Placental Causes of Anemia

Placental abnormalities may lead to fetal blood loss (Table 23.2).

Diagnosis

The usual approach is to examine maternal blood for fetal erythrocytes using the Kleihauer–Betke stain or flow-cytometric techniques [21, 22]. These two techniques correlate well [23, 24], but there are data to show that anti Hb F flow cytometry has greater precision [25] and some laboratories may only offer one of these tests. Anti-D flow cytometry is only useful in the setting of a mother who is D antigen negative and a fetus who is D antigen positive. The formula used to determine the amount of fetal blood in the maternal circulation is [26]:

% fetal RBCs × maternal blood volume = volume of fetal blood in maternal circulation.

Variations of this formula have been reported and a normal fetal Hct should be assumed rather than the actual fetal Hct as a massive FMH may cause severe fetal anemia [27].

Because fetal cells may be cleared quickly from the maternal circulation, delay in assessment may prevent the identification, or underestimate the volume, of fetal blood lost into the maternal circulation, especially if there is a blood-group incompatibility between the infant and mother. False-positive results of Kleihauer–Betke testing can occur if the mother has an increased percentage of hemoglobin F in her own cells, as may occur with the hereditary persistence of fetal hemoglobin, aplastic anemia, or use of cancer chemotherapy [28]. Combined antibody flow cytometry may occasionally useful in this setting [27]. Fetal ultrasound abnormalities and/or non-stress test may not be reliably sensitive to the identification of fetal anemia but Doppler studies of fetal middle cerebral artery (MCA) flow velocity are a useful technique to identify fetal anemia [29–31]. Fetal tachycardia and/or a sinusoidal wave pattern on fetal heart rate may be suggestive of fetal anemia [31, 32].

Management

As with acute hemorrhage, the initial management of the neonate with acute severe fetomaternal bleeding is volume expansion using isotonic crystalloid solutions and possibly red blood cell transfusion. Chronic bleeding, not resulting in severe or symptomatic anemia, can be managed with iron supplementation.

Outcomes

Rubod found that massive fetomaternal hemorrhage accounted for 1.6% of all fetal deaths identified over a 7 year review in two university hospitals for an overall rate of 1.3 deaths from this disorder per 10,000 live births [33]. Risk factors for adverse neonatal outcomes include an initial neonatal hemoglobin <4 g/dL, or an estimated fetal blood loss of >20 ml/kg [15, 33, 34]. Similarly, there was a 71% rate of adverse outcomes in Christensen’s series with risk factors including an initial Hb < 5 g/dL or birth at less than 35 weeks gestational age [16]. When the calculated fetal blood loss is corrected for the estimated fetoplacental blood volume, there is good correlation with the fetal/neonatal hemoglobin concentration [15].

Clinical Manifestations

Most infants with TTTS are born early and suffer complications of prematurity. Following laser therapy, prematurity is still a problem, occurring in 17% prior to 28 weeks, 30% before 32 weeks and 50% before 34 weeks [37]. The neonatal findings will then not only reflect the placental anastomosis-mediated diseases, but also the consequences of prematurity.

In a study of patients treated in their center, Verbeek et al. looked at the hematologic outcomes of the donor and recipient twins as to whether they had been treated conservatively (expectant management or serial amnioreduction), treated with complete laser coagulation [44]. In addition, they assessed those treated with complete laser coagulation but who had persistent TTTS or TAPS. The results, shown in Table 23.3 show the incidence of anemia in the donor twin and polycythemia in the recipient twin by whether the twins were treated conservatively, had a complete laser, had persistent TTTS after laser (incomplete laser), spontaneous TAPS, or acute peripartum TTTS. Table 23.4 shows the need for blood transfusions in donor twins and plasma exchange transfusion in recipient twins if treated conservatively or having persistent TTTS or TAPS, but much lower rates for twin pairs treated successfully.

In addition to plethora, a number of other systems may be involved in the recipient. Cardiac findings include biventricular hypertrophy and tricuspid regurgitation [45]. Hyperviscosity secondary to polycythemia perhaps with the addition of vasoconstriction due to activation of the renal angiostensin system can result in vascular occlusion which may manifest with limb necrosis [46, 47]. Broadbent identified 16 cases of postnatal limb ischemia in one of a twin pair [48]. In nine cases, TTTS was identified and in all the limb ischemia occurred in the recipient twin. In the remaining cases, sepsis was the cause in one and TTTS was neither reported nor excluded in the others [48]. Hypoxic/ischemic events have also been noted [39].

The donor twin may exhibit cutaneous erythropoiesis (manifested as blueberry-muffin rash [49, 50], neutropenia [51], and/or renal failure [52, 53]. Thrombocytopenia, usually self-limited, occurs more commonly in neonates affected by TAPS than in uncomplicated monochorionic twins [44].

