Sickle cell disease: Obstetric considerations

INTRODUCTION — Most pregnancies in individuals with sickle cell disease (SCD) result in live birth of healthy neonates.

However, there are maternal and fetal risks of which clinicians and patients need to be aware. These risks are due, at least in part, to the metabolic demands, hypercoagulable state, endothelial dysfunction, severe anemia, and increased vaso-occlusive episodes associated with pregnancy in individuals with SCD. Access to a multidisciplinary care team knowledgeable about SCD and obstetric management of complicated pregnancies can significantly decrease morbidity and mortality in both high-income and low-income settings.

This topic will discuss the management of pregnancy-related issues in individuals with SCD. Other considerations for individuals with SCD are reviewed separately.

●Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

●Pathophysiology – (See "Pathophysiology of sickle cell disease".)

●Diagnosis – (See "Diagnosis of sickle cell disorders".)

●Management – (See "Overview of the management and prognosis of sickle cell disease".)

BEFORE CONCEPTION

Counseling prior to pregnancy — Individuals with SCD are at increased risk of obstetric and fetal complications, as well as medical complications of SCD. (See 'Maternal risks' below and 'Pediatric outcomes' below.)

However, these complications can be significantly decreased by early management by a multidisciplinary care team [1-3]. Despite these increased risks, the majority of individuals with SCD who become pregnant have not had adequate or effective preconception counseling [4,5].

Assessment and counseling of individuals with SCD prior to conception should include the following:

●Information about the hemoglobin status of their partner and the likelihood of a newborn with SCD, the prognosis of an affected offspring, the option to speak with a genetic counselor, and discussion of available reproductive options. (See 'Likelihood of SCD in offspring and reproductive options' below.)

●Information about the risk pregnancy poses to the mother's health, based on pre-pregnancy health assessment. (See 'Baseline health assessment and risks to the patient' below.)

●Discussion of medication management, especially hydroxyurea. (See 'Vaccines and medication management' below.)

●Discussion of possible cord blood banking for a relative with SCD. (See 'Cord blood' below.)

●Appropriate vaccines and other routine preconception care. (See "The preconception office visit".)

Likelihood of SCD in offspring and reproductive options — The likelihood of SCD in offspring depends on the genotypes of both parents. Thus, it is important to verify the mother's diagnosis (homozygous Hb S versus Hb SC disease versus sickle-beta thalassemia), and to test the father for SCD and other hemoglobinopathies, as noted in 2014 guidelines [6,7].

Couples who are planning pregnancy when the mother has SCD should have extensive counselling about the mode of inheritance, associated risk to the fetus, and common complications to mother and fetus at each stage of the pregnancy. Culturally-sensitive and non-directive support for preconception genetic testing of the father is recommended [8].

If the father tests positive for any hemoglobinopathy, referral to a genetic counselor is useful to discuss the type and risk of inherited disease in offspring, and the variability of phenotype. This is also a good time to discuss the range of pregnancy options, as appropriate:

●If both parents are homozygous for Hb S, the risk of SCD in offspring is 100 percent.

●If one parent is homozygous for Hb S and the other is heterozygous for Hb S (sickle cell trait), the risk of SCD in offspring is 50 percent.

●If both parents are heterozygous for Hb S (sickle cell trait), the risk of SCD in offspring is 25 percent (figure 1).

●If one parent has no hemoglobinopathy variants, the risk of SCD in offspring is zero, regardless of the other parent's status.

●Other variants (Hb C, beta thalassemia) of either parent will impact the risk of SCD or other hemoglobinopathy in offspring.

The opportunity for discussion with a genetic counselor should be made available.

Reproductive options to avoid having an offspring with SCD include:

●Preimplantation genetic testing (PGT) to select unaffected embryos for implantation; PGT requires conception by in vitro fertilization (IVF). (See "Preimplantation genetic testing" and "In vitro fertilization: Procedure".)

●Sperm donation or oocyte donation from a donor without a hemoglobinopathy. (See "Donor insemination" and "In vitro fertilization: Overview of clinical issues and questions", section on 'Oocyte donation'.)

●Adoption. (See "Adoption".)

●Late first or early second trimester fetal diagnostic testing, with pregnancy termination if the fetus is affected. (See "Overview of pregnancy termination".)

Additionally, the use of a gestational carrier allows the patient to avoid the maternal and fetal risks associated with pregnancy complicated by SCD. A gestational carrier either agrees to carry a pregnancy for another couple using the couple's embryos or to undergo insemination using sperm from the father or a donor. The goals are to avoid the maternal and fetal risks of SCD in the mother as well as avoiding the possibility of SCD in the offspring. (See "Gestational carrier pregnancy".)

Baseline health assessment and risks to the patient

Maternal risks — SCD affects multiple organ systems and is generally associated with an increased risk of SCD-related morbidity during pregnancy (table 1).

Meta-analyses have found increased risk of maternal deaths and obstetric and fetal complications compared with controls who do not have SCD [9,10]. Individuals with underlying cardiomyopathy, pulmonary hypertension, or infection are particularly vulnerable to decompensation at delivery and in the first postpartum week.

●Vaso-occlusive events – Vaso-occlusive or acute painful episodes increase during pregnancy and are the most common maternal SCD complications, occurring in over 50 percent of pregnancies [11-18]. Compared with the nonpregnant state, pregnancy in an individual with SCD is associated with increased risk of vaso-occlusive pain episodes, acute chest syndrome, and venous thromboembolism (VTE). The rate of vaso-occlusive pain episodes and acute chest syndrome is highest in the third trimester and up to one week after delivery; these account for 90 percent of pain and acute chest syndrome events during pregnancy and postpartum [12,19]. The risk of vaso-occlusive events may be increased in multiple gestation [20].

●Venous and arterial thromboembolism – SCD confers a similar risk of venous thromboembolism (VTE) as a high-risk thrombophilia, as well as a possibly increased risk of arterial thromboembolism.

•In a 2023 study using administrative claims data for 6388 people with SCD and 17,110 age- and race-matched controls who were followed during pregnancy through the first year postpartum, the rates of VTE and arterial thromboembolism were increased substantially [21]:

-VTE – 11.3 percent, versus 1.2 percent in controls

-Arterial thromboembolism – 5.2 percent, versus 0.6 percent in controls

•In a large retrospective study from 2008, the odds ratio (OR) for DVT in pregnant individuals with SCD was 2.5 (95% CI 1.5-4.1) [22]. Cerebral vein thrombosis was also increased (OR 4.9, 95% CI 2.2-10.9).

•The risk of postpartum VTE in individuals with a major risk factor such as SCD who have a cesarean birth is estimated to be >3 percent [23].

Venous thromboembolism prophylaxis is discussed below. (See 'VTE prophylaxis' below.)

●Infections – In the 2008 study above, pregnant individuals with SCD had increased risks of the following infections compared with pregnant individuals without SCD [22]:

•Pneumonia (OR 9.8, 95% CI 8.0-12.0)

•Sepsis (OR 6.8, 95% CI 4.4-10.5)

•Asymptomatic bacteriuria (OR 6.8, 95% CI 3.1-14.9)

•Genitourinary tract infection (OR 2.3, 95% CI 1.9-2.7)

●Pregnancy complications – A meta-analysis found increased risks of preeclampsia (OR 2.05, 95% CI 1.47-2.85) and eclampsia (OR 3.02, 95% CI 1.20-7.58) [10].

