Case
A female infant was born to a 21-year-old G1P0 mother at 28 weeks of gestation. Her
prenatal laboratories were unremarkable except GBS-unknown. The blood type of the
mother and infant was O-positive. The pregnancy had been uncomplicated until 1 day
before delivery, when the mother noted decreased fetal movement. She was evaluated
at an outside hospital and then transferred to our high-risk obstetrics center. Although
it was not known at the time of delivery, upon further investigation, the parents
remembered that the mother had become ill 3 days before delivery with general malaise,
illness, and abrupt development of generalized edema.
A biophysical profile scored 2 out of 8. The infant was delivered via emergent cesarean
section. Rupture of membranes occurred at delivery, with clear amniotic fluid. The
fetus was in breech presentation with a double nuchal cord. The placenta was pale
but otherwise normal. Very thin cord blood was noted by obstetric team.
The baby required aggressive resuscitation in delivery room, including intubation
and positive pressure ventilation. The heart rate was initially low, but responded
to airway management. The infant was noted to be very pale. Apgar scores were 1, 3,
and 3 at 1, 5, and 10 minutes, respectively. The baby was intubated for both the 5
and 10 minute Apgar scores. Birth weight was 1335 g.
The infant was transferred to neonatal intensive care for further evaluation and management.
On admission, her vital signs were: temperature = 97.2 F, heart rate = 145 bpm, respiratory
rate = 40 on conventional mechanical ventilation with 100% O2, blood pressure (BP) = 42/21 mm Hg (meanBP = 28 mm Hg), and SpO2 = 92%. Physical exam revealed a very pale preterm infant with little spontaneous
movement and respiratory effort. Poor perfusion was noted with delayed capillary refill,
equal but weak peripheral pulses. The liver was palpable at the level of the umbilicus.
There was no evidence of peripheral edema or hydrops. Umbilical catheters were quickly
placed and a bolus of normal saline was administered. Blood collected from the umbilical
artery was thin and pink ([Fig. 1]). Initial arterial blood gas revealed severe metabolic acidosis, pH <6.8, pCO2 63 mm Hg, and a metabolic component beyond the limit of the point-of-care analysis
equipment (“to large to calculate”). The hematocrit was 5%, with hemoglobin of 1.4
g/dL. The white blood cell count was 18.1/uL and platelet count was 79,000/uL. Nucleated
red blood cell count was 104/100 WBCs. Serum lactate was 15.8 mmol/L. Due to persistent
hypoxemia, the baby received surfactant and was changed to high-frequency oscillatory
ventilation and nitric oxide was added. A sepsis evaluation and empiric antibiotics
were started. TORCH (toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes)
titers were obtained and were later noted to be normal. The placenta was sent for
pathological evaluation. Aside from the pale appearance, no abnormalities were detected.
There were biochemical markers of hypoxic injury to the liver and kidneys (abnormal
aspartate aminotransferase and alanine aminotransferase, increased creatinine and
blood urea nitrogen).
Figure 1 Filter paper for standard newborn screening collected from the infant in our case
presentation. A normal appearing sample is included for comparison. Notice that the
sample from our infant is pale, pink and separates on the paper.
An immediate transfusion of O-negative packed red blood cells (15 ml/kg) was ordered
due to the empiric clinical diagnosis of severe anemia as evidenced by the appearance
of the blood that was drawn from the UAC. When the hematocrit result returned from
laboratory, revealing the true extent of the profound anemia, a partial exchange transfusion
was performed with packed red blood cells (using whole blood would have delayed the
intervention by up to 6 hours). The post-transfusion hematocrit was 35%. She received
a platelet transfusion and two more packed red cell transfusions over the next 2 days.
The baby's blood gases continued to show profound metabolic acidosis for several hours
after delivery despite aggressive buffering. Eventually, the pH increased to 7.42
at 7 hours of age.
Echocardiogram on day-of-life (DOL) 1 revealed persistent pulmonary artery pressure
at 40 mm Hg and a patent ductus arteriosus with bidirectional shunting. Cardiac function
was normal. Cranial ultrasound on DOL 1 showed no intraventricular hemorrhage (IVH).