Neonatal Management

The type of antenatal therapy, if any, and results of post procedure can inform the neonatologist and hematologist of the most likely concerns for the neonate. The maternal fetal medicine and obstetrical teams should discuss this with in detail prior to delivery with the neonatologist. Depending on the acuity process preceding delivery, one or both of the neonates may be very non-euvolemic.

Postnatally, the donor twin may require volume expansion. If the twin is severely hypovolemic and/or anemic, then red blood cell transfusion may be indicated. Glucose infusions may be necessary for hypoglycemia in the donor twin. Long-term iron supplementation should be administered to the donor twin. The recipient twin should be evaluated for complications of the polycythemia/hyperviscosity syndrome, such as respiratory distress, jitteriness, seizures, hypocalcemia, hypoglycemia, and hyperbilirubinemia. The affected twin may require partial exchange transfusion. The complications and management of the polycythemia/hyperviscosity syndrome are discussed in Chapter 11.

Polycythemia in Infants of Diabetic Mothers

Infants of diabetic mothers have an increased incidence of polycythemia [70, 71]. Mimouni and colleagues found that the incidence of polycythemia (venous hematocrit (Hct) ≥65% at 2 hours of age) in IDMs was 29% versus 6% for infants matched for gestational age, mode of delivery, and Apgar scores [72]. The hematocrit of the infant did not correlate with maternal glycosylated hemoglobin levels but did correlate with neonatal hypoglycemia. In contrast, Cordero et al. identified polycythemia in only 5% of IDMs in their cohort, although Hb were not done specifically at 2 hours and only done in roughly half of their cohort [73]. Green and colleagues found that the hematocrit of IDMs correlated with maternal glycosylated hemoglobin levels at term (average gestation 38 weeks) but not at 36 weeks’ gestational age [74]. This may suggest that the maternal glucose control in late gestation has the greatest influence on the incidence of polycythemia.

Several factors may contribute to polycythemia in the IDM. Fetal hyperglycemia causes fetal hyperinsulinemia and insulin itself may promote erythropoiesis [75, 76]. Widness and colleagues found that the umbilical-vein erythropoietin concentrations were elevated in IDMs and correlated with maternal HbA1c levels taken the month before delivery [77]. Fetal erythropoietin concentrations correlate with fetal insulin levels [78]. Nucleated RBC levels, which may be a marker of fetal hypoxia, are also elevated in the IDM [79, 80]. There is a delayed switch from gamma- to beta-chain production in the IDM [81, 82]. Cetin et al. found a correlation between maternal β-hydroxybutyrate levels at 34–36 weeks and polycythemia in their newborns [83].

The complications of the polycythemia/hyperviscosity syndrome such as hypocalcemia, hypoglycemia, and hyperbilirubinemia should be expected and managed (see Chapter 11).

Thrombosis in Infants of Diabetic Mothers

The incidence of thrombosis, especially renal-vein thrombosis, is increased in IDMs [71]. Clinical manifestations of renal vein thrombosis may include shock, vomiting, hematuria, and a palpable kidney. Both venous and arterial thrombosis can occur in the IDM. While reported cases of peripartum gangrene of the limb are rare, 22% of one series were reported to be in IDMs [84]. One study found an association of perinatal arterial ischemic stroke with gestational diabetes [85].

It is likely that the increased incidence of thrombosis in the IDM is multifactorial. Polycythemia causes increased blood viscosity. Birth trauma, in part caused by macrosomia, may lead to vessel damage. Both platelet and plasma factors place the IDM at increased risk for thrombosis. Hathaway and colleagues suggested that there is increased platelet consumption [86]. Stuart and colleagues documented increased platelet reactivity and platelet endoperoxide formation in diabetic mothers and transiently in their infants [87]. Umbilical arteries from IDMs born to mothers with elevated HbA1c values produce significantly less prostacyclin, a potent inhibitor of platelet aggregation, than those obtained from control infants or IDMs of mothers with normal values for HbA1c [88]. Sarkar et al. found that protein C levels were lower in IDMs-either gestational diet controlled or insulin dependent, but there was no difference in the frequency of factor V Leiden, prothrombin gene mutation P20210A, methylenetetrahydrofolate reductase C677 T, or other common genetic risk factors [89]. Easa and Coen failed to find a difference in the prothrombin time, activated partial thromboplastin time, fibrinogen, factors V, X, or XII, or von Willebrand antigen [90]. Ironically, they found slightly lower levels for factor VIII and increased levels of antithrombin. Antiplasmin concentrations are increased in mothers with diabetes and their infants [91]. Elevated levels of homocysteine, a known risk factor for thrombosis have also been reported in IDM [92].

Thrombocytopenia in Infants of Diabetic Mothers

Mild thrombocytopenia is seen in IDM [86, 90]. The mean platelet count in IDMs was shown to be lower than in matched controls and did not correlate with maternal glycemic control [80]. Usually, no specific therapy is indicated.