The cesarean birth rate tends to be higher in individuals with SCD. The increased rate may be related to a higher frequency of pregnancy complications, along with other factors. Some centers have policies for a short trial of labor and early operative intervention at the first sign of a nonreassuring fetal heart rate tracing in individuals with SCD [24]. (See 'Vaginal versus cesarean birth' below.)

●Mortality – SCD is associated with increased risks of maternal death in observational studies, although SCD may be a surrogate for decreased access to health care, racial bias, or other health care disparities.

•A 2015 meta-analysis of cohort studies that included over 26,800 pregnancies in individuals with SCD and 26 million pregnancies in individuals without SCD found a relative risk (RR) of death associated with SCD of 5.98 (95% CI 1.94-18.44) [9]. SCD may be a surrogate for decreased access to health care; higher maternal mortality risk was most pronounced in regions with lower gross national income in this and other studies [10].

•A 2015 study from Ghana reported maternal death in two of 149 patients with SCD, which corresponds to a maternal mortality ratio of 1300 maternal deaths per 100,000 live births [2]. By comparison, in 2017, the overall maternal mortality ratio for Ghana was 308 per 100,000 live births and for the United States 19 per 100,000 live births [25].

•A 2008 study from the United States that included nearly 18,000 deliveries with a discharge diagnosis of SCD and 17 million deliveries without SCD found a disproportionate rate of maternal deaths associated with SCD (1 percent of maternal deaths, despite accounting for only 0.1 percent of pregnancies) [22]. There were 10 deaths in the SCD group (72 deaths per 100,000 deliveries versus 12.7 deaths per 100,000 deliveries without SCD).

•A study of data from the United States National Inpatient Sample (2012 to 2018) that included 3901 deliveries in people with SCD among a total of over 5 million deliveries found that the maternal mortality ratio in the SCD group was 26 times greater than in the non-Black control group without SCD and >10 times greater than in Black pregnant people without SCD (SCD: 133 deaths per 100,000 deliveries, Black race without SCD: 12 deaths per 100,000 deliveries, non-Black race without SCD: 5 deaths per 100,000 deliveries) [26].

The majority of deaths during pregnancy in SCD are sudden. Acute respiratory failure, often associated with acute chest syndrome or pulmonary embolism, is commonly described [27-30]. Acute multiorgan failure is often present.

SCD genotype may affect complication rates, as in nonpregnant individuals, but any individual with SCD may experience complications. Some studies have suggested a lower risk of complications with Hb SC disease than Hb SS, but others have not found differences [11,19,31-33].

Sickle cell trait has not been found to be an independent risk factor for pregnancy complications other than urinary tract infections and possibly VTE.

Pediatric outcomes — A pooled analysis of 16 studies conducted through 2014 revealed the following increased pediatric risks in SCD pregnancies [10]:

●Perinatal mortality (OR 3.76, 95% CI 2.34-6.06).

●Fetal growth restriction (OR 2.79, 95% CI 1.85-4.21).

●Preterm birth (OR 2.14, 95% CI 1.56-2.94).

●Low birthweight (OR 2.00, 95% CI 1.42-2.83).

Pre-pregnancy evaluations — The following evaluations are generally performed (table 1):

●Blood pressure – Measurement of baseline blood pressure. Hypertension may be due to sickle nephropathy and is a risk factor for stroke and development of superimposed preeclampsia. (See "Sickle cell disease effects on the kidney" and "Overview of the clinical manifestations of sickle cell disease", section on 'Stroke and TIA' and "Chronic hypertension in pregnancy: Prenatal and postpartum care", section on 'Patients with superimposed preeclampsia'.)

●Complete blood count (CBC) and ferritin – Individuals with SCD should have routine monitoring of hemoglobin or hematocrit. Ferritin levels may increase due to increased iron stores from transfusional iron overload. Iron deficiency is also possible but less common; reports from low- and middle-income settings where chronic blood transfusion is not used have documented that a significant proportion of individuals with SCD start pregnancy with iron deficiency anemia. Individuals with excess iron stores may benefit from treatment prior to becoming pregnant (or in delaying pregnancy until treatment is discontinued). (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy' and 'Other medicines to start or stop' below.)

●Kidney function – Chemistry panel, urinalysis, and creatinine to determine baseline organ function, particularly sickle nephropathy [34]. We obtain a baseline assessment of urinary protein excretion (eg, spot urine for protein to creatinine ratio or albumin to creatinine ratio). Urine albumin is less sensitive but may be used if resources are limited. Knowledge of baseline parameters is important because both pregnancy and preeclampsia (which is common in SCD patients) may worsen kidney function. (See "Sickle cell disease effects on the kidney" and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

●Pulmonary function – SCD management guidelines do not recommend routine pulmonary function tests prior to pregnancy; however, low forced expiratory volume in one second (FEV₁) in adults with SCD is known to be associated with earlier death and is predictive of acute chest syndrome [35]. Thus, at a minimum, baseline FEV₁ measurement and pulse oximetry are desirable because pregnancy in individuals with SCD carries increased risks of pulmonary embolism, acute chest syndrome, and broncho-reactive lung disease [36]. The underlying obstructive and restrictive airway disease in SCD as well as the physiological changes in lung function may have significant impact on pregnancy outcome; as an example, FEV₁ <60 of predicted value during pregnancy is associated with stillbirth [37]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Pulmonary complications'.)

●Urine culture – Asymptomatic bacteriuria and urinary tract infections are more common in individuals with SCD. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Asymptomatic bacteriuria'.)

●Viral and sexually transmitted diseases – All pregnant individuals, regardless of hemoglobinopathy status, are routinely screened for viral and sexually transmitted diseases including HIV, hepatitis B and C, and syphilis. (See "The preconception office visit", section on 'Laboratory assessment'.)

●Blood bank testing – Individuals with SCD have often received multiple transfusions and may have developed alloantibodies. These may complicate pretransfusion testing and identification of compatible red blood cell (RBC) units, as well as increase the risk of hemolytic disease of the fetus and newborn (HDFN), depending on whether the fetus expresses RBC antigens (due to variants inherited from the father) to which the mother carries alloantibodies [6,7]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

Pretransfusion testing and extended phenotypic matching (for RhD, C, E, and Kell antigens) is appropriate to facilitate transfusion if needed. Additional analyses such as molecular testing for RhD variants that create incomplete antigens may also be appropriate [38-42]. Discussion with a transfusion medicine and/or maternal-fetal medicine specialist may be warranted. (See 'Maternal care' below.)

If RBC alloantibodies are present, the father should be tested for the corresponding antigens and a determination made of whether there is a risk for HDFN [43]. Management is discussed separately. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

●Retinal evaluation – Early proliferative sickle retinopathy may worsen during pregnancy, and a dilated retinal examination by an ophthalmologist is appropriate if not done in the previous year. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Retinopathy'.)

