Dr Ali Naseh Neonatologist Assisstant proffesosor of Sbmu Taleghani Hospital

Fetomaternal hemorrhage Bidirectional passage of minute numbers of cells across the placenta is a physiological event even though the placenta is considered a barrier separating the maternal and fetal circulation Massive fetomaternal hemorrhage (FMH), however, can result in serious sequelae.

DEFINITION No universally accepted threshold defines the volume of fetal erythrocytes in the maternal circulation that constitutes a massive FMH; volumes of 10 to 150 mL have been proposed. To put this in context, fetoplacental blood volume is approximately 120 mL/kg estimated fetal weight prior to 32 weeks of gestation and 100 mL/kg after 32 weeks.

A better approach for assessing the magnitude of FMH is to estimate the percentage of the fetal blood volume represented by the FMH. looked at in this way, a FMH of 20 mL/kg, which represents 20 percent of the fetoplacental blood volume, is considered massive because it has been associated with significant fetal/neonatal morbidity or mortality.

Experiments in sheep show that the rapidity of fetal blood loss is an additional major factor affecting morbidity and mortality . Massive FMH is more likely to be fatal if blood loss occurs over minutes rather than hours, days, or weeks.

INCIDENCE FMH >20 to 30 mL at delivery is estimated to occur in approximately 1 in 200 to 300 deliveries . FMH >80 mL and >150 mL is estimated to occur in 1 in 1000 deliveries and 1 in 5000 deliveries, respectively.

RISK FACTORS: multiple gestation nuchal cord, Low birth weight

PATHOGENESIS The pathogenesis of FMH is unclear. A histological study of placentas observed that parenchymal and retroplacental hemorrhage, intervillous thrombi, and infarction increased the likelihood that fetal cells would be found in the maternal circulation, and the extent of the abnormality correlated with the size of the hemorrhage.

SPONTANEOUS VERSUS TRAUMATIC FMH Spontaneous FMH is defined as hemorrhage with no antecedent history of trauma and no clinical/histopathological evidence of abruption. Traumatic injuries to the placental interface are typically caused by invasive diagnostic procedures (eg, amniocentesis, chorion villus biopsy, fetoscopy) or blunt abdominal trauma (eg, external cephalic version, motor vehicle crash, fall).

CLINICAL PRESENTATION Massive FMH occurs in the second or third trimester and can be either acute or chronic (ie, intermittent recurrent FMH). The mother is usually asymptomatic, although symptoms suggestive of a transfusion reaction (eg, fever, chills, nausea) have been described in case reports.

Decreased or absent fetal movement is the most common antepartum presentation (present in 27 and 54 percent of cases in two series). Fetal heart rate (FHR) monitoring is typically performed for fetal assessment in this setting and may show a sinusoidal FHR pattern (Waveform), recurrent late decelerations or fetal tachycardia. Ultrasound assessment may yield a low biophysical profile score.

The triad of decreased fetal movement, sinusoidal FHR pattern, and hydrops fetalis are late signs of massive chronic FMH. In some cases, however, a massive FMH may not be suspected until fetal demise has occurred. After delivery, FMH may be suspected because of neonatal anemia. Increased production of red blood cell precursors and increased circulating reticulocyte counts suggest that FMH occurred one to two days prior to birth.

WHEN TO TEST FOR FMH Fetal demise or stillbirth ● Sinusoidal fetal heart rate (FHR) pattern ● Nonimmune hydrops fetalis ● Neonatal anemia

Fetal demise or stillbirth — Evaluation for FMH should be part of the diagnostic evaluation of unexplained intrauterine fetal demise after 20 weeks of gestation and stillbirth Causation is supported by FMH >20 to 25 mL/kg and especially >40 mL/kg of estimated fetal weight.

Abnormal fetal heart rate or hydrops fetalis: An abnormal fetal heart rate pattern or nonimmune hydrops fetalis may be related to fetal anemia. The peak systolic velocity (PSV) of the middle cerebral artery (MCA) with Doppler ultrasound>1.5 MoM was noted in 31/32 cases.

Neonatal anemia Evaluation for FMH should be part of the diagnostic evaluation of unexplained neonatal anemia. Severe cases may present with circulatory collapse

POSSIBLE INDICATIONS FOR TESTING FOR FMH Decreased fetal movement Some clinicians test for FMH in all cases of persistently decreased fetal activity, but the utility of this approach is unclear. Maternal abdominal trauma There is no consensus as to whether all pregnant women who have experienced abdominal trauma should undergo routine testing for FMH. We believe that testing in trauma patients may be cost effective in symptomatic Rh(D)-negative women over 20 weeks of gestation since a massive FMH, although rare, would necessitate administration of more than the standard dose of 300 micrograms of anti-D-immune globulin.

LABORATORY EVALUATION Two maternal assays are available for detecting FMH: the Kleihauer-Betke test and flow cytometry. Both are based on identification of hemoglobin F, the predominant fetal hemoglobin. Both assays measure the volume of fetal blood in the maternal circulation at a point in time and thus do not necessarily indicate the volume of blood loss over time, if bleeding was chronic or occurred on multiple occasions.

Kleihauer-Betke — The Kleihauer-Betke test is the main diagnostic test for detection and quantitation of FMH .Red blood cells from the maternal circulation are fixed to a slide that is exposed to an acidic pH solution. Adult red blood cells become "ghost" cells since hemoglobin A is soluble and eluted across membrane defects at a low pH. Fetal red blood cells remain pink because hemoglobin F is stable at pHs in this range.

