Narrative review of patient blood management and transfusion for obstetric care

Introduction

Historically, medical and surgical care in pregnancy has largely been reactive, focused on managing adverse outcomes. Transfusions have aided the care of pregnant individuals and their fetuses or newborns for decades. Advances in instrumentation, techniques, and pharmacologic therapies have progressively enhanced the safety and efficacy of transfusion practices across the antepartum, intrapartum, and postpartum periods. In this narrative review, we examine the role of transfusion medicine in obstetric care, along with adjunctive interventions used to address associated pathophysiological processes. This review highlights strategies for the prevention, mitigation, and treatment of conditions such as maternal anemia, postpartum hemorrhage (PPH), fetal anemia, and fetal thrombocytopenia, with the goal of reducing maternal and fetal morbidity and mortality. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-13/rc).

Methods

We conducted a comprehensive search of PubMed, Google Scholar and in references of other publications from March 1, 2015, to March 31, 2025. Eligible publications included literature reviews, meta-analyses, randomized and non-randomized studies, and case reports that addressed maternal anemia, PPH, fetal anemia, fetal thrombocytopenia, intrauterine transfusion (IUT), and obstetric blood management and transfusion practices. Exclusion criteria were publication not published in the English language. The search terms are available in Table 1. Identified literature was reviewed for relevant references that were included where appropriate. This article is presented in accordance with this journal’s narrative review reporting.

Discussion

Maternal anemia

Epidemiology

Anemia in pregnancy is common, occurring in over 30% of pregnant women and is associate with adverse fetal and maternal outcomes (1). It is defined as a hemoglobin of less than 11 g/dL in the 1st or 3rd trimester, or 10.5 g/dL in the 2nd trimester (2). Screening for anemia is recommended in the first trimester and again between 24–28 weeks’ gestation (2). Optimal level of hemoglobin at the time of delivery is >10.6 g/dL (3). Anemia can be physiological, due to an expansion of plasma volume relative to red blood cell volume (4), or pathological secondary to an underlying disorder. The most common causes of pathologic anemia are iron deficiency, other nutritional deficiencies such as vitamin B12 and folate, as well as hemoglobinopathies such as thalassemia and sickle cell disease.

Etiology

Iron deficiency is common in pregnancy due to iron loss in menstruating women and increased requirements from the growing fetus, often in sequential pregnancies. During the third trimester, there is a significant increase in iron requirements that are difficult to keep up with just by increasing intestinal absorption. Demands for iron in the third trimester include 300 mg for the fetus, 50 mg for the placenta, 450 mg for increased maternal red cell mass, 250 mg mother’s “basal” losses and 250 mg for blood loss during normal vaginal delivery (5). Maternal anemia has been associated with increased neonatal mortality, low birth weight, neurodevelopmental problems (6), increased risk of cesarean delivery, postpartum anemia, and five times increased risk of blood transfusion (7). Severity of anemia correlates with higher risks of placental abruption, PPH, increased length of stay, renal failure, pneumonia and maternal intensive care admission (8).

Identification/management

Iron deficiency is diagnosed with a ferritin less than 30 ng/mL. Ferritin screening is recommended by the Internal Federation of Gynecology and Obstetrics and the European Hematology Association (9), however, the United States Professional Services Task Force in 2024 stated there was insufficient evidence to recommend for or against ferritin screening (10).

Iron deficiency anemia can be treated with oral or intravenous iron. Oral iron is recommended in the 1st trimester (due to lack of safety studies of intravenous iron in the 1st trimester) and in mild iron deficiency in the 2nd trimester. There is increasing evidence that every other day dosing oral iron is as effective as daily dosing, while leading to fewer side effects (11,12). Oral iron is cheap and readily available, however, up to 70% of pregnant women have side effects such as nausea, gastrointestinal reflux, and constipation. Increases in hemoglobin can be seen within 2–4 weeks of therapy in uncomplicated cases. Intravenous iron is indicated when oral iron is not tolerated, or effective, and in later pregnancy when a hemoglobin increase is needed more quickly. Iron dextran, ferumoxytol, and ferric derisomaltose can be given in one infusion, while iron sucrose requires at least four infusions for the same dose; all are equally safe in pregnancy (13-15). Intravenous iron is well tolerated, with a small percentage of patients experiencing minor infusion reactions and a very low risk of anaphylaxis.