Immunologic Changes in Infants of Diabetic Mothers

A few reports of immunologic abnormalities in IDMs have been reported, but their significance is not yet clear. Mehta and Petrova reported decreased neutrophil chemotaxis, random motility and chemiluminescence in IDM when compared to neonatal controls [93]. Infants of IDDM and gestational diabetes have reduced natural killer cells compared to healthy controls [94]. Roll et al. reported decreased numbers of both T and B lymphocytes in infants of insulin-dependent mothers [95].

Neutropenia in Infants of Hypertensive Mothers

Although the association of neonatal neutropenia with maternal hypertensive disorders (particularly preeclampsia and its variants) is well established, there are conflicting data regarding the epidemiology of the association, risks of neonatal sepsis, and possible mechanisms.

In their classic paper defining the normal neonatal neutrophil count, Manroe and colleagues demonstrated a high incidence of neutropenia in the infants of the mothers with maternal hypertension (IMH) [97]. Since that time, other studies have demonstrated a 40%–50% incidence of neutropenia in infants of mothers with gestaional hypertension (IGH), using Manroe’s data for the normal range [98–100]. Doron and colleagues found an incidence of 48% using normative data developed for premature infants [101]. Of 95 extremely low birth weight (ELBW) infants found to have an ANC <1,000 per microliter in the first 3 days of life (from a total cohort of 388 infants) 68% were either SGA or IGH [102]. Smaller (<1,500 g), more premature (<30 weeks’ gestational age), and/or cesarean-section-delivered IGH are more likely to have neutropenia. The incidence of neutropenia increases with the severity of maternal hypertension [99, 101]. In contrast, some have failed to find an increased incidence of neutropenia in premature IGH compared with matched controls also using normative data developed for premature infants [103].

In a small series, Bolat et al. found neutropenia in 18 of 31 (58%) IMH vs. 6% in a control group. The neutropenia was mild in eight, moderate in six, and severe in four of the infants. Lymphopenia was noted in 36% of these infants and 19% of the control group [104].

It is yet unclear if it is the maternal hypertension or the SGA status of the infant that is the primary contributor to neonatal neutropenia and thrombocytopenia. Christensen et al. did a retrospective review of all infants born SGA with an absolute neutrophil count <1,000/mcL born within a large health system [105]. They excluded from analysis infants with other known causes of neutropenia including early-onset sepsis. Six percent of tested SGA infants had early-onset neutropenia vs. 1% of gestational-age matched controls. The I/T ratio of these infants was within the reference range and their neutrophil counts increased to the reference range by day 7. Sixty-four percent of these infants also had thrombocytopenia. The neutropenia was not independently associated with maternal hypertension beyond their SGA status [105]. In contrast, Bizerea found that neutropenia occurred in 33% of SGA infants of hypertensive mothers and 23% of AGA infants of hypertensive mothers as opposed to only 2.6% of SGA controls [106].

Koenig and Christensen identified decreased neutrophil production, perhaps due to an inhibitor of myelopoiesis, as the cause of neutropenia in the IMH [100]. Other possible causes of decreased white cell production in fetuses of hypertensive women include: a neutrophil production inhibitor in the placenta or in fetal blood; the erythrocyte steal phenomena with intrauterine hypoxemia in which there is a shift towards red cell production; down regulation of white cell production due to placental dysfunction; and FAS-FAS ligand interaction abnormalities [107]. Some studies have shown this neutropenia to last for less than 72 hours [98, 100], while another study reported more prolonged neutropenia [108]. Compared with infants with sepsis-induced neutropenia, the neutropenia in IMH occurs earlier in life and does not have an increased ratio of immature to total neutrophils [99]. Yet, Saini et al. reported that the expression of surface adhesion markers, indicating neutrophil activation, was increased in infants of preeclamptic mothers [109].

There have been conflicting studies as to whether the neutropenia in IMH is associated with an increased risk of infection. Doron and colleagues reported an increased rate of bacterial infection in the first 48 hours of life in neutropenic compared with non-neutropenic IMH [101]. Other studies have shown an increased incidence of late-onset infection, usually after the neutropenia had resolved [99, 100]. Stoll reported from a review of the National Institute of Child Health and Human Development Neonatal Research Network that the presence of maternal hypertension/preeclampsia actually decreased the risk of neonatal infection [110]. Sharma et al. did a retrospective study of IMH [107]. The vast majority of neutropenic children were born prematurely, 86.4% of those from multiple gestations and 80% of the singletons. In this series, only the neutropenic multiple-gestation infants were at increased risk of sepsis compared to non-neutropenic multiples; this was not true of singletons [107].

