no data about menopause in these patients.

 With a life expectancy of 50 years, however, women with SCD will need the help of gynecologists to manage menopausal symptoms. 

Increasing therapeutic options for women with SCD and a longer life span are changing how ob/gyns care for women with SCD. For more information please visit the website for the Foundation for Women and Girls with Blood Disorders at 

The author reports no potential conflicts of interest with regard to this article.

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Michlitsch J, Azimi M, Hoppe C, et al. Newborn screening for hemoglobinopathies in California. 

Chaturvedi S, DeBaun MR. Evolution of sickle cell disease from a life-threatening disease of children to a chronic disease of adults: The last 40 years. 

Yu CK, Stasiowska E, Stephens A, Awogbade M, Davies A. Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. 

Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. 

Oteng-Ntim E, Meeks D, Seed PT, et al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. 

Thame M, Lewis J, Trotman H, Hambleton I, Serjeant G. The mechanisms of low birth weight in infants of mothers with homozygous sickle cell disease. 

Kauf  TL, Coates T, Huazhi L, Mody-Patel N, Hartzema AG. The cost of health care for children and adults with sickle cell disease. 

Ngo C, Kayem G, Habibi A, et al. Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions. 

Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. 

Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle cell disease: effect on mortality. 

Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. 

Ghafuri DL, Stimpson SJ, Day ME, James A, DeBaun MR, Sharma D. Fertility challenges for women with sickle cell disease. Expert Rev 

Dovey S, Krishnamurti L, Sanfilippo J, et al. Oocyte cryopreservation in a patient with sickle cell disease prior to hematopoietic stem cell transplantation: first report. 

Demirci S, Uchida N, Tisdale JF. Gene therapy for sickle cell disease: An update. 

Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM. Progestin-only contraception and thromboembolism: A systematic review. 

Serjeant GR, Singhal A, Hambleton IR. Sickle cell disease and age at menarche in Jamaican girls: observations from a cohort study. 

Articles

Three cases illustrate the unique challenges ob/gyns face while caring for SCD patients at various life stages.

Reproductive issues in sickle cell disease

	Pictured above: A microscopic view of sickled red blood cells causing anemia disease.

	Sickle cell disease (SCD) is a devastating abnormality of red blood cells (RBCs) that results in circulatory impairment, tissue damage, infarctions, severe anemia, and life-threatening infections. SCD affects between 70,000 and 100,000 Americans, mostly of African descent, with a minority of Hispanic, southern European, Middle Eastern, and Asian Indian descent. Today, SCD is most often discovered during routine newborn screening.

	Although SCD is associated with major morbidity, more than 90% of children with SCD in the United States survive into adulthood. Compared to the general population, however, their lifespans are 2 or 3 decades shorter and limited by both acute and chronic morbidity.

	Acute complications of SCD include ischemic, vaso-occlusive (pain) crises, acute chest syndrome (which most closely resembles pneumonia, but may also result from fat embolism from bone marrow, intrapulmonary aggregates of sickled cells, atelectasis, or pulmonary edema), stroke, splenic sequestration, acute renal failure, and cholecystitis. Chronic complications include chronic pain, cholelithiasis, renal dysfunction, hypertension, pulmonary hypertension, and retinal problems.

	By the time they reach childbearing age, young women with SCD may have suffered many severe complications. Clinically apparent stroke occurs in 11% of those with SCD by age 20 and in 24% by age 45.

 Although the condition is not usually regarded as a thrombophilia, 25% of adults with SCD have experienced venous thromboembolism (VTE) by a median age of 30, which is comparable to the rate in adults with high-risk thrombophilias.

	The only established disease-modifying therapies are chronic transfusion and hydroxyurea. The latter is strongly recommended for adults with 3 or more severe vaso-occlusive crises per year, pain or chronic anemia interfering with daily activities, or severe or recurrent episodes of acute chest syndrome. Hydroxyurea therapy is also suggested for adolescents without regard to symptoms.