Folate and vitamin B12 deficiency are considered when anemia and macrocytosis are present, though the mean corpuscular volume (MCV) can be normal with concurrent iron deficiency or thalassemia. They are diagnosed by measuring serum levels, with a vitamin B12 <200 pg/mL and folate <2 ng/mL as diagnostic (16). Prenatal vitamins contain 1 mg folate. Approximately 5 mg/day can be taken by patients who are deficient or at high risk of neural tube defects (16), including those with chronic hemolysis. Dietary sources of folate include a diet rich in legumes, green leafy vegetables and fortified grains. This provides sufficient folate for non-pregnant women. Folate supplementation recommended dose is 400 µg/day beginning before conception, or as soon as pregnancy is confirmed, and is continued up to 3 months postpartum. Folate requirement increases 8-fold in the last trimester and during lactation. Folate deficiency should be suspected when anemia has no response to iron therapy (17). Vitamin B12 deficiency is rare but may be seen in vegans and in patients with malabsorption (i.e., after some bariatric operations). Both oral and parenteral vitamin B12 replacement are effective, although intramuscular administration is preferred in those with absorption deficits (bariatric surgery, pernicious anemia), or neurologic sequela.

Additional consideration in managing maternal anemia

Patient blood management is a concept in which saving the patient’s own blood is the safest, versus requiring a transfusion. Management is optimized via preoperative correction of anemia, mitigation of blood loss, better surgical techniques and correcting coagulopathies and utilizing blood components to correct anemia and coagulopathies. Patient blood management in the obstetric setting decreases the incidence of anemia at delivery and the need for transfusion and optimizes outcomes at the time of delivery (18). The safest blood is the patient’s own blood, and antenatal anemia optimization is essential to minimizing transfusion requirements peri and postpartum due to the expected blood loss that occurs with delivery.

PPH

Epidemiology

Although other definitions exist, PPH is currently defined by the American College of Obstetrics and Gynecology (ACOG) as a cumulative blood loss >1,000 mL, or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours, regardless of route of delivery (19). PPH is a significant obstetric complication and is the leading cause of maternal morbidity and mortality globally (20-22). Worldwide it is the second leading cause of maternal admission to intensive care unit (ICU) and the leading cause of maternal mortality among maternal ICU admissions (21.8%) (23). In the United States, obstetric hemorrhage is associated with 11.4% of maternal deaths with a Pregnancy-Related Mortality Ratio of 1.8 per 100,000 live births (23). Rate estimates vary due to different definitions, but the overall incidence is estimated to be 6% of all deliveries (24). These hemorrhages can be massive (25,26).

Risk factors

Anticipation and preparedness are critical components in the management of PPH. Risk factors identified both antepartum and intrapartum can help clinicians anticipate hemorrhage. Examples of the more common risks include: abnormal placentation, fibroids, multiple gestation, grand multiparity, prior PPH, thrombocytopenia, preexisting coagulation defects, chorioamnionitis, prolonged labor and oxytocin use, magnesium sulfate prophylaxis for eclampsia, operative vaginal delivery, cesarean delivery, retained placenta and lacerations (24). Unfortunately, PPH often occurs in women without identifiable risk factors and can be life-threatening. Therefore, all delivery units and providers should be prepared to respond to this true obstetric emergency.

Key antenatal features of preparedness for those considered at increased risk for PPH include antenatal correction of pre-existing anemia and multidisciplinary planning with abnormal placentation (placenta previa and placenta accreta spectrum) (25,27,28). Additional components of organized preparedness include having standardized protocols for PPH management, development of obstetric rapid response teams, communication pathways for team members, simulation drills, massive transfusion protocols (MTPs) and transfer policies when higher acuity units are needed (19,25,29-31). A recent review of the impact of care bundles suggests that implementation can reduce hemorrhage-related complications and severe maternal morbidity (30). Once admitted for delivery, regular assessments of risk status during the intrapartum and postpartum periods are critical to early recognition and timely responses to PPH. All team members, including the blood bank, should be notified when a patient is identified as having a significantly increased risk for hemorrhage.