The volume of fetal whole blood (mL) in the maternal circulation is: (% fetal cells) X (maternal hematocrit [%] divided by fetal hematocrit [%]) X (maternal blood volume( mL). In the usual clinical scenario, the maternal blood volume and the fetal hematocrit are not known and most laboratories do not request the maternal hematocrit for the calculation. The maternal blood volume is often assumed to be 5000 mL, yielding the following formula to calculate the volume of fetal whole blood (mL) in the maternal circulation: (% fetal cells) X 5000 mL. Thus, if the Kleihauer-Betke result is 0.1 percent, the FMH calculation is (0.001 X 5000) = 5 mL of fetal whole blood.

Patients who are smaller or larger than the mean would be expected to have circulating blood volumes smaller or larger than 5000 mLs The same Kleihauer-Betke test result will overestimate the volume of FMH in a smaller woman and underestimate the volume of FMH in a larger woman. A comparison of these formulas when fetal cells comprised 3 percent of cells in the maternal sample yielded FMH estimates ranging from 108 to 162 mL.

Flow cytometry Flow cytometry is another assay for detecting and quantitating FMH. A monoclonal antibody to hemoglobin F is conjugated to a fluorochrome and used to detect fetal hemoglobin in permeabilized cells as they pass through the channel of a flow cytometer. Comparative analysis of flow cytometry and the Kleihauer-Betke test has shown that flow cytometry is more accurate, more reproducible, and less labor intensive

MANAGEMENT OF SPONTANEOUS FMH Patients with nonreassuring fetal testing typically require urgent delivery, regardless of the cause. There are no high-quality data to guide decision making in these pregnancies. Management is based on fetal assessment and gestational age, taking into account the morbidity of prematurity, the morbidity of in utero therapy, and the uncertain clinical course of expectant management.

Massive hemorrhage/moderate to severe anemia For pregnancies ≥32 weeks of gestation with FMH ≥20 percent of the fetal blood volume or middle cerebral artery peak systolic velocity (MCA-PSV) ≥1.5 multiples of the median (MoMs), we suggest immediate cesarean delivery, with blood available for prompt neonatal transfusion. For pregnancies <32 weeks of gestation, especially with severe anemia (eg, hydrops fetalis), an intravascular intrauterine transfusion (IVT) of donor red blood cells can acutely correct fetal anemia and is probably associated with lower morbidity and mortality than preterm birth. Because of the risk for preterm delivery, a course of antenatal corticosteroids is administered to enhance fetal lung maturity and a course of intravenous magnesium sulfate is administered for fetal neuroprotection in pregnancies ≥23 weeks

Small hemorrhage/no or mild anemia Pregnancies with FMH <20 percent of the fetal blood volume or MCA-PSV <1.5 MoMs can be followed expectantly as long as nonstress tests and/or biophysical profiles scores are reassuring. These pregnancies are evaluated daily for one week to look for evidence of chronic FMH.

PROGNOSIS Perinatal prognosis depends upon the acuity of the FMH, as well as the volume of the hemorrhage. Reported morbidity and mortality rates were derived from case reports and case series involving a range of gestational ages, both acute and chronic bleeds, and wide diversity in clinical presentation and management.

RECURRENCE Recurrent significant FMH in successive pregnancies has been described in case reports. There is no evidence on which to base a recommendation for following these women. Attention to fetal activity and prompt evaluation of decreased fetal activity is a reasonable approach

SUMMARY AND RECOMMENDATIONS There is no universally accepted threshold for diagnosis of massive fetomaternal hemorrhage (FMH). We use ≥20 percent of the fetoplacental blood volume because this threshold has been associated with significant fetal/neonatal morbidity or mortality. Absolute thresholds of 10 to 150 mL have also been proposed. Massive FMH may occur spontaneously or result from trauma.

Fetomaternal bleeding may be acute or chronic Fetomaternal bleeding may be acute or chronic. The mother is usually asymptomatic, but may have symptoms suggestive of a transfusion reaction (eg, fever, chills, nausea). Fetal findings associated with massive FMH include absent or persistently decreased movement (most common finding), heart rate abnormality (eg, sinusoidal fetal heart rate [FHR] pattern, recurrent late decelerations, tachycardia), low biophysical profile score, hydrops fetalis, and death.

When fetal anemia is suspected, the peak systolic velocity (PSV) of the middle cerebral artery (MCA) should be determined with Doppler ultrasound. A MCA-PSV value ≥1.5 multiples of the median (MoM) strongly correlates with moderate to severe fetal anemia. Either a Kleihauer-Betke stain or flow cytometry can be used for diagnosing FMH. The volume of fetal blood loss should be calculated as a percentage of the estimated fetoplacental blood volume.

Patients with nonreassuring fetal testing typically require urgent delivery, regardless of the cause. For pregnancies ≥32 weeks of gestation with FMH ≥20 percent of fetal blood volume or moderate to severe fetal anemia by Doppler, we suggest urgent delivery rather than intrauterine transfusion. For pregnancies <32 weeks of gestation with FMH ≥20 percent of fetal blood volume or moderate to severe fetal anemia by Doppler, we suggest intravascular fetal transfusion rather than urgent delivery (Grade 2C). Intrauterine transfusion can correct severe fetal anemia and thus avoid risks of very preterm birth.

Small FMHs with only mild fetal anemia can be followed expectantly Small FMHs with only mild fetal anemia can be followed expectantly. We perform daily Kleihauer- Betke or flow cytometry tests, MCA Doppler velocimetry, and fetal monitoring for one week and deliver the fetus if there is evidence of persistent FMH. Rh(D)-negative women should receive anti-D immune globulin. Perinatal prognosis depends upon the acuity of the FMH, as well as the volume of the hemorrhage. Recurrent significant FMH in successive pregnancies has been described in case reports.