	Long-term transfusion therapy is used to prevent stroke in children with abnormal transcranial Doppler velocity. Potential consequences of long-term transfusion therapy are alloimmunization and iron overload. Because transfused blood contains iron that circumvents the normal pathways of iron regulation, excess iron can accumulate in tissues and can become pathological. Chelation therapy can be used to remove excess iron in patients with evidence of iron overload.

	During pregnancy, SCD poses problems to both mother and fetus. Maternal problems can arise from chronic underlying organ dysfunction such as renal disease or pulmonary hypertension, from acute complications of SCD such as vaso-occlusive crises and acute chest syndrome, and from pregnancy-related complications.

	In normal, iron-replete women, RBC mass should increase by 400–450 mL during pregnancy to support the 40%–50% increase in blood volume.

 This increase in RBC mass is not achievable in women with SCD. During pregnancy 50%–70% of women with SCD require at least one hospitalization and 30%–40% require transfusion.

 In one cohort, women with SCD were hospitalized an average of 6 days during pregnancy.

	Women with SCD not only require transfusion, but also have frequently been transfused previously and, according to published reports, 20% to 50% of SCD patients are alloimmunized.

 Limited blood products are available to women who are alloimmunized and need transfusion, but the most serious consequence is the maternal risk of developing a delayed hemolytic transfusion reaction, which can be life-threatening.

	Another potentially life-threatening problem is pulmonary hypertension. It affects 6%–11% of SCD patients

 and is especially morbid in pregnancy due to the increased cardiopulmonary demands of gestation. Although maternal mortality from pulmonary hypertension was previously reported to be 30%–50%, mortality remains in the range of 16%.

	Perhaps because of underlying renal disease, hypertension, or placental ischemia, women with SCD are more likely to experience preeclampsia and eclampsia.

 They are also more likely to experience VTE, infections (urinary tract infections, pneumonia, sepsis, and postpartum infections), acute renal failure, and death.

	 In the United States, the maternal mortality rate is approximately 10 times higher than it is for women without SCD.

 Similarly increased rates are seen in other countries.

	Fetal concerns for women with SCD include the consequences of utero-placental insufficiency, alloimmunization, and opioid exposure. Studies from multiple cohorts, including large population studies, have documented the increased risk of fetal growth restriction, preterm delivery, and stillbirth.

 Fetal growth appears to start normally, then lag after 25 weeks’ gestation.

 When fetal growth restriction occurs, it has been described as asymmetric.

	Women with SCD who have formed antibodies to fetal RBC antigens that are associated with hemolytic disease in the fetus or newborn and who are alloimmunized are at risk of having an anemic fetus or a stillbirth.

 Although there are no data specifically for infants born to mothers with SCD, in a retrospective cohort study of infants born at Mayo Clinic between 1998 and 2009, neonatal withdrawal syndrome occurred in 5.6% of infants exposed to chronic narcotic use in utero.

	Couples contemplating pregnancy should be aware of the increased risks to a woman’s health of SCD during pregnancy.

	Prior to pregnancy, the physician should assess a woman’s overall health and her potential risks during pregnancy. She and her partner should be counseled accordingly. Some studies have found poorer outcomes in women with sickle cell anemia as opposed to other SCD genotypes, but other studies have found no differences.

	It is the experience of the author and her colleagues that a history of frequent hospitalizations and/or episodes of acute chest syndrome correlates with poorer overall health and increased risks during pregnancy. An assessment of urine protein and a retinal examination should be performed.

 Hypertension should be treated to lower systolic blood pressure to ≤140 mmHg and diastolic blood pressure to ≤90 mmHg.

	Some experts recommend that all SCD patients be screened for pulmonary hypertension with Doppler echocardiography.

 At a minimum, any woman with signs of pulmonary hypertension should undergo Doppler echocardiography.

 Women with significant pulmonary hypertension should be counseled that pregnancy is contraindicated and that if it occurs, termination should be considered.

	All patients with SCD should receive immunizations according to the Advisory Committee on Immunization Practices, but with particular attention to the immunizations recommended for people who have functional asplenia. These include pneumococcal, haemophilus influenza type b, and meningococcal vaccinations.