●Echocardiogram – We generally perform a screening echocardiogram in individuals with possible symptoms of pulmonary hypertension (dyspnea or chest pain at rest or with exertion, sleep-disordered breathing, syncope or presyncope) and asymptomatic individuals with a history of pulmonary embolism, recurrent acute chest syndrome, or resting hypoxemia, consistent with a 2022 practice advisory from the American College of Obstetricians and Gynecologists (ACOG) [44].

There are no formal guidelines to screen for pulmonary hypertension in individuals with SCD prior to pregnancy. Limited preliminary evidence justifies screening with an echocardiogram for pulmonary hypertension and early cardiac dysfunction, which are associated with increased mortality during pregnancy [45]. Until additional evidence becomes available, we favor an individualized approach to determining the use of echocardiography. (See "Acquired heart disease and pregnancy" and "Overview of the clinical manifestations of sickle cell disease", section on 'Cardiac complications'.)

Vaccines and medication management

Vaccines — Immunization status should be reviewed and updated, as needed, to comply with current guidelines. Polyvalent pneumococcal, Haemophilus influenza type B, and meningococcal vaccines are recommended for pregnant patients with SCD. Additional vaccines appropriate for all pregnant individuals, including COVID-19, influenza, tetanus, diphtheria, and pertussis, should follow the latest guidelines from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). Pregnancy should be avoided for at least four weeks after administration of any live vaccine, such as the live-attenuated influenza vaccine, and no live vaccines should be administered during pregnancy. (See "Standard immunizations for nonpregnant adults" and "Immunizations during pregnancy".)

Hydroxyurea — Hydroxyurea (hydroxycarbamide) is the major disease modifying therapy for SCD; it has been clearly demonstrated to improve survival and to reduce the incidence of acute chest syndrome, vaso-occlusive pain, and other complications. (See "Hydroxyurea use in sickle cell disease", section on 'Evidence for efficacy'.)

Discussions regarding continuing or temporarily stopping hydroxyurea are appropriate for both parents and should occur before conception. Education should be provided based on the latest available evidence and guidance, with shared decision-making. The following may be relevant:

●Females

•Fetal risks – Evidence regarding the effect of hydroxyurea on the risk of congenital anomalies is limited to animal studies and small numbers of case reports; reports of prenatal exposure to hydroxyurea, alone or in combination with other drugs, are few.

A 2022 review of 1788 pregnancies in individuals with SCD documented that 241 (16 percent) occurred while the mother was taking hydroxyurea [46]. On multivariate analysis, use of hydroxyurea at conception (including the month prior to conception) and continuing during pregnancy was associated with an increased risk of miscarriage or stillbirth (odds ratio [OR] 2.21, 95% CI 1.40-3.47) and an increased risk of low birth weight (<5.5 pounds/2500 grams) in full-term live born infants (OR 2.98, 95% CI 1.09-7.38), but not with increased risk for preterm birth, serious medical problems, or congenital anomalies. The increased risks for miscarriage, stillbirth, and low birth weight were not observed in patients who only used hydroxyurea up to the time of conception and stopped it once aware of the pregnancy. These associations do not demonstrate causality, as individuals who continued to take hydroxyurea during pregnancy may have had other risk factors or comorbidities that affected outcomes.

An increase in congenital anomalies was not seen in the 2022 study and a 2021 study of similar size [46,47]. However, animal studies have demonstrated teratogenic effects of hydroxyurea when administered during organogenesis [48-51].

•Whether to discontinue – The choice to continue or discontinue hydroxyurea must balance the risks of vaso-occlusive complications, which could in turn harm the fetus, and direct fetal harm from the medication itself. Other considerations include how quickly the individual will become pregnant, which impacts the length of time they would be deprived of a disease-modifying therapy, and the presence (and spectrum) of RBC alloantibodies, which could impact the ability to find compatible RBC units for transfusion as an alternative to hydroxyurea.

We generally do not discontinue hydroxyurea during pregnancy, since we are unaware of direct evidence of teratogenicity in humans, whereas evidence is very strong for increased vaso-occlusive complications without hydroxyurea. However, each individual must consider the risks and benefits for their individual situation.

-Continuing the medication may be acceptable for individuals with frequent or severe vaso-occlusive complications.

-Discontinuing may be acceptable for those with mild disease (eg, sickle-beta⁺ thalassemia) who place a high value on avoiding unknown effects on fetal development or pregnancy loss.

The 2014 SCD guideline suggests that hydroxyurea should not be used during pregnancy and breastfeeding but notes that the quality of the evidence was low [7].

•Timing – Individuals who choose to discontinue hydroxyurea may stop the medication as early as three months prior to attempted conception. Since the greatest time of potential risk of miscarriage or teratogenesis is the first trimester, discontinuation at the time of conception is another option. Resumption may occur after delivery (longer interval without hydroxyurea), or during the second and third trimesters (shorter interval without hydroxyurea). The risk-benefit calculation may change in the second and third trimesters, where teratogenicity is no longer a major concern and vaso-occlusive pain events and acute chest syndrome are more frequent.

Use of hydroxyurea during breastfeeding is also of unclear risk. Shared decision-making should occur to determine the overall best plan for the mother and infant, including potential benefits of breastfeeding for both the mother and infant. Evidence is discussed below. (See 'Breastfeeding' below.)

●Males

•Risks – Some observational studies have suggested that hydroxyurea can reduce sperm counts and sperm motility, with improvement after hydroxyurea is discontinued (a reversible effect) [52-56]. A 2022 Cochrane review concluded there was insufficient evidence to conclude whether hydroxyurea affects fertility [57]. SCD may independently affect sperm quality [54].

•Whether to discontinue

-Fetal outcomes – We believe there is a very low risk of adverse fetal outcomes if the father has SCD and is taking hydroxyurea during attempted conception [58]. In contrast, continuing hydroxyurea may reduce vaso-occlusive complications in the father. Fathers can make an informed decision about whether to discontinue hydroxyurea during attempted conception based on available research and their own clinical status.  

-Paternal outcomes – Data and decision-making related to possible effects on fertility are discussed separately. (See "Hydroxyurea use in sickle cell disease", section on 'Fertility'.)

•Timing – If a decision is made to discontinue hydroxyurea, a suggested interval is three to six months prior to attempted conception.

●Regular transfusions as an alternative to hydroxyurea – For individuals who choose to discontinue hydroxyurea and experience (or expect to experience) an increase in vaso-occlusive complications, regular blood transfusions may be an alternative, provided that phenotypically matched blood is available and transfusions are feasible. Other individuals may choose to reserve transfusions for acute complications.

Other medicines to start or stop — All medications should be reviewed and discussed to ensure that there is an opportunity to stop potentially harmful medications (after appropriate risk-benefit discussion) and appropriate medicines such as folic acid are being taken at the optimal dose.

●Hydroxyurea – Discussed above. (See 'Hydroxyurea' above.)

●Start or continue

•Prenatal vitamins; iron only if needed – Individuals with SCD can take a prenatal vitamin, but they may need to supplement with extra folic acid, as discussed below. If the ferritin level is increased (or iron overload is known to be present), they should use a prenatal vitamin without iron.

Individuals with iron deficiency should be treated with iron. In limited resource settings, where the cost of iron studies may be prohibitive, selected use of iron supplementation is offered to patients when the clinical assessment suggests iron deficiency. (See "Anemia in pregnancy", section on 'Treatment of iron deficiency'.)