The etiologies for PPH generally fall into one of 4 categories referred to as the “4 T’s”: Tone, Tissue, Trauma and Thrombin (19,32). Uterine atony (poor muscle tone) accounts for up to 80% of PPH cases and is easily identified on physical examination. Oxytocin is commonly recommended after deliveries to reduce the risk for hemorrhage from uterine atony (33). Tissue-related etiologies for PPH include retained products of conception (placenta and membranes) and can be clinically identified by manual uterine exploration or ultrasound. Focally invasive placentas can sometimes present this way. Trauma from lacerations, uterine inversion, uterine rupture or tissue injury after both vaginal and cesarean deliveries can be a significant cause of bleeding. This can usually be identified by careful examination of the areas of concern with attention to adequate visualization. Lacerations may be difficult to identify when there is active bleeding obscuring the visual field. Inherited or acquired coagulation disorders are an infrequent, but important group of etiologies for PPH. Examples of pre-existing coagulation defects that might be already known include thrombocytopenia disorders, platelet function abnormalities, Von Willebrand disease (VWD), hemophilia, and other factor deficiencies. There are acquired coagulopathic conditions such as disseminated intravascular coagulopathy (DIC), which is most commonly secondary to hemorrhage, but can also develop rapidly after a large placental abruption, sepsis, severe preeclampsia or amniotic fluid embolism. Importantly, DIC is initially a clinical diagnosis based on various observations of delayed clot formation, as well as diffuse bleeding from previously hemostatic sites, from venipuncture sites and from other surfaces. PPH may often involve mixed etiologies, especially since both atony and DIC may develop after any significant hemorrhage that disrupts uterine perfusion, regardless of the reason.

Identification of PPH

The clinical diagnosis of PPH commonly relies on clinical judgment, which is variable and often inaccurate. Providers can overestimate losses, which can lead to unnecessary treatment, or underestimate losses that are higher than average, leading to delays in vital treatments (34). Visual analog systems are more useful (25). Another way to assess blood loss volume is quantitative blood loss (QBL). QBL uses weights and measures to assess blood loss, usually at the time of delivery, while subtracting other fluid volumes that can interfere with more precise measurement. While QBL is not perfect, it is considered more accurate than simple blood loss estimation by clinicians (31,34,35).

Management of PPH

Assessing the severity of a PPH can be challenging due to the nature of a rapidly evolving situation. One useful way to assess severity is to use class categories of stage 0–3 developed by the California Maternal Quality Care Collaborative (31). Briefly, stage 0 is the baseline for all patients and the normal postpartum bleeding management with expeditious delivery of placenta, uterine massage and oxytocin. Stage 1 includes all patients with >1,000 mL of estimated blood loss without evidence for clinical instability. Stage 2 is when there is ongoing bleeding with blood loss <1,500 mL. Management should be escalated based on estimated blood loss and not wait for clinical signs of instability. This typically includes transfusion of blood products. Stage 3 (massive bleeding) is considered with ongoing bleeding with an estimated blood loss >1,500 mL, vital sign instability, coagulopathy, or a continued need for blood products. Once stage 3 PPH is reached, the risks for severe maternal morbidity and mortality increase significantly and often require MTP.

Interventions to treat PPH should ideally target the specific etiology for the hemorrhage, although many of the management options are applicable to all etiologies and mode of delivery (Figure 1). The initial approach to PPH includes uterine massage and uterotonic medications to maintain or improve tone since atony is the primary etiology. Common medications include oxytocin (intravenous or intramuscular) and methylergonovine (intramuscular). Other medications such as misoprostol (oral or rectal), prostaglandin 15-methyl F2 alpha (intramuscular or intra-myometrial injection), prostaglandin E2 (rectal), and misoprostol (oral, sublingual or rectal) can be used after excluding other etiologies. Concurrently, there should be a uterine exploration with or without ultrasound to assess for retained tissue and careful examination for lacerations or traumatic injuries. Retained tissue can be removed manually or by curettage, and lacerations repaired as appropriate (19,25,31).

Figure 1 Management of postpartum hemorrhage. Reproduced in modified form by permission of Taylor & Francis Group from: Expecting Trouble: Early Warnings and Rapid Responses in Maternal Medical Care (1st edition), by Editor: Lauren Plante. Authors: Flicker A, Brown C, Smulian JC. Copyright 2018 by Imprint. CBC, complete blood count; IV, intravenous; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell.

Persistent bleeding requires additional interventions. Tranexamic acid (TXA) administration is considered in all cases of suspected or actual hemorrhage when activating a protocol, since there is little downside to its use and early administration is essential to effectiveness. TXA should be started as soon as PPH is recognized and within 30 minutes of initiation of uncontrolled bleeding. TXA studied in the WOMAN trial showed decreasing survival benefit of 10% with each 15 minutes delay in starting this medication, though, some benefit is present up to 3 hours after initiation of bleeding (36,37). The initial dose can be repeated in 30 minutes if needed. When using uterotonics there is no clear benefit of routinely giving TXA prophylactically for either vaginal delivery or caesarean section. However, prophylactic use for women at high risk for hemorrhage can be considered given the excellent safety profile (38).