	A ferritin level should be checked before prescribing any iron. (A serum ferritin level >1000 ng/mL is suggestive of iron overload.) The American College of Obstetricians and Gynecologists recommends 4 mg of folate per day during pregnancy.

	Women with SCD who have been transfused should be tested for RBC alloantibodies. If a woman has RBC alloantibodies and the antibodies are known to cause hemolytic disease in the fetus or newborn, her partner should also be tested for the corresponding RBC antigen(s). If the partner tests positive, the couple should be counseled about the risks of hemolytic disease, how it is monitored, and how it is treated.

	Couples should also be counseled about the potential fetal and neonatal effects of maternal medications, including chronic opioids. Angiotensin-converting enzyme (ACE) inhibitors, which are used to treat microalbuminuria in adults with SCD, should be discontinued.

	Hydroxyurea, which has caused birth defects in experimental animals who were given very high doses, has not been associated with an increased risk of birth defects in infants with in utero exposure.

 Nonetheless, it is generally not prescribed to pregnant women. Women who are trying to become pregnant or who become pregnant while on hydroxyurea therapy are generally advised to discontinue it.

	Women with SCD are at risk of having a child affected with SCD if their partners have SCD, HbS, ï¢-thalassemia trait, or are carriers of another abnormal hemoglobin such as HbC. Women with SCD whose partners’ sickle cell or thalassemia status is unknown should be referred for hemoglobin electrophoresis.

	Women whose partners carry one of the traits listed above can avoid an affected pregnancy by undergoing preimplantation genetic diagnosis. Alternatively, after spontaneous conception, prenatal diagnosis of SCD is possible by chorionic villus sampling in the first trimester or by amniocentesis in the second trimester. Couples who are at risk of having a child affected with SCD should be referred for genetic counseling.

	During pregnancy, evaluation should include consultation with a hematologist and a maternal-fetal medicine specialist. Pertinent history includes the patient’s genotype, history of transfusions, hospitalizations, episodes of acute chest syndrome, vaso-occlusive crises, Doppler echocardiography, stroke, VTE, cholecystectomy, status of spleen, renal evaluations, and immunizations.

	Issues not addressed before conception should be addressed early in pregnancy. An assessment of iron stores is usually made with the initial complete blood count (CBC). Most patients with SCD have elevated serum ferritin levels and should not receive additional iron supplementation, but should continue to receive folic acid. Hydroxyurea therapy, chelating agents, and ACE inhibitors should be discontinued, although only ACE inhibitors have been associated with congenital anomalies.

	Women with SCD are at high risk of preeclampsia and both arterial thromboembolism and VTE. Therefore, it is reasonable to initiate low-dose aspirin after the first trimester.

 Women with a history of VTE should receive anticoagulation with low-molecular-weight heparin (LMWH) during pregnancy and the postpartum period.

	Care during pregnancy includes maternal and fetal surveillance. Monthly CBCs are typically performed to monitor for severe anemia. In the only randomized controlled trial published to date, prophylactic transfusion was associated with a decreased risk of pain crises and severe anemia, but no difference was observed in pregnancy outcomes.

	Other therapies that have shown promise in reducing vaso-occlusive crises and would potentially be safe in pregnancy (such as propranolol and LMWH) have not been confirmed in multicenter trials and have not been studied in pregnancy.

	Risks of adverse fetal outcomes are reduced, but not eliminated, with fetal surveillance, which may lead to planned early delivery. Fetal surveillance should include, at a minimum, serial ultrasonography for fetal growth every 3–4 weeks starting in the third trimester with initiation of antepartum fetal testing at 32 weeks’ gestation or sooner if indicated.

	A contributing factor to the increased incidence of stillbirth is utero-placental insufficiency, but sudden and unpredictable stillbirths do occur. Some experts recommend induction of labor after 37 weeks’ gestation.5 Plans for the mode of delivery should be according to obstetric indications while recognizing that the rate of cesarean delivery is higher in women with SCD.