•Folic acid – All individuals who are or may become pregnant are advised to take supplemental folic acid to reduce the risks of neural tube defects. Individuals with SCD also have chronic hemolytic anemia, which further increases folate requirements. There is consensus among experts that individuals with SCD should take a higher dose of folic acid (4 mg daily, rather than 0.4 to 0.8 mg daily that is recommended for individuals without SCD or in prenatal vitamins [1 mg]) [59,60]. We provide this dose for the entire pregnancy, due to ongoing increased RBC turnover. In low-resource settings, especially in sub-Saharan Africa where the combined effects of SCD, malaria, and malnutrition may compound the risk of anemia, 4 mg folic acid daily, started at least three months before pregnancy, may be vital [61]. A 2020 guideline from the European Hematology Association recommends using at least 0.8 to 1 mg of folic acid daily in high-resource settings [62]. (See "Preconception and prenatal folic acid supplementation".)

•Analgesics – SCD can cause chronic and severe vaso-occlusive pain that must be adequately controlled. In general, therapies used when the individual is not pregnant can be continued, with the exception of nonsteroidal antiinflammatory drugs (NSAIDs), which can have adverse fetal effects when used for >48 hours, particularly after 30 weeks. Details of the pain evaluation (to help determine whether pain is due to vaso-occlusion or another complication) and management (including use of a pain plan) are discussed separately. (See "Evaluation of acute pain in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)

Management of pain episodes during pregnancy is discussed below. (See 'Prevention and treatment of acute painful episodes' below.)

•Malaria prevention, if indicated – (See "Malaria in pregnancy: Prevention and treatment" and "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

●Discontinue

•ACE inhibitors and ARBs – Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are known human teratogens that should not be used during pregnancy. Individuals using these agents should be switched to an alternative medication, ideally at least one month before attempted conception. Extended-release nifedipine, labetalol, and methyldopa are antihypertensive medications with a good safety profile in pregnancy. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy" and "Sickle cell disease effects on the kidney", section on 'Hypertension' and "Treatment of hypertension in pregnant and postpartum patients", section on 'Choice and safety by drug class'.)

•Iron chelators – Use of iron chelation is rare in individuals attempting conception. If an individual is taking an iron chelating agent, they can discontinue it when they become pregnant. In animal studies, deferasirox did not increase the risk of congenital anomalies at doses lower than those used in humans, but deferoxamine was associated with congenital anomalies [63,64]. Exposure data are limited in humans, but no toxic or teratogenic effects have been reported [65]. Individuals with excessive iron stores should consider delaying pregnancy until iron stores have been reduced. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Individuals of reproductive potential who are taking these medications should keep close track of their menstrual cycles and take a pregnancy test if menses are late.

Most individuals with SCD discontinue prophylactic penicillin at approximately age five years, and we do not initiate penicillin during pregnancy.

Sickle cell trait — It is not clear whether individuals with sickle cell trait require any modification to routine pre-pregnancy or pregnancy care because of their carrier status, with the exception of genetic counseling, paternal hemoglobinopathy testing, and maternal urine culture once per trimester. (See 'Counseling prior to pregnancy' above and 'Likelihood of SCD in offspring and reproductive options' above and 'Maternal care' below.)

A study that reviewed medical records of Black females with sickle cell trait and Black females without sickle cell trait did not find an association of sickle cell trait with increased risk of VTE; however, the study was underpowered to detect small differences [66]. In a nonpregnant population, others have observed an increased risk of VTE (albeit weak) in African Americans with sickle cell trait compared with controls [67,68]. This should be taken into consideration but generally does not warrant pharmacologic VTE prophylaxis based on sickle cell trait alone. (See "Sickle cell trait", section on 'Venous thromboembolism' and 'VTE prophylaxis' below.)

DURING PREGNANCY

Maternal care — Complication risks vary from individual to individual and may be lower with certain genotypes (Hb SC or Hb S-beta⁺ thalassemia); all pregnancies in individuals with SCD are considered high risk and warrant the higher level of expertise of a maternal-fetal medicine physician and access to multidisciplinary care.

Implementation of active management protocols for pregnancy in SCD have demonstrated survival benefits, such as a decrease in the mortality rate from 27 percent to 1.8 percent in Benin, Africa [69]. A multidisciplinary care protocol in Ghana resulted in a nearly 90 percent reduction in the risk of maternal death [3]. A 2022 meta-analysis of studies from low- and middle-income countries showed that multidisciplinary care resulted in consistently lower maternal and perinatal mortality rates for individuals with SCD compared with lack of multidisciplinary care [70].

In the SCD obstetric care protocol by the obstetric SCD comprehensive program in Ghana, we provide a joint antenatal review by an obstetrician with experience in high-risk pregnancy and a hematologist with interest in SCD in a program coordinated by the SCD nurse [71]. We advocate a similar approach elsewhere.

Care includes the following (table 1):

●Baseline health assessment and counseling – Baseline health assessments and counseling are provided if not done prior to conception. Even if counseling was provided, there may be a benefit of reviewing information and allowing the individual to ask additional questions. (See 'Baseline health assessment and risks to the patient' above and 'Counseling prior to pregnancy' above.)

●Routine prenatal evaluations – Individuals with SCD should be provided with the same routine prenatal care as the general obstetric population; these are listed separately. (See "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters" and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs".)

Pregnancies with maternal alloantibodies (or a history of alloantibodies) should be evaluated for risk of hemolytic disease of the fetus and newborn (HDFN) and managed accordingly. In addition, the blood bank should be notified so that compatible blood is available for transfusion, if needed. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy" and 'Transfusion therapy' below.)

●SCD-specific evaluations – Early detection of SCD complications is essential, as is distinguishing pregnancy complications from SCD complications. As an example, in patients with neurological signs and symptoms, it is important to distinguish preeclampsia with severe features from cerebrovascular disease related to SCD. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Preeclampsia: Clinical features and diagnosis", section on 'Neurologic'.)

Given the possibility of placental ischemia, monitoring fetal growth with ultrasound and fetal well-being with nonstress tests or biophysical profile scoring is recommended during the third trimester [72,73]. (See "Fetal growth restriction: Evaluation" and "Overview of antepartum fetal assessment".)

Management of preeclampsia, placental abruption, or fetal growth restriction is the same as for individuals without SCD. (See "Preeclampsia: Antepartum management and timing of delivery" and "Acute placental abruption: Management and long-term prognosis" and "Fetal growth restriction: Pregnancy management and outcome", section on 'Prenatal care'.)

●Pain plan – It is useful to have an individualized pain care plan available to all clinicians who may be responsible for the patient if they have a vaso-occlusive painful episode. Individualized pain care plans should provide a sequence of medications to try at home and an algorithm for when to send the patient to a day hospital (or emergency department), with opioid doses and other interventions. (See "Acute vaso-occlusive pain management in sickle cell disease".)

●Hydration – Adequate hydration should be advised. During pregnancy, adequate fluid intake is estimated to be approximately 2.3 L/day (76 fluid ounces or approximately 10 cups). Additional water is consumed in foods to meet the total adequate intake of 3 L/day. Ambient temperature, humidity, exercise, and other physical activity should also be taken into consideration in determining the daily total fluid requirement. If there is nausea or vomiting, we err on the side of aggressive treatment. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Fluid requirements'.)