Later on DOL 1, the infant demonstrated abnormal movements, which were suggestive
of seizures, and was started on phenobarbital. The infant was weaned from respiratory
support and extubated on DOL 5. Serial cranial ultrasounds showed progressively worsening
IVH, eventually reaching grade IV. There was also progressive hydrocephalus which
required serial lumbar punctures and eventually a ventricular reservoir ([Fig. 2]), results which were confirmed with magnetic resonance imaging. Retrospectively,
there has been discussion as to the nature of the hydrocephalus being either ex vacuo
or actually a large porencephalic cyst related to the severe hypoxic injury. Nevertheless,
the ventriculomegaly stabilized and the infant did not require shunt placement.
Figure 2 Cranial ultrasound from the infant in our case showing severe hydrocephalus. There
remains discussion among the treating physicians as to the cause of the findings.
Possible explanations include posthemorrhagic hydrocephalus, hydrocephalus ex vacuo,
or a large porencephalic cyst. Regardless of the etiology, long-term developmental
disability is expected.
Over the course of her stay in the neonatal intensive care unit, the infant required
supplemental oxygen, had feeding difficulties and temperature instability, all of
which contributed to her prolonged length of stay. She was discharged to home on DOL
72 with an apnea monitor.
A Kleihauer–Betke (KB) test performed on the mother's blood shortly after delivery
showed 3.8% fetal red cells suggestive of ~190cc of fetal blood in the maternal circulation,
a volume larger than the expected total blood volume for an infant this size.
Discussion
The ability of fetal red cells to cross into maternal circulation was first hypothesized
by Wiener in 1948,[1] and was later confirmed as a cause of neonatal anemia by Chown in 1954.[2] It is now known that the placenta can be a conduit for movement of both nucleated
cells and red corpuscles in a bidirectional fashion between the mother and fetus.[3] Laube suggested that fetal-maternal hemorrhage (FMH) was responsible for nearly
14% of unexplained fetal deaths and 3% of all fetal deaths.[4]
It seems that nearly all pregnancies result in some fetal red cells crossing into
maternal circulation.[3] Zipursky et al, estimated the incidence of FMH at 21 to 75% of pregnancies.[5] Another author reported 15 to 31% of pregnancies with some degree of FMH, but only
1.5 to 6% with bleed volume >0.1 mL.[6] In 1997, Jorgansen proposed an incidence of 39 to 95% of pregnancies resulting in
some fetal blood in maternal circulation.[7] Bowman suggested that 75% of all pregnancies have a degree of FMH.[8] Sebring showed that 93% of FMHs result in <0.5 mL of fetal blood being transferred.[9] These results were supported by Dupre et al, who showed that 98% of FMHs result
in <0.1 mL of fetal blood being transferred.[10]
Some authors have attempted to define a clinically significant, or “massive,” FMH
by taking into account the volume of blood lost from the fetus. Cardwell defined a
massive hemorrhage as one half of the infant blood volume.[11] Other authors have used a volume of 30 mL as the definition of massive because this
is the volume of fetal blood that will require one full unit of Rh immune globulin
to prevent Rh sensitization in a mother with concerns for alloimmunization.[12] Another author chose 80 mL as an important volume of blood loss because, at this
volume, patients in their study population exhibited “anemia,” although a strict definition
of anemia was not given.[13] A review article focused on bleeding volumes of >50 mL because this volume was “likely
to affect the outcome of the pregnancy.”[14] Still others have proposed 150 mL as an important blood volume.[3] Other authors have attempted to correlate the volume of blood loss with clinical
outcomes. Sebring found that hemorrhages of >30 mL resulted in 26.5% of infants being
stillborn or dying within 72 hours of birth.[9] Other authors found an increased risk of “adverse outcome” with a blood loss of
20 mL/kg of fetal weight.[15] These authors also found that at 80 mL/kg of blood loss two-thirds of the infants
suffered in utero fetal demise.
Defining significant FMH in terms of volume lost alone is probably not helpful. Animal
studies have shown that the rate of blood loss is another important factor. Brace
found that in fetal sheep, a blood loss of 30% of the estimated total volume of the
fetus was tolerated better if it occurred over 2 hours rather than 10 minutes.[16]
[17] Blood loss over 2 hours resulted in a more rapid restoration of fetal intravascular
volume, 3 hours versus 6 hours in the 10-minute group. Another sheep study found that
red cell mass was normal 1 week after a loss of 40% of blood volume over a 2-hour
period.[18]
Given the ambiguity of the definition of a clinically relevant volume of hemorrhage,
it is clear that more factors than blood volume alone are pertinent to this discussion.