 An anesthesiologist should be consulted in the third trimester or during any hospitalization.

	Although prophylactic transfusion was not shown to improve pregnancy outcomes in patients with SCD, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended in patients with sickle cell anemia (HbSS and HbSï¢

-thal), and should be considered in patients with other genotypes.

 When a transfusion is clinically indicated in the patient with SCD, the objective is to lower the percentage of HbS to approximately 40% while simultaneously raising the total hemoglobin concentration to about 10 g/dL.25

	Since the need for cesarean delivery cannot be predicted, and women with SCD are at high risk of cesarean delivery, it may be reasonable to aim for this total hemoglobin concentration in the last month of pregnancy.

	Women with SCD have a risk of thrombosis comparable to that in patients with high-risk thrombophilia. Women with SCD should have pneumatic compression devices during antepartum hospitalizations, during labor, and at the time of cesarean delivery. For women who are not already receiving anticoagulation for a history of VTE, some consideration should be given to prophylactic or low-dose anticoagulation during pregnancy and for 6 weeks postpartum.

	The rare pregnant patient with SCD who has undergone stem-cell transplantation (see sidebar) should be evaluated and managed as are other women with SCD. This patient may be at reduced risk of vaso-occlusive crises, but will likely have been selected for transplantation due to some chronic organ damage and may have suffered additional tissue damage from bone marrow-suppressive chemotherapy. Regimens typically include busulfan, which should prompt an evaluation of pulmonary function.

	There are no randomized trials on the safety and efficacy of interventions (transfusion, oxygen therapy, fluid replacement analgesia, and/or steroids) for treating pain crises during pregnancy.

	A pregnant woman with SCD who presents with pain should be evaluated for other complications, and pain should be treated promptly and aggressively.

 Nonsteroidal drugs are contraindicated, so opioids should be used. Many women with SCD have a high tolerance for opioids, but they still need adequate and appropriate medication to control pain during vaso-occlusive crises in pregnancy. Opioids should not be withheld due to concerns for addiction.

	Transfusion should be administered only if there are other indications.

 Oxygen should be given if saturation is less than 95% by pulse oximetry.

 Incentive spirometry should be initiated for patients who are hospitalized for a vaso-occlusive crisis.

	Hormonal contraception may provide women with SCD with decreased menstrual blood flow and improved hemoglobin levels. VTE is the primary risk associated with combined hormonal methods containing estrogen.

	Intrauterine devices (IUDs) and implants carry risks associated with the insertion procedure, and sterilization carries risks associated with the surgical procedure. Nonetheless, these risks are trivial compared to the risks associated with pregnancy. Copper IUDs (as opposed to progestin IUDs) may increase bleeding, which is a more significant problem for women with SCD. Systematic reviews of the literature have demonstrated the safety of progestin-only contraception for patients with SCD.

	During pregnancy, SCD poses problems to both mother and fetus. Maternal problems can arise from chronic underlying organ dysfunction such as renal disease or pulmonary hypertension, from acute complications of SCD such as vaso-occlusive crises and acute chest syndrome, and/or from pregnancy-related complications.

	Fetal problems include alloimmunization, opioid exposure, growth restriction, preterm delivery, and stillbirth.

	Couples should be counseled that a pregnancy with SCD is high risk for both fetus and mother and be made aware of the increased risks of adverse pregnancy outcome. Risks of adverse fetal outcomes are reduced but not eliminated with fetal surveillance. 

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Pregnancy is risky for women with sickle cell disease. This overview examines concerns for the mother and fetus to help you manage the risks.

Sickle cell disease in pregnancy

Management of reproductive issues in women and girls with bleeding disorders requires knowledge of both reproductive physiology and hematology. Ob/gyns may not be familiar with a particular blood disorder or the latest therapy for its management, whereas hematologists most likely are not prepared to manage impact on aspects of reproduction including menstruation, ovulation, gestation, and delivery. 

This article reviews some key concerns for ob/gyns faced with caring for women with common nonmalignant blood disorders. 