●Hemoglobin testing and transfusion plan – Hemoglobin is monitored monthly. For those receiving chronic transfusions, the percentage of Hb S should also be determined.

•Iron – Individuals receiving chronic or intermittent transfusions are unlikely to have iron deficiency. In regions of the world where transfusion for SCD is not commonly used, evaluation of iron status may be appropriate and may inform decision-making about the need for iron supplementation [74]. If the ferritin is low, indicating iron deficiency, then treatment is appropriate. Pregnancy and SCD both increase ferritin levels, and revised normal ranges may be required. If iron overload is present, prenatal vitamins without iron should be used. (See "Anemia in pregnancy".)

•Transfusions – Indications for transfusion should be clearly documented in the patient's medical record. The main purpose of transfusion is to reduce the percentage of Hb S and decrease vaso-occlusive complications, as well as to treat severe anemia and acute blood loss. Data on obstetric outcomes (stillbirth, growth restriction, preterm birth) are limited to a single trial that did not show an effect [75]. Details are discussed below. (See 'Transfusion therapy' below.)

Close communication with the transfusion service helps ensure that compatible blood is available for transfusion if needed.

●Infections – Individuals with SCD and sickle cell trait are at risk for bacteriuria and hematuria. Screening and treatment of bacteriuria are indicated because asymptomatic bacteriuria during pregnancy increases the risk of pyelonephritis and has been associated with preterm birth and low birth weight infants. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)

•If bacteriuria is present on initial urine culture, we provide antibiotic therapy and retest monthly until delivery. If bacteriuria recurs or persists, we give suppressive therapy for the remainder of pregnancy.

•If the initial urine culture is negative, some clinicians screen once per month and some screen once per trimester each trimester [73]. We do a culture once every four to six weeks in individuals with SCD and once per trimester in those with sickle cell trait. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Management'.)

●Medications

•Hydroxyurea – (See 'Hydroxyurea' above.)

•Folic acid – Folic acid is continued during pregnancy (typical dose for individuals with SCD who are pregnant, 4 mg daily). (See 'Other medicines to start or stop' above.)

•Low-dose aspirin – The incidence of preeclampsia is high in individuals with SCD (approximately 10 to 33 percent based on meta-analyses) [10,76]. We administer low-dose aspirin daily from the beginning of the second trimester or after 12 weeks, unless contraindicated [77]. This is consistent with multiple medical society guidelines. Dosing and supporting evidence are reviewed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

•LMW heparin

-During hospitalization – Unless contraindicated, all hospitalizations except labor and delivery should include venous thromboembolism (VTE) prophylaxis. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis'.)

VTE prophylaxis around the time of delivery and postpartum is discussed below. (See 'VTE prophylaxis' below.)

-Ambulatory/outpatients – Patients with SCD have an increased risk of VTE, and VTE prophylaxis during the entire pregnancy is appropriate for some high-risk patients (such as those with a history of VTE or a high-risk thrombophilia). (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Patients who are pregnant' and "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)

•Anti-D immune globulin – Recommendations are the same as for individuals without SCD. (See "RhD alloimmunization in pregnancy: Overview" and "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

●Home-based prophylactic oxygen therapy – In SCD, oxygen demands may be increased due to several factors including anemia, sleep-disordered breathing, nocturnal desaturations, hypoxia, and/or asthma. Preliminary data from a retrospective study suggest that prophylactic nocturnal oxygen therapy may decrease transfusion requirements and complications, particularly in high-risk individuals, but this is not routinely practiced [78]. In this study, oxygen was administered at 2 to 3 L/minute via an appropriately sized nose piece.

Prenatal (fetal) diagnosis of SCD — Invasive and noninvasive methods for diagnosis of SCD in the fetus are available if this information would inform decisions about termination of pregnancy or if the mother desires this information for other reasons. SCD does not present until approximately six months of age (when beta globin production increases), so there are no known implications for fetal health. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Chorionic villus sampling (CVS) – Performed at 10 to 14 weeks of gestation. (See "Chorionic villus sampling".)

●Amniocentesis – Can be performed as early as 15 to 16 weeks. (See "Diagnostic amniocentesis".)

●Cell-free fetal DNA in maternal blood – Technology is available for single gene noninvasive prenatal testing (NIPT) for HBB (the beta globin gene) [79-81]. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis", section on 'Fetal diagnosis'.)

Spontaneous pregnancy loss (miscarriage) and termination — Spontaneous pregnancy loss and termination are usually well-tolerated in individuals with SCD, but the risk of complications may be greater (eg, due to baseline anemia [82]).

We generally recommend surgical rather than medical management of spontaneous pregnancy loss or pregnancy termination, similar to all patients with bleeding disorders or severe anemia. In a randomized trial on medical versus surgical management of spontaneous pregnancy loss in the general population, surgical management was associated with overall less blood loss [83]. For this reason, we prefer surgical over medical management for individuals with severe anemias or bleeding disorders.

Details are presented separately. (See "Pregnancy loss (miscarriage): Description of management techniques", section on 'Surgical management (uterine aspiration)' and "First-trimester pregnancy termination: Uterine aspiration".)

Prevention and treatment of acute painful episodes

●Prevention – The cornerstone of prevention includes use of disease-modifying therapies (see 'Hydroxyurea' above and 'Transfusion therapy' below) and avoiding precipitating factors. Dehydration, hypoxia, acidosis, infection, and cold should be avoided as they may precipitate an acute pain event [59].

●Treatment – There are limited data on SCD pain management specific to pregnancy, and our approach to management parallels management in nonpregnant individuals [84]. Standard aspects of management include:

•Prompt evaluation for precipitating factors (dehydration, hypoxia), potential causes (particularly infection), and alternative diagnoses.

•Oral or intravenous fluid resuscitation.

•Aggressive and rapid pain control, similar to that used for individuals with SCD who are not pregnant [85].

-Mild pain may be treated with acetaminophen. Nonmedicinal strategies (massage, warm heating pads, mind-body techniques) may be sufficient to manage the pain or hasten recovery. Nonsteroidal antiinflammatory drug (NSAID) use should be minimized, but a short course (<48 hours) is reasonable given the lack of a clearly safer alternative. Whether NSAID use in the first trimester increases the risk of miscarriage, cardiac anomalies, or gastroschisis is unclear; epidemiologic studies have reported conflicting results [63]. NSAIDs are generally avoided after approximately 30 weeks of gestation because of an increased risk of premature narrowing or closure of the ductus arteriosus and oligohydramnios. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Inhibition of acute preterm labor", section on 'Fetal side effects'.)

-Moderate pain may be treated with hydrocodone with or without acetaminophen. Nonmedicinal strategies may be a helpful adjunct.

-For severe pain, opioids are the therapy of choice. Continuous infusion by patient-controlled analgesia (PCA) is useful because it provides the most even pain control within the therapeutic window without side effects, along with the option for self-administration of additional doses for breakthrough pain. However, PCA administration requires rigorous monitoring and appropriate expertise to determine the correct settings and avoid complications.

-Epidural analgesia may be appropriate in some cases for extreme pain, but this is unusual.