Indeed the rate of blood loss and the chronicity of the bleed are important. Gestational
age is also an important factor given that the intravascular volume, as calculated
in mL/kg, varies throughout the pregnancy and preterm infants are at increased risk
for adverse outcomes that a term infant would not experience. The preterm infant is
also likely to have less ability to tolerate the stress associated with a massive
FMH.
Despite the problems with defining significant FMH by volume, many authors still present
incidence data in terms of volume. One study reported an incidence of 1:1146 live
births if a volume of 80 mL is used to define significance and 1:2813 if 150 mL is
used.[13] This study also looked at a group of selected high-risk women whose blood samples
were referred for fetal blood testing due to stillbirth, neonatal anemia, or fetal
distress. In this selected population, 64.5% of these samples indicated a fetal hemorrhage
of >150 mL. Forty-six percent of these infants had adverse outcomes. Another author
suggested that hemorrhages of >30 mL occur in 1 out of 300 otherwise normal pregnancies.[9] In a more recent article, hemorrhages of >20 mL were found to occur in 4.6/1000
live births, volumes of >30 mL occurred in 3.8/1000 live births, and >80 mL occur
in 0.7/1000 live births.[15] Recurrent FMH in subsequent pregnancies has been reported in a few case reports.[19]
[20]
[21] However, these events are quite rare.
FMH can physiologically occur as early as 4 weeks of gestation with the combination
of vascularization of the chorionic villi and initiation of contraction in the primitive
heart.[22] Fetal placental blood vessels have higher blood pressure than the intervillous space.
If there is disruption of the maternal-fetal barrier, hemorrhage will occur from the
fetus to the maternal circulation. In the setting of ABO incompatibility, the maternal
clotting system may be activated, limiting the effect of the hemorrhage. If there
is ABO compatibility, clotting is less likely to be activated and the hemorrhage may
continue with dramatic effects.[22] This was shown as early as 1968 when Devi et al hypothesized that placental clots
were protective against extension of massive fetal hemorrhage.[23]
FMH can follow maternal abdominal trauma.[24]
[25] Hemorrhages have occurred following maternal falls and motor vehicle accidents.[6] It has also been linked to various obstetric procedures such as external cephalic
version,[26] manual removal of a retained placenta,[27] or amniocentesis.[6]
[28]
[29] Placental anomalies such as tumors or chorioangiomas,[6]
[30]
[31] abruption,[32] and monochorionic–monoamnionic twins[33] have also been identified as causes of abruption. However, 82% of cases arise spontaneously,
with no identifiable history of an inciting event.[14]
The initial symptoms of an acute FMH are often subtle and nonspecific. Most are diagnosed
retrospectively after an infant is stillborn, experiences unexplained fetal distress
or is born with symptoms consistent with a hemorrhage.[34] Prenatally, the mother may present with a history of decreased or absent fetal movement.[13] A 1997 study found in 27% of cases, decreased or absent fetal movement was the presenting
symptom of a fetal hemorrhage.[14] Other forms of fetal distress were present in 7% of cases and IUGR was the presenting
symptom in 3%. Unexpected stillbirth was the only presenting sign in 12.5% of cases.