PPH unresponsive to these measures may require escalation with interventions using devices such as balloon or suction tamponade devices (39). In the absence of these devices, multiple foley catheters with inflated balloons or gauze packing can be used, but effectiveness is limited. Uterine artery embolization is an important adjunct if available through interventional radiology. Continued escalation may require surgical interventions with uterine devascularization sutures, compression sutures and sometimes hysterectomy. However, there is limited data on the impact of these interventions from well-designed clinical trials (40).

Blood products for PPH

Timely administration of blood products is essential to the management of ongoing PPH. Blood products are temporizing measure to support the cardiovascular system while allowing the diagnosis and management of the primary etiology for the bleeding to occur. In stage 2 PPH (<1,500 mL blood loss), the pregnant patient may have stable vital signs but is at risk for compromised tissue perfusion. Since blood loss is usually acute, hemoglobin levels may not accurately reflect risk in the initial stages (41). Coagulation studies (including platelets counts) are needed to assess coagulation status. Therefore, when the estimated blood loss approaches 1,500 mL in the setting of ongoing bleeding, transfusion with 2 units of red blood cells (RBCs) should be considered empirically. This may initially require use of O negative Rh negative blood type, if the blood type is unknown, until appropriately cross-matched blood can be obtained. In-line filters and warming devices should be used as well given the need for rapid infusions. Coagulation factor replacement is generally not needed until blood loss exceeds 1,500 mL unless the INR is ≥1.7. However, delayed use of fibrinogen replacement should be avoided (42).

Massive transfusion is defined as replacement of one or more blood volumes, the need for 10 units RBC in 24 hours, or transfusion of 4 units RBC within one hour (43). Once a PPH becomes stage 3 (≥1,500 mL), a MTP should be activated (19,31) (Table 2). With this degree of PPH, there is usually a dilutional and consumptive coagulopathy. Therefore, therapy includes RBC and coagulation component replacement. Most MTPs require infusion of products in a fixed ratio of RBCs to fresh frozen plasma (FFP). Typically, there should be 1 single donor apheresis platelets administered for every 6 units of RBC and FFP (44). With the activation of the MTP, the first step is generally 4 units of both RBC and FFP and one single donor platelet pack (2 units of RBC have already been given). If additional blood products are needed, then the next administration should target a total of 6:6:1 of these products, based on the assessment of ongoing bleeding. This can be repeated, although the FFP volume may be reduced when combined with cryoprecipitate. Cryoprecipitate is often used in conjunction with FFP to replace fibrinogen with a lower risk of volume overload than FFP and should be considered with fibrinogen levels <200 or after the second round of MTP infusions (42). Frequent laboratory monitoring along with the degree of ongoing bleeding and clinical status will determine the need for continuation of blood product replacement. Laboratory evidence for successful resuscitation includes international normalized ratio (INR) <1.6, fibrinogen levels >200 mg/dL and platelets >100/µL. A hemoglobin level between 8–10 is generally sufficient to maintain organ oxygenation, although values may take a while to stabilize from the significant fluid shifts that occur with severe PPH and the use of MTP.

While there has been considerable support for the use of whole blood products for transfusion in acute trauma patients, the literature on the use of whole blood transfusions in the setting of obstetric hemorrhage is limited. Whole blood has been associated with less hemodilution, has a higher oxygen carrying capacity, and is intrinsically infused in a proper ratio compared with component transfusion (45). Several small case series have reported on the successful use of low-titer group O RhD-positive whole blood with few complications (46-48). Nevertheless, a whole blood transfusion program must consider the risk of isoimmunization in the transfused mothers and product inventory management. More research is needed to assess risk vs benefits of whole blood in this setting, as well as to determine optimum protocols.