Routine use of oxygen is not indicated during an acute vaso-occlusive pain episode unless there is evidence of a clinically significant decrease in hemoglobin oxygen saturation from the individual's baseline (typically, of more than four percentage points). The rationale is that supplemental oxygen may mask a decline in clinical status or reduction in oxygen saturation and result in delays in care. Additional information about evaluating pain and treating vaso-occlusive pain is presented separately. (See "Evaluation of acute pain in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)

Management of other complications of SCD — Complications of SCD such as acute chest syndrome or infection are generally managed as in nonpregnant individuals. Maintaining a high index of suspicion and acting promptly is critical. Fever is a medical emergency as individuals with SCD are immunosuppressed due to functional asplenism. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Risk of life-threatening infection'.)

●Evaluation and differential diagnosis – Early evidence of impaired pulmonary, liver, kidney, or central nervous system function should be considered a sign of an impending life-threatening event, and investigation for the cause of the worsening function should be undertaken immediately [30]. Concern about the possible effects of ionizing radiation should not prevent medically indicated diagnostic imaging studies using the best available modality for the clinical situation. Although ultrasound and magnetic resonance imaging are preferred in pregnancy, when imaging studies requiring ionizing radiation are necessary, various techniques can be employed to minimize the radiation dose.

The standard differential diagnosis of SCD complications should be expanded to include pregnancy-related disorders. (See "Overview of the clinical manifestations of sickle cell disease".)

•Respiratory symptoms may be due to acute chest syndrome, pulmonary embolism, cardiomyopathy, pulmonary hypertension, severe anemia, asthma exacerbation, or other causes. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)" and "Pulmonary embolism in pregnancy: Clinical presentation and diagnosis" and "Overview of the pulmonary complications of sickle cell disease".)

•Neurologic changes (headache, visual changes, seizures) may be a component of multiorgan failure or may be due to transient ischemia, stroke, meningitis, or preeclampsia/eclampsia. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Preeclampsia: Clinical features and diagnosis" and "Evaluation and management of fever in children and adults with sickle cell disease".)

•Liver function abnormalities may be related to hepatic sequestration crisis, preeclampsia with severe features, or HELLP syndrome. (See "Hepatic manifestations of sickle cell disease" and "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

A missed or delayed diagnosis of pulmonary embolism can pose a greater risk than the hazard associated with ionizing radiation. (See "Diagnostic imaging in pregnant and lactating patients" and "Pulmonary embolism in pregnancy: Clinical presentation and diagnosis", section on 'Diagnostic imaging'.)

●Interventions – Pain should be treated effectively, and appropriate supportive care should be provided as needed (oxygen, hydration). (See 'Prevention and treatment of acute painful episodes' above.)

Transfusion is appropriate for acute chest syndrome, acute stroke, multiorgan failure, and aplastic crisis. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Individuals with SCD who require hospitalization for a complication (SCD-related or obstetric) should generally receive VTE prophylaxis with a low molecular weight (LMW) heparin or unfractionated heparin, unless contraindicated. However, anticoagulation may preclude or delay administration of neuraxial anesthesia for labor and delivery. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis' and "Use of anticoagulants during pregnancy and postpartum" and "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

Other interventions depend on the specific complication.

●Medication risks – The risks of specific medications used to treat or prevent these complications during pregnancy can be checked by searching the drug name in UpToDate and reading the reproductive and pregnancy considerations sections of the drug information topic. The pregnancy risks need to be weighed against the risks of alternative medications or no treatment. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)" and "Evaluation and management of fever in children and adults with sickle cell disease".)

Transfusion therapy — Transfusions are commonly used during pregnancy to treat acute complications, in preparation for surgery, and in selected preventive transfusion programs.

In most cases, the purpose of transfusion is to reduce the percentage of Hb S, not to increase the total Hb level. An exception is acute parvovirus infection, which can cause transient aplasia and severe anemia in individuals with chronic hemolytic anemia.

In fact, raising the Hb too high (>10 mg/dL) may be detrimental to most individuals; the baseline Hb in many individuals with SCD is approximately 8 g/dL. Increased Hb can cause hyperviscosity syndrome. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Risk of hyperviscosity syndrome from simple transfusion'.)

Specific uses of transfusion include:

●Acute complications – Certain acute vaso-occlusive complications of SCD are treated with transfusions, which can decrease morbidity and in some cases mortality. Accepted indications for therapeutic transfusion therapy in individuals with SCD include acute stroke, acute chest syndrome, acute multiorgan failure, acute symptomatic anemia, reticulocytopenia (most commonly associated with Parvovirus B19 infection, but can occur with any infection), or following hepatic or splenic sequestration. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

●Preparation for surgery – Simple transfusion is used prior to many surgeries in SCD. The rationale is based on improved outcomes, as discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.)

Simple transfusion can also be used prior to scheduled cesarean birth. (See 'Labor and delivery' below.)

●Chronic/prophylactic transfusion – Chronic prophylactic transfusions are one of the few effective disease-modifying therapies for SCD other than hydroxyurea, and they may be needed in individuals with frequent vaso-occlusive complications (acute chest syndrome, acute pain episodes) who have temporarily stopped hydroxyurea during pregnancy. (See 'Hydroxyurea' above.)

The routine use of chronic transfusions during pregnancy remains controversial, despite several observational studies and randomized trials, and there is no clear consensus on when to use this approach. The 2020 American Society of Hematology (ASH) guideline on transfusion in SCD suggests that regular transfusion be considered if there is a history of severe SCD-related complications, either prior to the current pregnancy or with previous pregnancies; or if other high-risk features are present such as other comorbidities or nephropathy [86]. In these individuals, transfusions may be given during the third trimester (when vaso-occlusive complications are most common) or earlier. (See 'Maternal risks' above.)

Evidence for pregnancy outcomes (fetal growth restriction, preterm birth) is limited. Available evidence on maternal outcomes includes:

•In the seminal randomized trial including 72 pregnant patients with SCD, routine prophylactic transfusions led to a reduction in acute painful episodes (5 of 36 patients [14 percent] receiving chronic transfusions versus 18 of 36 controls [50 percent], p<0.01) [87]. Other outcomes were not affected, but the number of patients and events was small.

•A 2015 meta-analysis that included 12 observational studies (1291 patients) found that prophylactic transfusions were associated with reduced maternal mortality (odds ratio [OR] 0.23, 95% CI 0.06-0.91), reduced painful episodes (OR 0.26, 95% CI 0.09-0.76), and reduced pulmonary complications (OR 0.25, 95% CI 0.09-0.72) [88]. However, these studies had a moderate to high risk of bias and low event rates.

•In nonpregnant individuals with SCD, chronic transfusions are effective in reducing some complications such as stroke in individuals at increased stroke risk [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Evidence for chronic transfusion'.)

Potential reductions in adverse events must be weighed against the harms and burdens of transfusion, including transfusion reactions, risk of alloimmunization, hospitalization rate, and cost.

Transfusion techniques, including using leukoreduced RBCs, extended phenotypic matching, and choice between simple and exchange transfusion, are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

LABOR AND DELIVERY

Vaginal versus cesarean birth — There are no medical contraindications to a trial of labor and vaginal birth, and in general, cesarean birth is reserved for standard obstetric indications. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Indications'.)