Fetal heart rate monitoring may show a sinusoidal pattern, a lack of acceleration,
and recurrent late decelerations.[35]
[36] The sinusoidal heart rate pattern, with or without decreased fetal movement, is
a common presenting sign in published reports of FMH.[14]
[19]
[37]
[38] In the event of massive fetal blood loss, the mother may experience a transfusion
reaction expressed as nausea, edema, fever, and chills.[39]
[40] If the mother and fetus have Rh incompatibility, sensitization can occur and Rh
immune globulin injection is indicated.[41]
If the fetus can compensate for the blood loss, the pregnancy may continue to delivery
of an infant with varying degrees of anemia. Initially, the fetus may increase cardiac
output, with fetal tachycardia reported as a presenting symptom.[42] The increased cardiac output results in increased blood flow in the fetus that can
be measured with Doppler ultrasound studies. Sueters correlated increased flow in
the fetal middle cerebral artery with anemia.[38] Flow in the umbilical vessels can also be increased.[38] Evidence of increased hemopoetic activity may be present in the infant with evidence
of placental and hepatic hemopoesis and erythroblasts and/or reticulocytes present
in the neonate's peripheral blood smear.[14]
In the setting of uncompensated anemia, the fetus may develop high-output heart failure
and hydrops fetalis[43] due to changes in the hydrostatic (oncotic) pressure. The triad of decreased fetal
movement, sinusoidal heart rate, and hydrops fetalis are symptoms of severe anemia
associated with massive FMH. However, this combination is a late presentation of the
disease.[13]
[14]
When a massive fetal hemorrhage occurs, the only hope for improved outcome is prompt
recognition and intervention.[13] Unfortunately, the symptoms as described are nonspecific and subtle. In the uncommon
event that fetal anemia is recognized before delivery, the risks and benefits of immediate
delivery should be evaluated. If the infant is near-term gestation, immediate cesarean
delivery is indicated. C-section is the delivery method of choice because the compromised
placenta may not support the stress of labor.[44] If the fetus is still of preterm gestation, in utero transfusion can be considered
and has been shown to be an effective method to safely temporize the effects of fetal
anemia.[45]
[46] If the hemorrhage continues, serial transfusions may be indicated. Giacoia reported
providing 17 in utero transfusions to 9 infants, 8 of whom survived.[14]
Neonatal anemia has been reported to be the presenting sign in 35% of cases.[14] In severe cases, signs of shock and circulatory failure are present.[47] If anemia is present, it should be corrected slowly to avoid volume overload and
exacerbation of heart failure. In cases with the most profound anemia, exchange transfusion
may allow for rapid correction of the anemia while avoiding the complications associated
with excessive volume or cardiac compromise.[48]
[49] Exchange transfusion with whole blood may be preferred. However, if the child's
clinical condition is unstable, packed red cells may be more readily available. Calcium
gluconate, protein, and other blood products may need to be replaced after an exchange
transfusion.
When a FMH is suspected, maternal blood can be checked for the presence of fetal red
blood cells. Of historical significance is the Rosette test. This is a qualitative
screening test that identifies Rh-positive blood in Rh-negative mothers.[50] Even if the Rosette test is positive, a quantitative test is still required. Hemoglobin
electrophoresis has been used to detect fetal hemoglobin in one case report.[19] However, this test can be distorted by pathologic conditions that result in increased
hemoglobin F (Hg-F) or the physiologic rise in Hg-F associated with pregnancy. Flow
cytometry is less labor intensive than other tests that are available but requires
specific equipment that may not be widely available. Flow cytometry can identify cells
by size (fetal red cells are larger than maternal cells).[51] This phenomenon is also responsible for the increased red cell distribution width
detectible in maternal blood when fetal cells are present.[37] Fetal cells can also be tagged with monoclonal antibodies that can be identified
with flow cytometry techniques.[52] Following fetal hemorrhage, increased levels of α-fetoprotein (AFP) can be measured
in maternal serum. While AFP is stable for storage and not influenced by red cell
agglutination, AFP levels vary with gestational age, complicating the estimation of
the fetal hemorrhage.[9]
The most common test for fetal blood in maternal circulation is the acid elution test
commonly referred to as the KB test.[53] In this test, maternal blood is fixed, washed with acid, and then stained. The maternal
cells are not stable after the acid treatment and do not take-up the stain, appearing
as ghost cells on the slide. Several cells are manually counted and the volume of
hemorrhage can be calculated by accounting for the percentage of fetal cells present
on the slide extrapolating to the expected maternal blood volume. Unfortunately, the
KB test is affected by many factors that result in inaccurate interpretation of the
results.[9] Blood used for the KB test can be affected by temperature, pH, and the time since
the blood sample was collected. The expected maternal blood volume varies with gestational
age and can be affected by the presence of maternal anemia. In some cases, the fetal
cells may not stain as well as expected, resulting in inaccurate interpretation of
the results. After fetal transfusion, tests for fetal hemoglobin in maternal circulation
are no longer helpful in assessing the extent of continued bleeding as transfused
blood cells will be of adult origin and therefore not distinguishable in maternal
circulation. Likewise, maternal hemoglobinopathies that result in increased fetal
hemoglobin will also make interpretation of these tests difficult. The problems with
the KB test can result in calculation of blood volumes greater than are likely possible
in most physiologic conditions. One report in the literature included calculation
of 400 mL of fetal blood lost to a mother who was known to be anemic.[37] Another report calculated 410 mL of fetal blood loss.[22] Another report calculated 700 mL of fetal blood loss following a chronic hemorrhage.[54]
Since minor FMHs are nearly ubiquitous in pregnancy, the overall outcomes from these
events are negligible. However, in cases of massive bleeding, morbidity and mortality
rates are quite high and are directly related to the degree of hypovolemic shock experienced
by the fetus/neonate.[14] At birth, these infants are often pale with evidence of poor perfusion. Respiratory
distress is common. It may present as a general respiratory failure. Also, since bicarbonate
is usually found in the red blood cells, the severe anemia depletes the infant's bicarbonate
stores, leading to a profound acidosis which can exacerbate pulmonary hypertension.