Menorrhagia is common in women with bleeding disorders and prevalence ranges from 10% to 100%, depending on the specific bleeding disorder.

   Bleeding disorders also are more prevalent in women with menorrhagia: Studies indicate that 5% to 32% of women with menorrhagia have bleeding disorders. Although menorrhagia is the most common reproductive-tract manifestation of a bleeding disorder, it is not the only sign. Women with bleeding disorders also appear to have an increased risk of developing hemorrhagic ovarian cysts and possibly endometriosis. 

Women suspected of having a bleeding disorder (or who are hemophilia carriers) should undergo diagnostic testing before becoming pregnant to ensure appropriate preconception counseling and pregnancy management. During pregnancy, women with bleeding disorders may have an increased risk of bleeding complications. At delivery, affected women are more likely to experience postpartum hemorrhage, particularly delayed or secondary postpartum hemorrhage. 

As women with bleeding disorders age, they may be more likely to experience conditions that present with bleeding, such as fibroids, endometrial hyperplasia, and polyps.

   They are also more likely to undergo hysterectomy and to have the procedure at a younger age. In a survey of women with VWD enrolled in US hemophilia treatment centers, 25% reported having had a hysterectomy, compared with 9% of matched controls.

   Women with bleeding disorders are at risk of the same obstetric and gynecologic problems that affect all women, but they appear to be disproportionately affected by conditions that manifest with bleeding (see "Resources for physicians").

VWD is the most common inherited bleeding disorder.

   It is caused by deficiency in or dysfunction or absence of von Willebrand factor, which is necessary for platelet adhesion at sites of vascular injury and for protection of clotting factor VIII from proteolysis in the circulation.

   VWD manifests with mucocutaneous bleeding, including uterine bleeding. The prevalence of VWD in the general population ranges from 0.6% to 1.3%, depending upon the number of individuals with bleeding symptoms, family history, and laboratory abnormalities. VWD affects both men and women, but its implications for women are more serious than for men because they experience menstruation, pregnancy, and childbirth.

   Among women with menorrhagia, prevalence of VWD is reportedly 5% to 20%, and it may be as high as 36% in adolescents with menorrhagia.

   VWD is of en overlooked in women and girls because of lack of awareness among providers and patients. Bleeding symptoms of en manifest in the reproductive tract, so clinicians may diagnose and treat the condition as a gynecologic problem without appreciating the contribution of the underlying bleeding disorder. 

In 2004, the National Heart, Lung, and Blood Institute of the National Institutes of Health convened a panel of experts to develop evidence-based practice guidelines for diagnosis, evaluation, and management of VWD by primary care providers and specialists. The guidelines were published in 2008 and excerpted for ob/gyns in 

   Other consensus guidelines have been published by various government agencies and hemophilia organizations, as summarized in 

   Te American College of Obstetricians and Gynecologists (ACOG) issued a Committee Opinion on VWD in women in 2009.

Bleeding disorders can create problems with reproductions.

Impact of bleeding disorders on reproduction

Inherited bleeding disorders in women and girls represent unique management challenges for the ob/gyn. Conditions such as von Willebrand disease (VWD) can increase risk of menorrhagia and postpartum hemorrhage, whereas inherited thrombophilias can predispose patients to thrombosis during pregnancy or if they are exposed to estrogen-containing contraceptives or postmenopausal hormone therapy. Incidence of medical and pregnancy-related complications is increased in women with sickle cell disease and those who are carriers of the X-linked condition hemophilia. Clearly, inherited bleeding disorders impact the health of women and girls at every stage of their reproductive lives (Table).

Management of reproductive issues in requires knowledge of both reproductive physiology and hematology. Ob/gyns may not be familiar with a particular blood disorder or the latest therapy for its management, whereas hematologists most likely are not prepared to manage impact on aspects of reproduction including menstruation, ovulation, gestation, and delivery.

Andra H. James, MD, MPH

Articles

Reproductive issues in sickle cell disease

Sickle cell disease in pregnancy

Impact of bleeding disorders on reproduction

Bleeding Disorders: Impact on Reproduction