Neutropenia in IMH may respond to granulocyte colony stimulating factor injections [111]. However, the need for routine use of this medication in the uninfected preterm infant with neutropenia has not been demonstrated to be necessary [103, 112]. Sixteen percent of the infants in Christensen’s series were treated with IVIg or G-CSF without an effect on outcome [105].

Thrombocytopenia in Infants of Mothers with Hypertensive Disorders of Pregnancy

Thrombocytopenia in neonates that presents in the first 72 hours of life is often found in the setting of placental insufficiency and maternal hypertension is a common cause. According to Chakravorty et al., this form of thrombocytopenia is usually benign and is rarely severe, uncommonly results in a rapid drop in platelet count and usually does not require treatment [113]. Early onset thrombocytopenia that differs from this pattern warrants further work up regarding etiology [114].

While thrombocytopenia is seen in 15%–36% of IMH [98–100, 104, 115), it is often but not always mild. In a prospective study from India, platelet counts were assessed in 97 IMH [116]. Of these, 36.1% had thrombocytopenia and in 20% the platelet count was <30,000/μL. Thrombocytopenia was significantly more likely in male children (OR 2.54, CI 1.08–5.95), with a trend towards increased risk associated with prematurity and low birth weight [116]. In a study of thrombocytopenia in hospitalized neonates, McPherson and Juul, using combined data for SGA and IMH, found the percentage of uninfected neonates with thrombocytopenia was higher in SGA/IMH vs. AGA infants for gestational ages <27 weeks (80% vs. 30%); 27<30 weeks (50% vs. 13%) and 30<34 weeks (30% vs. 8%) [117]. Most of their cases of thrombocytopenia attributed to SGA/IMH resolved within 2 weeks. In an analysis of ELBW infants, Christensen found that SGA or IMH was the most common diagnosed cause of thrombocytopenia, accounting for 37% of all cases [118]. There are similar rates of thrombocytopenia for infants born to mothers with HELLP as compared with maternal eclampsia/preeclampsia [119–121]. Disseminated intravascular coagulation (DIC) has been reported in IMH whose mothers’ platelet counts were <50,000/μl [115]. In studies to determine the etiology of thrombocytopenia in IMH, Tsao et al. showed that soluble fms-like tyrosine kinase 1 levels were higher in IMH and inversely correlated with infant platelet counts [122]. Infants with high levels of soluble fms-like tyrosine kinase 1 were more likely to have lower platelet counts, maternal preeclampsia and to be SGA [122]. Thrombopoietin levels did not differ between infants of mothers with and without MH [123]. Megakaryocytopoeitic defects have been postulated [124].

Polycythemia in Infants of Hypertensive Mothers

An increased incidence of polycythemia in IMH has been reported [125]. Brazy and colleagues found the mean hemoglobin level to be 5% higher in IMH [115]. The recommendations regarding the management of polycythemia are outlined in Chapter 11.

Neonatal Lupus Erythematosus

The neonatal lupus erythematosus (NLE) syndrome is believed to be due to the transplacental passage of autoantibodies, usually anti-Ro (SS-A) or anti-La (SS-B). Irreversible congenital heart block arising in the second trimester is the most devastating complication of the NLE syndrome. Cutaneous manifestations of NLE often begin after birth. Other complications include hepatitis and occasionally neurologic manifestations, including seizures.

Transient thrombocytopenia has been noted in roughly 10% of infants with NLE [126, 127]. Zuppa et al. followed 50 infants identified with anti-SS/Ro antibodies at birth; 90% of the antibodies resolved by 9 months of age [128]. Anemia was found in 2% at birth, 24% at 3 months, and 12% at 6 months. Neutropenia was found in 4% at birth, 24% at 3 months, 12% at 6 months, and 2% at 9 months. Thrombocytopenia was found in 2% at birth and none thereafter. None of the hematologic findings in Zuppa’s series caused complications or required treatment [128]. Hariharan and colleagues reported a case of NLE-associated microangiopathic anemia with severe thrombocytopenia that responded to intravenous gammaglobulin and corticosteroid treatment [129]. Recently, a newborn with a perinatal stroke was described who along with his mother had anti-SS/Ro antibodies [130]. There are multiple new agents available for management of individuals with autoimmune disease. Pediatricians should be aware of recommendations regarding the use of such agents in pregnancy and lactation as they develop [131].

Antiphospholipid Antibody Syndrome

An association between the presence of anticardiolipin antibodies and recurrent fetal loss has been well described. The presence of these antibodies in the mother may increase the risk for fetal growth restriction [132]. The presence of anticardiolipin antibody and/or the lupus anticoagulant is associated with an increased risk of maternal venous and arterial thrombosis, although the majority are venous. The cause of the increased thrombosis is not certain, but it appears to be related to platelet activation in the maternal circulation. The IgG isotype of the anticardiolipin antibody can cross the placenta [133].