The acidosis can be difficult to treat because red blood cells are the natural compartment
for bicarbonate in blood. The infant may appear hydropic or have evidence of heart
failure, such as cardiomegaly or hepatomegaly. Bleeding disorders can occur with disseminated
intravascular coagulation having been reported. Central nervous system dysfunction
is common with hypoxic-ischemic encephalopathy, cerebral infarction, IVH, and periventricular
leukomalacia all having been reported.[14] Fay first reported a link between FMH and cerebral palsy.[48] However, actual occurrence rates are difficult to assess. A study of FMHs in Canada
found adverse outcomes in 46% of affected infants, with 10 of 26 patients dead within
6 months of birth and 1 infant with spastic quadripalegia.[13] Giacoia reported no difference in long-term outcomes for lowest hemoglobin levels
greater than or less than 6 g/dl or estimated bleed volumes greater than or less than
200 mL.[14] However, given the problems with chronicity of bleeding, estimating the bleed volume
and the fetus' ability to compensate for blood loss, these findings are not necessarily
surprising.
When an infant is born with unexpected anemia, in addition to FMH, physicians should
consider alternative diagnoses such as isoimmune hemolytic anemia (Rh incompatibility),
or autoimmune causes, congenital infections that result in bone marrow suppression
(TORCH) or bacterial sepsis.[55] A sepsis evaluation and empiric antibiotics are warranted. Congenital erythrocyte
defects of structure (membrane defects: spherocytes, elliptocytes) or function (G6PD,
pyruvate kinase deficiency) or congenital hemoglobinapathies (α-thalassemia) can also
cause anemia.[55] Congenital hypoplastic anemia (Diamond-Blackfan syndrome, congenital leukemia) should
also be considered in the differential diagnosis.[55]
Given that the etiology of FMH events is unclear, it is difficult to quantify the
risk in future pregnancies for the mother and difficult to recommend strategies to
prevent recurrence. It is reasonable to counsel the patient on the importance of fetal
movement counts and to institute antepartum evaluation in the third trimester. This
should include a reasonable schedule of nonstress tests and sonograms to assess for
signs of anemia and hydrops. Serial KB tests can be considered in cases with a history
of previous catastrophic FMH or with an obstetric history concerning for possible
multiple risk factors for poor outcome. However, once a FMH has occurred, the interpretation
of serial KB tests in that pregnancy is controversial.
The infant in our case presented with many of the classic signs associated with FMH.
The pregnancy had been normal until she presented with decreased fetal movement. After
delivery, she related a history of general illness and increased edema 3 days before
delivery, symptoms which were not recognizable at the time as what we now hypothesize
to have been a transfusion reaction. The fetal heart tracing, while not sinusoidal,
showed absent beat-to-beat and long-term variability, signs of a severely compromised
fetus. The low score on the biophysical profile prompted an emergent cesarean delivery.
The infant was immediately recognized to be pale with poor perfusion and symptoms
of hypovolemic shock. The infant had a severe metabolic acidosis related to the lack
of red blood cells available to carry buffer. The infant had severe respiratory distress
and elevated pulmonary artery pressure, treated with aggressive ventilation and inhaled
nitric oxide. There was an elevated nucleated red blood cell count, consistent with
increased hematopoesis. The hemoglobin of 1.4 gm/dl was the lowest level we could
find in the literature in a surviving infant. Unfortunately, the infant suffered a
severe hypoxic brain injury that resulted in loss of white matter and hydrocephalus.
Long-term follow-up is pending, but we necessarily remain pessimistic about her neurologic
outcome.