Additional considerations for PPH management

Early use of fibrin products decreases the total hemorrhage, decreases the incidence of pulmonary edema and decreases the volume of transfusion (42). Additional adjuncts to guide transfusion and coagulopathy management are the use of a rapid viscoelastic hemostatic test to evaluate need for coagulation factors (replace with FFP) fibrinogen (replace with cryoprecipitate or fibrinogen concentrate) and platelet replacement, use of intravenous (IV) calcium to replete Ca²⁺ (to correct to levels >1.1 mmg/dL) and treatment of hyperkalemia (43,49-52). Hypothermia should be avoided since it is associated with worsening coagulopathy, cardiac arrhythmias and overall worse outcomes (52). Patients should be monitored for transfusion reactions, although detection of direct complications of transfusion may be difficult with very unstable patients. Fluid overload may require the use of diuretics. Following lactic acid levels can be used to evaluate tissue perfusion and lactate levels correlate with the need for transfusion in PPH (53). With a half-life of 20 minutes, it quickly decreases as tissues are perfused adequately.

Data supporting the use of recombinant factor VIIa in refractory severe PPH are limited, although it has been approved for this indication by several agencies in Europe; nevertheless, use is still guided by expert opinion (54,55). There is little information on the use of prothrombin concentrates in the management of PPH. Cell salvage may be used to decrease the use of blood components and crystalloids. It is especially helpful in patients who decline blood products for personal or religious reasons. Cell salvage is generally considered safe in obstetric procedures. There is a low risk of bacterial contamination (56), and it may also decrease the length of hospital stay (57). However, there often is not time to engage a cell-saver protocol and it may not be cost effective. It may also increase the risk of maternal fetal hemorrhage and alloimmunization (58-60).

Finally, there are several uncommon bleeding diatheses that can be associated with PPH. The most common of these is VWD, which is a group of quantitative or qualitative deficiencies in von Willebrand factor (vWF). These can be associated with immediate or even delayed PPH occurring 24 hours to several weeks after delivery. Therapy for hemorrhage in these cases may include desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP), vWF/factor VIII concentrates or more general factor replacement, preferably with cryoprecipitate rather than FFP, if factor concentrate is unavailable. Involvement of a hematology consultant is recommended in these cases since some subtypes of VWD have special care recommendations (61-64).

Fetal anemia

Epidemiology

Fetal anemia is defined as fetal hemoglobin that is more than 2 standard deviations below the mean for the gestational age (65). The incidence of fetal anemia may be due to many factors. These include isoimmunization status, pregnancy characteristics, medical conditions, genetic conditions and susceptibility to various environmental exposures including infectious agents. Likewise, there is no readily available statistic to estimate the incidence of fetal anemia sufficiently severe to require an IUT.

Risk factors

There are many immune and non-immune causes of fetal anemia (Table 3) and alloimmunization is the most common. Maternal sensitization most often occurs after maternal transfusion. In alloimmunization, maternal immunoglobulin G (IgG) antibodies cross the placenta and bind fetal RBCs with the corresponding, paternally derived RBC antigen. This results in a variety of sequelae including premature RBC destruction through hemolysis, extramedullary hematopoiesis, fetal hydrops, and fetal demise (65-67). The risk for fetal anemia due to alloimmunization is usually determined by assessing maternal antibody titers in the context of obstetric history. Once a critical titer is reached or if there is a history of a prior affected pregnancy, the current pregnancy is considered at risk. Historically, IUTs were primarily performed for severe hemolytic disease of the fetus/newborn (HDFN) secondary to anti-D, which is the most common cause of fetal alloimmunization. However, with the use of RhD immunoglobulin (RhIg) prophylaxis, the prevalence of anti-D alloimmunization has decreased and other maternal RBC antibodies for the non-D Rh antigens (C, c, E, e), Kell (K, k), Duffy (Fy^a), Kidd (Jk^a, Jk^b) and others have played a more important role in HDFN (65-68). Despite historic gains in the prevention of anti-D alloimmunization, recent supply chain issues leading to worldwide shortages of RhIg have the potential to adversely impact rates of anti-D Rh disease (69).

Infections are the most common non-immune cause of severe fetal anemia and, of these, parvovirus B19 is seen most often (65,70-72). Parvovirus B19 is a common viral infection of childhood. It is highly transmissible and, therefore, non-immune pregnant women who have children are vulnerable to infection. It can cause fetal anemia primarily by suppressing RBC maturation (erythropoiesis) in the fetus, especially with infections between 10–20 weeks of gestation (73). IUT has been shown to improve outcomes for fetal parvovirus B19 associated with severe anemia. Other infections such as cytomegalovirus (CMV), toxoplasmosis and syphilis are also known to cause fetal anemia, although the role of fetal transfusions is less certain in these cases. Note that many congenital infections are also associated with fetal thrombocytopenia.