There have been numerous case reports of fetal and neonatal thrombosis with the maternal antiphospholipid syndrome including the CNS vessels, renal vasculature, vena cava, and aorta [134]. Boffa and Lachassinne described 16 episodes of neonatal thrombosis in infants of mothers with APL: 13 (of 16) were arterial and 8 (of 16) were strokes [135].

The presence of the anticardiolipin antibodies in the newborn is usually transient but may persist for months due to the half-life of transplacentally acquired maternal IgG [136]. Persistent antiphospholipid antibodies have been reported in a cohort of infants with perinatal stroke [137].

Neonatal thrombosis associated with this syndrome should be managed as described in Chapter 19.

Placental Metastases

While primary placental malignancies arise from gestational trophoblastic neoplasia including partial and complete hydatiform moles and choriocarcinoma, maternal malignancy rarely spreads to the fetus or the placenta [160]. In 2002, Walker et al. reviewed 68 cases of maternal malignancy metastatic to the fetus (21%) and placenta (79%) [161]. Malignant melanoma is the most common malignancy to metastasize to products of conception, followed by breast cancer, leukemia/lymphoma, and lung cancer [161]. Hurley et al. describe a case where the mother died shortly of non-Hodgkins lymphoma shortly after delivery while the infant was diagnosed with a histologically identical tumor at 2 months of age [162]. Hence, the placenta should be carefully examined in cases of known maternal malignancy.

Effects on Hemostasis

Vitamin K deficiency is seen in 10%–66% of newborns whose mothers have been treated with anticonvulsants, including phenobarbital, phenytoin, and carbamazepam [163–165]. Hemorrhagic disease of the newborn with intraventricular hemorrhage has been reported. The coagulopathy can be reversed with vitamin K administration. While there have been recommendations for pregnant women taking enzyme-inducing anti-epileptic drugs to receive prenatal vitamin K prior to delivery [166], an assessment of the evidence could not confirm or refute the efficacy of this practice [167]. Vitamin K deficiency can also be caused by maternal warfarin ingestion, rifampicin, and isoniazid [168].

As described above, cancer chemotherapeutic agents can cause neonatal thrombocytopenia. Heparin-induced thrombocytopenia (HIT) occurs in a small percentage of individuals treated with heparin. It is manifested by mild thrombocytopenia and, paradoxically, an increased risk for thrombosis. HIT is caused by an antibody directed against the heparin–platelet factor 4 complex. HIT occurs in pregnant women; since the HIT antibody is an IgG antibody that is transported transplacentally, it has been found in cord blood [169].

The risk of venous thromboembolism increases four to five fold during pregnancy and even more in the 3 months following delivery [170]. Low molecular weight heparin and occasionally unfractionated heparin have been the mainstays of management and do not cross the placenta. Other than the potential for HIT as above, they should not affect neonatal hemostasis [170]. Both warfarin and direct thrombin inhibitors cross the placenta and warfarin has been associated with a fetal embryopathy. At this point, direct thrombin inhibitors are not recommended for use in pregnancy [170]. Women with very high thrombotic risk such as those with mechanical heart valves or HIT should be managed by a multidisciplinary team and the pediatrician should be aware of such treatment. Pediatricians should be aware that warfarin may be used in women with mechanical heart valves and be prepared to manage infants exposed in utero [170, 171].

Effects on Red Blood Cells

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is by far the most prevalent genetically transmitted erythrocyte enzymopathy, with millions of individuals affected. Fetal hemolysis in G-6-PD deficient fetuses can be triggered by maternal ingestion of compounds known to induce hemolysis in deficient RBCs, including naphthalene, fava beans (broad beans), and several medications such as aspirin, some antimalarials, several sulfonamids, and others. The neonatal manifestations of G-6-PD deficiency are described in Chapter 10.

Anemia and thrombocytopenia was seen in 10/13 infants whose mothers received natalizumab for multiple sclerosis during pregnancy [172]. As more biologic and biosimilar agents are used for a variety of conditions, the pediatrician will need to stay current on potential hematologic toxicities in the newborn.

Effects on Leukocytes

Barak and colleagues reported that infants whose mothers received antenatal administration of betamethasone within 36 hours of delivery had higher leukocyte and neutrophil counts than control infants, and that this effect lasted for up to 7 days [173]. However, the role of antenatal betamethasone exposure in causing leukemoid reactions and their potential sequelae in small infants is less clear. Leukemoid reactions have been noted in infants whose mothers received antenatal dexamethasone [174]. Juul and colleagues found neutrophilia in 28% but also neutropenia in 26% of infants <32 weeks gestational age with antenatal betamethasone exposure [175]. Of 6 infants <34 weeks gestational age with leukemoid reaction in the first 4 days of life, four had antenatal betamethasone exposure within 48 hours of birth [176].