Discussion of the birth plan should be initiated early to allow an ongoing discussion. The plan should be individualized based on maternal and fetal health, and the patient should be prepared for the possibility that their plan may change over the course of the pregnancy and that cesarean birth may be necessary. Optimally, cesarean birth can be scheduled, but labor complications may necessitate an urgent/emergency procedure.

Timing — The risk of stillbirth and preeclampsia increases with increasing gestational age, but no high-quality studies have determined the optimal gestational age for delivery in individuals with SCD.

We generally recommend delivery at 37 to 39 weeks, with the exact timing decided on an individual basis.

●Evidence to support delivery at 39 weeks comes from the 2018 ARRIVE trial, which compared induction of labor at 39 weeks and 0 days to 39 weeks and 4 days of gestation versus expectant management for >6000 low-risk nulliparous patients (general United States population, not SCD-specific) [89]. Induction at 39 weeks resulted in a reduction in cesarean birth, a reduction in hypertensive disorders of pregnancy, and a trend toward a reduction in the composite of perinatal death or severe neonatal complications, compared with expectant management. (See "Induction of labor with oxytocin", section on 'At 39 weeks'.)

●Delivery closer to 37 weeks may be appropriate for individuals with high-risk genotypes (Hb SS or Hb S-beta⁰-thalassemia) or those with known SCD complications or comorbidities such as frequent vaso-occlusive episodes or hypertension. The reasoning is based on the high risk of placentally-mediated complications (growth restriction, oligohydramnios) [90].

Monitoring and supportive care

●Transfusion prior to cesarean birth – If there is time, simple transfusion prior to cesarean birth is reasonable in patients at increased risk of complications because of chronic lung disease, central nervous system disease, or multiorgan dysfunction. We target a hemoglobin of ≥8 g/dL, if possible, at one to two hours before delivery. Evidence from nonpregnant individuals with SCD demonstrates improved perioperative outcomes with preoperative transfusion, as discussed separately. (See 'Transfusion therapy' above and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.)

●Fetal monitoring – Continuous intrapartum fetal heart rate monitoring is appropriate due to the high risk of complications. (See 'Maternal risks' above and 'Pediatric outcomes' above and "Anesthesia for labor and delivery in high-risk heart disease: General considerations".)

●Preventing vaso-occlusive complications – The patient should be kept warm, hydrated, and well oxygenated to reduce the risk of acute pain events and other vaso-occlusive complications.

•Hydration – Adequate fluid intake (oral or parenteral) is important so the mother is well hydrated. Fluid balance is important because some individuals with SCD are at risk for fluid retention from subclinical cardiomyopathy [91].

•Analgesia/anesthesia – Neuraxial anesthesia is useful to reduce maternal cardiac demands due to pain and anxiety during labor. For patients undergoing cesarean birth, neuraxial anesthesia is generally preferable to general anesthesia, but the choice is influenced by a variety of factors, such as the urgency of the procedure, maternal hemodynamic status, and physician and patient preference. (See "Neuraxial analgesia for labor and delivery (including instrumental delivery)" and "Pharmacologic management of pain during labor and delivery" and "Anesthesia for cesarean delivery".)

•Oxygen – Supplemental oxygen should be given as needed to maintain O₂ saturation ≥95 percent. For cesarean births, intranasal oxygen should be given intraoperatively for regional anesthesia and continued for 12 to 24 hours after surgery. Incentive spirometry, every two hours while the patient is awake, should be instituted for 48 hours after cesarean birth to reduce the risk of acute chest syndrome [71]. Continuous positive airway pressure (CPAP) should be considered if chest signs and/or symptoms develop or if O₂ saturation drops to <92 percent [59]. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Prevention'.)

●Antibiotics – Antibiotic prophylaxis should follow local standards (ie, patients with SCD do not require more aggressive antibiotic therapy). (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Antibiotic prophylaxis'.)

Cord blood — An umbilical cord blood specimen collected at the time of birth can be used for newborn screening for hemoglobinopathy and other disorders (as an alternative to heel stick). Details of testing methodologies and interpretation are presented separately. (See "Diagnosis of sickle cell disorders", section on 'Newborn screening'.)

Umbilical cord blood also may be harvested for use in hematopoietic stem transplantation (HSCT) for a relative with SCD; cord blood can be used for HSCT if the child is unaffected with SCD or if they have sickle cell trait. (See "Collection and storage of umbilical cord blood for hematopoietic cell transplantation" and "Hematopoietic stem cell transplantation in sickle cell disease".)

POSTPARTUM CARE

Surveillance for maternal complications — Close maternal surveillance for infection and thromboembolism is important, especially after cesarean birth (table 1).

Anorexia, nausea, urinary tract infection, wound infection, endometritis, and venous thromboembolism (VTE) are more common after cesarean than vaginal birth. The risk of fat and bone marrow embolism may increase during the postpartum period [92].

VTE prophylaxis — VTE risk is increased in individuals with SCD, as outlined above. (See 'Maternal risks' above.)

Based on this increased risk, for individuals with SCD, we follow the recommendations for postpartum VTE prophylaxis in high-risk populations and use prophylactic anticoagulation (typically, low molecular weight [LMW] heparin) [93]. VTE prophylaxis should be continued for six weeks postpartum. (See "Inherited thrombophilias in pregnancy", section on 'Our approach to patients with high-risk thrombophilias'.)

This is consistent with guidelines from the American Society of Hematology (ASH) and the American College of Obstetricians and Gynecologists (ACOG) on thromboembolism prevention in pregnancy, both of which recommend prophylactic anticoagulation postpartum in individuals with high-risk thrombophilias [23,93,94].

Mechanical thromboprophylaxis (pneumatic compression) is recommended for all individuals undergoing cesarean birth and is suggested in addition to anticoagulation for those at highest risk of VTE due to multiple risk factors. Early ambulation and adequate hydration are also helpful.

Sickle cell trait is a weak risk factor for VTE but the risk is not great enough to warrant pharmacologic VTE prophylaxis based on sickle cell trait alone. Clinicians should take this into consideration but should follow the general protocols for VTE prevention in pregnancy. (See "Venous thromboembolism in pregnancy: Prevention", section on 'Indications' and "Sickle cell trait", section on 'Reproductive issues'.)

Breastfeeding — Breastfeeding should be encouraged for its maternal and infant health benefits. (See "Maternal and economic benefits of breastfeeding" and "Infant benefits of breastfeeding" and "Initiation of breastfeeding" and "Breastfeeding: Parental education and support".)

While breastfeeding was previously discouraged in individuals taking hydroxyurea, research from 2020 shows that there is very little transfer of hydroxyurea into breastmilk. In a study involving 16 individuals who were taking hydroxyurea, a mean of 2.2 mg of the drug was present in breastmilk for a 1000 mg daily maternal dose, corresponding to a relative infant dose of 3.4 percent, which is below the 5 to 10 percent safety threshold [95]. Approximately 1.2 mg are excreted during the first three hours after taking hydroxyurea; beyond hour 3, there is very little hydroxyurea in breast milk, and by hour 6 there is essentially none. Thus, as a precaution, the individual can take her daily dose immediately after a feeding or pumping or can consider a single after-dose pump and dump maneuver [95].