There are also a few inherited conditions associated with fetal anemia including hemoglobinopathies (74). Alpha thalassemia major (hemoglobin H or Bart’s disease) is one of the most encountered, especially in at-risk populations, and IUT may allow for in utero survival in order to become eligible for a bone marrow transplant (75). Many of the other inherited conditions can be suspected based on a prior affected pregnancy or through detailed genetic screening tests that have become more common. There are other miscellaneous causes of fetal anemia, many of which can be identified by prenatal ultrasound (Table 3).

Diagnosis of fetal anemia

Historically, fetal anemia was diagnosed using spectrophotometric analysis of the amniotic fluid obtained by invasive amniocentesis to determine the delta optical density 450 (bilirubin) as a measure of hemolysis. This is no longer routinely used (76). Pregnancies at risk for anemia, identified either by having reached a critical RBC antibody titer in alloimmunization cases or having another identified fetal anemia risk factor are now monitored for fetal anemia by fetal ultrasound. Current evaluations for fetal anemia use non-invasive fetal pulse Doppler interrogation of the fetal middle cerebral artery (MCA). Peak systolic velocities that are greater than 1.50 multiples of the median for gestational age (angle of insonation of close to 0°) are considered suggestive of clinically significant fetal anemia with a pooled sensitivity of 79%, specificity of 73% and false positive rate of 27% (65,66,68,70,77-79). The accuracy is technique dependent.

Management of fetal anemia

There are several approaches to the management of significant fetal anemia. IUT is a specialized procedure in which blood products, most commonly red blood cells or platelets, are delivered directly to the fetus to address life-threatening hematologic conditions such as severe anemia or thrombocytopenia (65,66,76,77,80). In 1963, Dr. Albert William Liley reported the first successful intraperitoneal IUT in fetuses with hemolytic disease due to Rh incompatibility, which was a key milestone in fetal therapy (81). IUT demands a multidisciplinary team that includes maternal-fetal medicine, neonatology, obstetric anesthesia, and transfusion medicine specialists. Advancements in ultrasound technology and blood product preparation have continuously refined this procedure, improving both safety and outcomes for affected fetuses.

Once fetal anemia is suspected with fetal MCA Doppler assessment by ultrasound, fetal blood sampling and IUT via cordocentesis should be offered (65,66,70,80). Depending on placental location, fetal position, clinical scenario and clinical preference, the transfusion site may vary between umbilical cord insertion, intrahepatic umbilical vein, a free loop of cord, intracardiac or the fetal intraperitoneal space. The most common location for needle placement is at the umbilical cord insertion site in the placenta, which has relatively low complication rates. However, some data suggest that intrahepatic vein transfusions are technically straightforward with few complications (82,83). The procedure involves ultrasound-guided placement of a sufficiently long needle (20–22 gauge) into the planned infusion vessel or intraperitoneal space. Smaller needles are preferred if there is a risk for fetal thrombocytopenia. For intravascular transfusions, a sample of fetal blood is obtained, and a rapid fetal hematocrit is obtained to establish the degree of anemia. This is used to estimate the amount of blood to transfuse. A MCV of the sample can help confirm that the sample is fetal and not maternal blood since fetal MCV values are higher than for adults. This confirmation is often omitted if the hepatic vein is used for the transfusion. Use of a short-acting neuromuscular blocking agent such as atracurium, rocuronium or vecuronium (IM or IV) can be given directly to the fetus to temporarily reduce or stop fetal movement, which may make the procedure easier (65,67,70,77,80,82).

Typically, a transfusion is initiated while waiting on the results of the initial blood sample. Once obtained, the total amount of blood to be transfused can be calculated at the bedside using the starting hematocrit, the fetal weight estimate, the blood product RBC concentration, and the desired post transfusion hematocrit. The goal for post transfusion hematocrit should be between 40–50% (65,67,70,77,80). There are a number of formulas that can be used to determine the volume to be transfused (77,84). The primary source of donated blood is from O-negative typed blood that is cross-matched with maternal blood, screened for human immunodeficiency virus (HIV), hepatitis B and C, and CMV. If possible, extended antigen matching should be used to reduce the risk for alloimmunization to other clinically significant blood group antigens (85). The blood should be irradiated to lower the risk of graft versus host disease and should occur within 24 hours of the anticipated procedure to minimize the risk for hyperkalemia (86). The blood should preferably be donated within 7 days and packed to a hematocrit of >75% using an automated cell washer or manual centrifugation with discarding of the supernatant which reduces the risk for IUT-related fetal hypervolemia (70,82). Finally, the blood should be gradually warmed above the storage temperature to decrease the risk for fetal bradycardia (87). There is a useful step-by-step guide to performing an IUT described in the clinical guideline #8 from Society for Maternal-Fetal Medicine, although there can be variations specific to institutions or clinical circumstances (65,82).