Maternal Iron Deficiency Anemia

In 2011, the global prevalence of iron deficiency anemia was estimated to be 38% and in high income countries about 25% [180]. During pregnancy, the mother and the fetus both require iron. The mother’s blood volume increases, both the red cell volume and the plasma volume. The fetus requires iron for use in many cellular processes as well as for red cell production. The average daily requirement for absorbed iron during pregnancy is 4.4 mg/day and increases from 0.8 mg/day in the first 10 weeks to 7.5 mg/day in the last 10 weeks [181]. Iron is required to support the additional red cell volume in the mother, the fetal red cell volume, placental requirements, average daily losses and average perinatal blood loss with delivery [179]. The fetal iron endowment is 75 mg/kg [182]. Iron deficiency may be caused by inadequate nutritional intake, excessive blood losses, including those of preceding pregnancies, or a combination of these problems. In addition to maternal iron deficiency and perinatal blood loss, factors that increase erythropoiesis in the fetus such as maternal diabetes, maternal smoking and fetal growth restriction may be associated with fetal iron deficiency through increased iron demands by the erythron leaving less iron for other tissues [183, 184]. After birth, the supply of iron in breast milk for exclusively breast-fed infants is critical.

It would seem, therefore, that there would be clarity about the benefits of identifying pregnant women with iron deficiency anemia and treating them. The American College of Obstetricians and Gynecologists has recommended (and this was reaffirmed in 2017) that all pregnant women should be screened for anemia during pregnancy and that those with IDA should be supplemented [185]. Contrary to this, the United States Preventive Service Taskforce report in 2015 concluded that the “current evidence is insufficient to assess the balance of benefits and harms of routine iron supplementation for pregnant women or for screening for iron deficiency anemia” [186]. They cited an absence of any study that evaluated the direct effects of routine screening in asymptomatic women on either maternal health or birth outcomes, even though there is evidence that a pregnant woman’s blood counts and indices are improved with these measures.

Many studies of pregnancy outcomes, both maternal and neonatal, have been done in developing countries and may not be generalizable to high income countries. Data regarding the direct effect on neonatal anemia is not robust. There is conflicting data about the association of maternal iron deficiency anemia even indirectly with factors that influence neonatal health. The majority of iron transfer to the fetus occurs late in the 3rd trimester [187]. As such, any association of maternal iron deficiency anemia with preterm birth could influence total body iron for the infant.

In a meta-analysis done to evaluate the population attributable fraction of maternal anemia to poor birth outcomes, Rahman et al. found significant associations with low birth weight (RR 1.31, 95% CI 1.13–1.51), preterm birth (RR 1.63, 95% CI 1.33–2.01), perinatal mortality (RR 1.51, 95% CI 1.30–1.76), and neonatal mortality (RR 2.72, 95% Ci 1.19–6.25) [180]. They calculated that the population attributable fraction in low and middle income countries of maternal anemia to be 12% for low birth weight, 19% for preterm birth and 18% for perinatal mortality.

Counter to that, the Cochrane Collaboration in 2015 analyzed 61 randomized, or quasi-randomized trials to assess the association of maternal preventive iron supplementation on maternal and neonatal outcomes [188]. They found much of the work to be of low quality. Supplementation did significantly reduce maternal anemia at term by 70% (RR 0.30, 95% CI 0.19–0.46), iron deficiency anemia by 67% (RR 0.33, 95% CI 0.16–0.69) and iron deficiency at term (RR 0.43, 95% CI 0.27–0.66). They did report that low quality data showed a reduction in low birth weight babies (8.4% in supplemented patients, 10.3% in unsupplemented patients), they did not find a significant difference in preterm births. Similarly, in a retrospective cohort from a birth registry in the Aberdeen region of Scotland, investigators found no increased rate of premature births [189].

Folate

Folate is a required cofactor in many one-carbon-transfer reactions. Such reactions are components of the purine and thymidine synthetic pathways and, hence, affect DNA synthesis. Because this step is critical for hematopoiesis, folate deficiency can be a cause of anemia, thrombocytopenia, and neutropenia. Folates are also important in the degradation of histidine and homocysteine. Folate is found in many foods, especially leafy vegetables, fruits, and yeast. It is also found in human and cow’s milk, but it is very low in goat’s milk [198].

In addition to diet, several other factors can affect maternal folate levels. Excessive cooking inactivates folate. Methotrexate, pyrimethamine, and trimethoprim inhibit dihydrofolate reductase and interfere with the production of 5,6,7,8-tetrahydrofolic acid, the active form of folate in one-carbon transfers [199]. Women with hemolytic anemias, tropical or nontropical sprue, other malabsorptive states, as well as those taking anticonvulsive medications and high-dose oral contraceptives have increased folate requirements [199]. Folate deficiency is also seen in women who have undergone bariatric surgery [178].