The safety of other medications during breastfeeding can be checked by searching the drug name in UpToDate and reading the breastfeeding considerations section of the drug information topic, or by searching the drug name in other resources such as LactMed.

Restarting medications

●Hydroxyurea – If an individual was taking hydroxyurea prior to pregnancy and discontinued therapy during pregnancy, we restart hydroxyurea at the steady state dose the patient was on prenatally. This may be delayed during breastfeeding, or the individual may take the approach of breastfeeding while taking hydroxyurea, due to the health benefits of both and the very small amount of hydroxyurea in breast milk. This can be further reduced by timing the daily hydroxyurea dose just after feeding or pumping or considering a single after-dose pump and dump maneuver. (See 'Breastfeeding' above.)

It may take as long as six months after restarting hydroxyurea to reach the full therapeutic effect. (See "Hydroxyurea use in sickle cell disease", section on 'Increased Hb F production'.)

●Iron chelation – Individuals who were taking an iron chelator prior to pregnancy should have their iron status reevaluated postpartum, since pregnancy depletes at least 1 to 2 grams of iron. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Monitoring iron stores' and "Anemia in pregnancy", section on 'Iron deficiency'.)

Contraception — All individuals should be offered contraception. The choice of method is individualized. (See "Contraception: Counseling and selection".)

Because of the increased risk of VTE and stroke in females with SCD, combined hormonal contraceptives (with estrogen), which increase the risk of VTE and stroke, should be avoided. Progestin-only contraceptives (except for depot medroxyprogesterone acetate [DMPA]) are preferred [96]. DMPA, as opposed to other progestin-only contraceptives, has been found to increase the risk of VTE approximately twofold [96].

The levonorgestrel intrauterine device (IUD) decreases menstrual bleeding and is an excellent contraceptive choice. The copper IUD increases menstrual bleeding, which makes it less desirable in individuals with SCD. (See "Intrauterine contraception: Candidates and device selection".)

Infant care — Routine care is appropriate, and breastfeeding is encouraged. (See "Overview of the routine management of the healthy newborn infant" and 'Breastfeeding' above.)

In addition, the following SCD-specific considerations may apply:

●Hemoglobinopathy testing – This testing is part of routine newborn care in most of the United States. (See "Overview of newborn screening".)

In parts of the world where screening for hemoglobinopathy is not routine and paternal testing is not common, the neonate of a mother with SCD should be tested for hemoglobinopathy due to the high prevalence of hemoglobinopathy in offspring. In one study from Ghana, approximately 15 percent of offspring born to mothers with SCD also had SCD [2].

●Maternal opioid use – If the mother was receiving chronic opioid therapy during pregnancy to reduce vaso-occlusive pain episodes, the neonate should be monitored for neonatal abstinence syndrome. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

●Breastfeeding with hydroxyurea – Some individuals may breastfeed while restarting hydroxyurea (details to minimize risk are discussed above), some may forego breastfeeding to start hydroxyurea, and some may delay restarting hydroxyurea to allow breastfeeding. (See 'Breastfeeding' above and 'Restarting medications' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Before conception

•Counseling – Discuss the likelihood of sickle cell disease (SCD) in a child, reproductive options, possible cord blood banking, plans regarding hydroxyurea, and the option of genetic counseling. (See 'Counseling prior to pregnancy' above and 'Likelihood of SCD in offspring and reproductive options' above and 'Spontaneous pregnancy loss (miscarriage) and termination' above.)

•Maternal and fetal risks – Maternal risks include increased vaso-occlusive complications (pain, acute chest syndrome), infections, preeclampsia, and mortality, especially in the third trimester. Fetal risks are increased for preterm birth, low birth weight, intrauterine growth restriction, and perinatal mortality. (See 'Maternal risks' above and 'Pediatric outcomes' above.)

•Evaluations – Evaluations are required to assess iron status and red blood cell (RBC) alloantibodies, prevent infection, and document underlying organ function (table 1). (See 'Pre-pregnancy evaluations' above.)

•Medications – A nuanced discussion should occur regarding whether to continue hydroxyurea, timing of discontinuation, and use of transfusions. Iron chelators and other contraindicated medicines are discontinued. Opioids can continue. Appropriate vaccines are administered. Prenatal vitamins can be used, but some individuals should omit iron, and the recommended dose of folic acid is higher (4 mg daily) (Grade 2C). (See 'Vaccines and medication management' above.)

●During pregnancy

•Assessments – Review baseline health assessments and counseling. Second- and third-trimester assessments include blood pressure; urine protein; fetal screenings (including hemolytic disease of the fetus and newborn (HDFN) in individuals with alloantibodies or a history of alloantibodies); and, in addition to routine prenatal testing, testing for asymptomatic bacteriuria (table 1). We increase ultrasound screening for fetal growth restriction and fetal assessment in the third trimester. (See 'Maternal care' above.)

•Complications – Vaso-occlusive pain prevention involves disease-modifying therapies (hydroxyurea or transfusions) and avoiding dehydration, hypoxia, acidosis, infection, and cold. Pain is treated promptly and adequately. Nonsteroidal antiinflammatory drugs (NSAIDS) are avoided. Transfusions may be used to treat or prevent complications. (See 'Prevention and treatment of acute painful episodes' above and 'Management of other complications of SCD' above and 'Transfusion therapy' above.)

●Labor and delivery

•Delivery – There are no medical contraindications to vaginal delivery; cesarean birth is reserved for obstetric indications. Induction of labor at 37 to 39 weeks is reasonable (even without maternal or fetal complications), with details individualized to genotype and comorbidities. (See 'Vaginal versus cesarean birth' above and 'Timing' above.)

If time allows, simple transfusion prior to cesarean birth is reasonable in patients at increased risk of complications. Continuous fetal heart rate monitoring is appropriate. The patient should be kept warm, hydrated, and well oxygenated. Umbilical cord blood can be used for newborn screening and harvested for hematopoietic stem cell transplant if desired. (See 'Monitoring and supportive care' above.)

•Venous thromboembolism (VTE) prophylaxis – After cesarean or vaginal delivery, we suggest prophylactic dose low molecular weight (LMW) heparin rather than no VTE prophylaxis (Grade 2C). (See 'VTE prophylaxis' above.)

●Postpartum

•Breastfeeding and medications – Breastfeeding should be encouraged and is possible in individuals taking hydroxyurea. If hydroxyurea was restarted, it may take up to six months for full therapeutic effect. Iron status should be evaluated before restarting chelation. (See 'Breastfeeding' above and 'Restarting medications' above.)

•Contraception – Contraception should be discussed. Progestin-only contraceptives or nonhormonal methods are preferred. Estrogen-containing contraceptives and depot medroxyprogesterone acetate (DMPA) increase the risk of VTE and generally are not the best choice. The levonorgestrel intrauterine device (IUD) decreases menstrual bleeding and is an excellent contraceptive; the copper IUD increases bleeding, making it less desirable in individuals with SCD. (See 'Contraception' above.)

•Infant – Hemoglobinopathy testing is routine in some countries; if not, it should be performed. If the mother was receiving chronic opioid therapy, the neonate should be monitored for opioid withdrawal. (See 'Infant care' above.)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges Elliott P Vichinsky, MD, who contributed to earlier versions of this topic review.