Oftentimes serial transfusions are needed throughout the pregnancy up to 34–35 weeks of gestation. Transfusion is generally repeated every 1–2 weeks but may be needed as early as 48 hours if the post-transfusion hematocrit goal was not achieved (66,65,70,82). This procedure poses potential risks of infection, preterm labor, premature rupture of membranes, abruption, fetal or maternal bleeding, worsening alloimmunization and fetal death. The risk of fetal death has been reported to be between 1–3% and higher risk for fetal gestation less than 24 weeks or in the presence of hydrops (65).

Additional considerations for the management of fetal anemia

There are several situations that warrant special consideration. If there is very severe fetal anemia with cardiomegaly or hydrops, it is prudent to perform the initial transfusion in stages several days apart. This can give the fetus time to adapt to the IUT and avoid an acute volume overload from high volume transfusion that can lead to cardiovascular collapse and fetal demise (88). When a fetus is less than 18–20 weeks gestational age or if there is no easy access to fetal vessels, an intraperitoneal IUT can be considered (89). Blood infused into the fetal intraperitoneal cavity can be absorbed through the lymphatic system into the fetal vascular system. Advantages include easier access and slower sustained absorption to correct the anemia. Disadvantages include variability in absorption, limited absorption once fetal ascites has developed and potentially cardiovascular compromise with acute increased in intraabdominal pressure. Finally, in a pregnancy with a history of early severe fetal disease, intravenous immunoglobin (IVIG) can be started prior to 18 weeks. This may reduce early fetal hemolysis and allow the pregnancy to advance to a gestational age where an IUT can be performed more readily (66).

Recent advancements in noninvasive prenatal testing have expanded its scope beyond conventional aneuploidy screening to include the detection of fetal red blood cell antigens through cell-free fetal DNA (cfDNA) analysis (90-92). There are additional targeted antibody-based approaches seeking to limit maternal anti-RBC antibodies’ ability to induce hemolysis (93,94). In the future, gene therapy may offer a definitive solution for selected hereditary causes of fetal anemia, including alpha-thalassemia and other severe hemoglobinopathies (95,96). Experimental approaches employing viral vectors, or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based, gene editing seeks to correct or modulate pathogenic genes in utero, thereby potentially preventing anemia and its complications from the outset (97-99). Although these genetic approaches remain largely in the preclinical realm, early data indicate their feasibility and potential to shift care paradigms from reactive intervention to proactive prevention (100).

Fetal thrombocytopenia

Epidemiology and risk factors

Fetal thrombocytopenia is uncommon with the incidence dependent on the etiology. There are several risk factors and etiologies for fetal thrombocytopenia including immune associated, congenital infections, genetic/inherited and neoplasia (101,102) (Table 3). Immune-associated thrombocytopenias are among the most common of etiologies and fetal and neonatal alloimmune thrombocytopenia (FNAIT) is considered one of the most challenging. FNAIT affects about 1/2,000 live births, is often severe and is associated with intrauterine fetal intracranial hemorrhage (103). FNAIT is similar to RBC alloimmunization in that maternal anti-platelet antibodies cross the placenta and attack paternally derived human platelet antigens (HPAs). Accelerated platelet destruction leads to severe fetal and neonatal thrombocytopenia with subsequent significant risk for intrauterine intracranial hemorrhage, fetal death and other fetal or neonatal sequelae. Between 7–10% of HPA-1a antigen negative women will have antibodies (103-105).

Other immune disorders can be associated with fetal thrombocytopenia. Approximately 10–20% of pregnancies with immune thrombocytopenia due to lupus, or immune thrombocytopenic purpura, will have fetal thrombocytopenia, although the majority are not severe (102). The degree of thrombocytopenia in these conditions does not seem to respond to maternal therapy and is not correlated with the severity of the maternal thrombocytopenia.

Other causes of fetal thrombocytopenia include a variety of fetal infections such as CMV, toxoplasmosis, parvovirus B19, rubella, HIV, enterovirus, and adenovirus. Aneuploidy has been associated with fetal thrombocytopenia, although it is usually not severe. There are other genetic or inherited conditions that have been associated with fetal thrombocytopenia, some of which can be suspected based on ultrasound findings, family history or broad scope genetic screening and testing (101,102) (Table 3).