Folate deficiency in unsupplemented pregnant women is common but may be masked by concomitant iron deficiency. Maternal folate deficiency is associated with an increased risk for fetal neural-tube defects, and fetal growth restriction [200]. Current recommended daily intake for women of childbearing age for folate is 400 μg/day [201]. Folate is transported against a gradient in the placenta and cord levels of plasma folate are higher than maternal levels [199]. In many areas of the world, including North America, folate is added to foods to decrease the incidence of preconceptual maternal folate deficiency and subsequent neural tube defects, however, this is not done universally [202].

Because of the preferential transport of folate to the fetus, deficiency in the immediate newborn period is unlikely. Neonates of mothers with even severe megaloblastic anemia have normal hemoglobin concentrations [203]. Postnatal events such as hemolysis, infection, malnutrition, diarrhea, and liver disease increase the likelihood of folate deficiency in the neonate [199]. The diagnosis should be suspected in the malnourished infant with persistent anemia, especially when associated with thrombocytopenia and/or neutropenia. Bone-marrow examination may reveal megaloblastic hematopoiesis, and hypersegmented neutrophils may be seen on the peripheral blood smear. The diagnosis is confirmed by reduced serum or erythrocyte folate concentrations. Erythrocyte folate levels would be expected to decline more slowly than serum folate levels [199]. Total plasma homocysteine levels may be elevated in folate deficiency.

Cobalamin deficiency should be sought is patients diagnosed with folate deficiency as cobalamin deficiency causes reduced erythrocyte folate concentrations [199], and folate treatment may improve the hematologic parameters but neurologic damage may progress [204]. Inherited disorders of folate metabolism, in particular hereditary folate malabsorption, may affect folate levels or mimic folate deficiency [205].

Cobalamin

Cobalamin, or vitamin B12, is a cofactor in the conversion of homocysteine to methionine and methylmalonyl coenzyme A to succinyl coenzyme A. The former reaction is critical for creation of intracellular polyglutamated tetrahydrofolate, the functional metabolite of folic acid. Hence, cobalamin deficiency impairs DNA synthesis. In addition to megaloblastic anemia, a peripheral neuropathy with degeneration of the lateral and posterior columns of the spinal cord can occur.

Cobalamin is present primarily in foods of animal origin [206]. A complex series of reactions leads to the absorption and distribution of cobalamin in humans. Intrinsic factor, produced in saliva and gastric juice, combines in the gastrointestinal tract with cobalamin and facilitates binding to a specific receptor in the ileum. The complex is then absorbed, metabolized, and transported through the blood by transcobalamin II [199].

The RDA for cobalamin for pregnant women is 2.6 µg/day and for lactating women 2.8 µg/day [207]. There is preferential transport of cobalamin from the mother to the fetus [207]. While this causes a decline in maternal serum cobalamin levels during pregnancy, the fetal cobalamin content of 50 μg is but a small fraction of the usual maternal stores. Neonatal serum cobalamin levels are higher than maternal levels [208], but fall over the first 6 weeks of age [209]. Maternal cobalamin levels correlate with neonatal levels in infants of mothers with omnivorous diets [209].

Cobalamin deficiency in pregnant women is very common in many underdeveloped areas of the world including the Latin America, sub-Saharan Africa and South Asia [210]. Unlike folate, vitamin B12 is not routinely added to foods. Pernicious anemia is the most common cause of severe vitamin B12 deficiency [206]. Maternal dietary deficiency, due to vegetarian/vegan diets without supplementation may lead to eventual infantile B12 deficiency [211, 212], especially if the infants are exclusively breast fed [206]. In addition to nutritional deficits, other potential causes of maternal B12 deficiency include pernicious anemia, gastrectomy or gastric bypass surgery, ileal resection, inflammatory bowel disease, tropical sprue, gastritis, fish tapeworm infestation, sprue, intestinal bacterial overgrowth, or medications that block vitamin B12 absorption such as metformin or gastric acid inhibitors [199, 206, 210, 213].

Maternal B-12 deficiency is associated with an increased risk for adverse perinatal outcomes including early miscarriage, spontaneous abortion and neural tube defects [210]. It is important to obtain a nutritional, surgical, and medication history from the mother of an infant suspected of having B12 deficiency, however, mothers may be deficient in this vitamin without a history of veganism and without diagnostic abnormalities on their blood counts [214].

Hematologic manifestations of vitamin B12 deficiency include anemia, which is often macrocytic, thrombocytopenia, leucocytopenia and hypersegmented neutrophils [199, 204]. However, cobalamin deficiency was not seen in a series of infants and children with red cell macrocytosis [215]. Bone marrow megaloblastic changes may be seen [204]. Serum cobalamin levels are usually low, but can lack sensitivity and specificity. Additionally, folate deficiency can cause reduced serum cobalamin levels [204]. Therefore, especially in the absence of megaloblastic changes, the diagnosis is confirmed with metabolic markers of functional cobalamin deficiency including elevated homocysteine and methylmalonic acid levels [199]. Nonspecific findings of cobalamin deficiency include elevation of the serum lactate dehydrogenase (LDH), hyperbilirubinemia, and an elevated ferritin [204].

In addition to hematologic findings, symptoms of vitamin B12 deficiency in the infant can include neurologic manifestation that can be severe including hypotonia, neurodevelopmental delay, tremors, hyperirritability, and cerebral atrophy. These may not be fully reversible [199, 206, 214]. Hypogammaglobulinemia has been seen as well [216].

Other causes of B12 deficiency in an infant include malabsorption from resection of the terminal ileum as may occur with necrotizing enterocolitis or congenital disorders that affect cobalamin absorption such as intrinsic factor deficiency, Imerslund–Gräsbeck syndrome or transcobalamin II deficiency [199]. Congenital disorders of cobalamin metabolism may present with similar findings but normal cobalamin levels [199].

Congenital Protozoal Infection

Congenital Bacterial Infection

Congenital Viral Infections

Herpes Simplex

Herpes simplex virus (HSV), like all members of the herpesvirus family, establishes latency after acute infection and then may reactivate periodically, sometimes with symptoms and sometimes without. There are two distinct antigenic types of HSV. Although an old paradigm holds that HSV-1 usually infects the oral region while HSV-2 typically involves the genital region, there is much overlap in both the epidemiologic and clinical manifestations of the two viruses. Acquisition generally occurs through intimate contact. Seropositivity to HSV-2 parallels the onset of sexual activity [285]. Older serologic tests did not distinguish reliably between HSV-1 and HSV-2, but more recently approved assays are able to do so [286]. Unless the exposure was recent, a negative serologic test should exclude prior infection in the mother [287]. Recommendations for the diagnosis of neonatal HSV infection include surface swab specimen (mouth, nasopharynx, conjunctivae, and anus) HSV PCR, vesicular PCR, and CSF and blood PCR [288]. Cell culture may still be available in some places, but most institutions have replaced cell cultures with PCR testing. Most infants with congenital HSV are born to asymptomatic mothers [285]. Factors that increase the risk of neonatal infection include primary maternal infection during gestation, infection late in gestation (preventing the transmission of maternal HSV-specific antibody to the fetus), the use of fetal scalp electrodes, and prolonged rupture of membranes [285].

The incidence of perinatal HSV in the USA is approximately 11–33 per 100,000 live births [285]. Infection of the neonate can occur in utero, during delivery, or postnatally. Intrauterine transmission is uncommon but may cause signs and symptoms similar to those of other congenital infections, such as toxoplasmosis and CMV, or it may cause unusual skin manifestations that are not readily recognized as herpetic [289]. More commonly, the newborn is exposed to virus from maternal genital fluids during delivery [285]. Perinatal HSV usually presents in the first month of life, with two-thirds of cases presenting in the first week [290]. Infection may also occur with exposure to infected caregivers, including mothers, fathers, and other providers [285, 291]. Perinatal infections are classified as localized disease to the skin, eyes, and mucous membranes (often called “SEM” disease); encephalitis with or without SEM involvement; and disseminated disease [285]. Disseminated disease is often fatal and may involve the liver, lungs, heart, CNS, skin, and other organs.

Diagnosis

In the absence of skin vesicles, the diagnosis of disseminated neonatal HSV can be challenging. After 24 hours of age, swab specimens of conjunctivae, nasopharynx, and rectum should not be positive for HSV by either PCR or culture unless the neonate is infected. When skin lesions are present, the diagnosis can be confirmed by rupturing vesicles, scraping the base of the vesicles, and submitting the specimens to the laboratory for PCR testing (or viral culture, where available). Treatment should be instituted at the first suspicion of HSV disease. Cerebrospinal fluid cultures are often falsely negative, even in the presence of significant encephalitis, and therefore PCR is the gold standard for diagnosing CNS disease [288, 292]. Studies show a broad range of sensitivity for CSF PCR in HSV encephalitis [285]; acyclovir should be continued if there are other features strongly suggestive of HSV CNS disease, such as focal seizures, abnormalities localized to the temporal lobes on imaging studies, or paroxysmal lateralizing epileptiform discharges (“PLEDS”) on electroencephalography. Elevation of liver enzymes may be an early clue to the diagnosis of disseminated disease in febrile neonates [293].

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Related posts:

Chapter 1 – A Historical Review Chapter 6 – Newborn Genetic Screening for Blood Disorders Chapter 7 – A Guide to Identifying the Cause of Anemia in a Neonate Chapter 13 – Acquired Thrombocytopenias Chapter 19 – Neonatal Thrombosis Chapter 20 – Transfusion Practices

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