Diagnosis of fetal thrombocytopenia

FNAIT may be suspected if fetal intracranial hemorrhage is diagnosed on ultrasound (106). Approximately 95% of cases of FNAIT are caused by five antigens. The most common are HPA-1a and HPA-5b, followed by HPA-2, 3 and 15; HPA-1a accounts for 80–90% of cases (103). Testing is recommended for suspected cases. This testing is performed in selected reference laboratories that are set up to perform this specific testing. FNAIT is usually identified based on a history of a previous pregnancy that was affected. Unfortunately, subsequent pregnancies often have worse outcomes. The highest risk pregnancies are in those with a prior affected pregnancy complicated by a fetal intracranial hemorrhage (103-105).

Invasive testing for thrombocytopenia is not currently recommended for most other causes of fetal thrombocytopenia. The presence of associated infections is usually managed based on the specific infection, independent of thrombocytopenia risk. Therefore, the diagnosis of low platelets is usually made in the neonatal period. Although there are promising options for the future, there are currently no widely used non-invasive tests to screen for fetal thrombocytopenia.

Management of fetal thrombocytopenia

The two main approaches to manage severe fetal thrombocytopenia due to FNAIT includes: maternal administration of intravenous immunoglobin with or without steroids, and intrauterine platelet transfusions (80,103,107-109). IVIG is considered the standard of care first line management. IVIG has been shown to reduce the risk for severe thrombocytopenia and intracranial hemorrhage, when combined with a scheduled cesarean delivery (107-109). Due to success of medical management of fetal thrombocytopenia, the increased procedural risks of needle induced hemorrhage and short half-life of the transfused platelets, intrauterine fetal platelet transfusion is considered a distant secondary treatment option (70,80,103,110). Although there are other causes of fetal thrombocytopenia, none has been shown to benefit from a platelet transfusion protocol. However, if a cordocentesis is performed to diagnose a suspected fetal infection, a platelet count should be measured, and the team should be prepared to administer a platelet transfusion if needed to decrease the risk for bleeding from the puncture site (72,80).

There are several considerations for fetal platelet transfusions if this is selected as a therapeutic option. IUT of platelets should be withheld for platelet counts >50,000 U/L, should be prepared from HPA compatible donors and should be irradiated and CMV-safe (110,111). Warming prior to transfusion is recommended with a slower infusion than for RBCs to decrease the risk of stroke (87,111). One commonly used formula to estimate the volume of platelet concentrate to transfuse is: volume to transfuse= [fetal weight × 0.14 × (fetal platelet count desired − fetal platelet count pretransfusion) divided by platelet count of donor unit] (111). Although rarely used, percutaneous intrauterine fetal sampling without transfusion has been used to determine route of delivery in patients with fetal thrombocytopenia since fetuses with platelets below 50,000 may have an increased risk of intrapartum intracranial hemorrhage with labor. Most fetuses with FNAIT or suspected severe anemia are delivered by cesareans with careful technique to minimize the risk for delivery-related intracranial hemorrhage.

Other considerations for the management of fetal thrombocytopenia

Several investigations have demonstrated the feasibility of detecting HPA-1 in maternal circulation using cfDNA to offer earlier and more precise risk stratification for FNAIT (112-114). There are novel strategies underway to develop anti-HPA-1a monoclonal antibodies that selectively block maternal immunoglobulins from binding to fetal platelets, thereby reducing or obviating the need for intrauterine platelet transfusions (115,116).

Conclusions

This review highlights the prevention, mitigation, and treatment of high-risk pregnancies in order decrease morbidity and mortality due to conditions and complications such as maternal anemia, PPH, HDFN and FNAIT. Improvement of obstetric care to mitigate maternal anemia and acute obstetric hemorrhage using strategies for anemia optimization, better evaluation of blood loss with improvement in QBL assessments, optimization of MTP to include better laboratory testing and coagulation therapies, can improve outcomes. The management of PPH, HDFN and FNAIT is currently mostly reactionary, which leads to areas of clinical care that can be significantly improved upon with further technological advances. Ultimately, a combination of advanced prenatal diagnostics, immunomodulatory treatments, and gene-targeted interventions could reshape the management of fetal hemolytic disease and thrombocytopenia, shifting care from reactive to proactive and offering better outcomes for both mother and child.

Acknowledgments

None.

Footnote

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