Fetomaternal hemorrhage is defined by the passage or transfusion of fetal blood into the maternal circulation before or during delivery. No universally definition of massive fetomaternal hemorrhage has been accepted, and threshold volumes vary from 10 to 150 mL.1 Depending on the cutoff volume chosen, the frequency of fetomaternal hemorrhage appears to vary from 1 to 3 per 1,000 births, but few series have been reported.1,2 Massive fetomaternal hemorrhage may cause severe fetal anemia. Diagnosis is often retrospective, after fetal or intrapartum death. Some survivors are reported to have neurological sequelae that may legitimately be related to rapid and severe fetal anemia. In these situations, the prognosis is difficult to assess because series are scarce, retrospective, and small.1–4
To learn more about the incidence and prognosis of massive fetomaternal hemorrhage, we studied the fetal, neonatal, and long-term outcome of consecutive cases of massive fetomaternal hemorrhage in two university hospitals over an 8-year period. The results were compared with data from the literature to evaluate the prognosis of massive fetomaternal hemorrhage.
PARTICIPANTS AND METHODS
This study was retrospectively conducted from 1996 to 2003 in two university hospitals. Fetomaternal hemorrhage was diagnosed according to Kleihauer tests conducted in the hematology department of each hospital at the request of the obstetrician or the pediatrician.5 Both departments used the same protocol, which includes performing a Kleihauer test routinely at birth for Rh-negative patients (for prevention of alloimmunization) and when fetomaternal hemorrhage is suspected for any other patients.
To make comparisons within the previous published series,1–4 we defined massive fetomaternal hemorrhage as at least 40 fetal erythrocytes per 10,000 maternal erythrocytes,4 corresponding to a transfused fetal volume of 20 mL or more.5 To assess the severity of the hemorrhage, we corrected the transfused fetal blood volume for fetal weight estimated by ultrasonography at diagnosis. Thus, we expressed hemorrhage volume in milliliters per kilogram of body weight. (The total blood mass of a fetus is generally considered to range from 80 to 90 mL/kg.6,7) Women with thalassemia, multiple pregnancies, delivery before 22 weeks, or medically indicated termination of pregnancy were excluded from our study.
We assessed fetal, neonatal, and long-term prognosis after massive fetomaternal hemorrhage. Maternal and fetal data were collected from obstetric and pediatric charts, including maternal age, parity, number of pregnancies, reason for and gestational age at Kleihauer test, ultrasound examination, fetal heart rate patterns, type of delivery, and immediate neonatal outcome. Fetal death was defined as in utero death at 22 weeks or more of gestation. Long-term prognosis was assessed in June 2005 based on each child’s carnet de santé (national child health record). This record includes the pediatric examinations performed at 8 days, at 4, 9, and 24 months, and then between 3 and 4 years and 5 and 6 years. The form includes multiple-choice and open questions about the child’s living conditions, physical examination, and psychomotor development at each examination.
The data were recorded and analyzed with Epi Info 6.04 (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA). All results are expressed as means and standard deviations of the distributions and percentages. For comparison of percentages, data were classified into predetermined classes. Each cutoff point (10, 20, 40, and 80 mL/kg) was tested separately (one class versus all lower volume classes). We used Fisher exact test to compare percentages and Wilcoxon rank sum test to compare means. Statistical significance was set at P<.05. We also report 95% confidence intervals (CIs).
During the study period, there were 45,180 deliveries at the two study centers and 48 cases of massive fetomaternal hemorrhage were observed (that is 1.1 per 1,000 births, 95% CI 0.8–1.4) (Table 1). Kleihauer tests were performed because of maternal abdominal trauma (n=5), signs of fetal distress (n=3), fetal death (n=4), or unexplained neonatal pallor or distress (n=7). In the remaining 29 cases (60.4%), Kleihauer tests were routinely requested in the immediate postpartum period for Rh-negative patients who gave birth to Rh-positive children. Related to estimated fetal weight, the transfused fetal blood volume averaged 37.3±51.3 mL/kg in our series (range 6.1–199.3, median 15.8 mL/kg).
In the majority of the cases (83.33%, 40 of 48), no cause was found in our series. In rare situations, we noticed risk factors similar to those listed in the literature: placenta previa (n=2), manual external version (n=1), and maternal abdominal trauma (n=5).
Two fetal deaths occurred during the period between admission and release of the Kleihauer test results, increasing the number of fetal deaths to six overall (12.5%). These six deaths accounted for 1.6% of all fetal deaths in the two study centers during this period (6 of 378, 95% CI 0.6–3.4). Accordingly, fetomaternal hemorrhage caused 1.3 fetal deaths per 10,000 births (6 of 45,180, 95% CI 0.0–2.9).
Nine of the 42 liveborn children were transferred to the intensive care unit (21%). Neonatal hemoglobin was measured in 13 children (31%), and all had anemia (mean hemoglobin 10.3±3.5 g/dL, range 4.8–15.4). In our population of infants transferred to intensive care (nine children), neonatal hemoglobin was always greater than 4 g/dL (mean hemoglobin 9.1±3.3 g/dL, range 4.8–15.4). Five infants needed blood transfusions. There were no neonatal deaths. Besides global hypotonia at discharge in one infant, no neurological anomalies were observed.
Only 31 of the 42 children (73.8%) could be located to study the long-term prognosis. At fetomaternal hemorrhage diagnosis, the mean transfused volume did not differ significantly between these children and those lost to follow-up (24.1±20.9 versus 32.6±32.9 mL/kg, P=.33). The mean age of the children followed was 56.4±25.0 months (range 18–107, median 59 months). The newborn discharged with neonatal hypotonia showed developmental delay at 1 year of age, which was related to mitochondrial cytopathy diagnosed by muscle biopsy. Cerebral magnetic resonance imaging was normal. Except for this child, none of the children in our follow-up group died or had neurological sequelae (0 of 30, 95% CI 0.0–11.6).
Maternal and fetal data were compared between the routinely tested population (n=29) and the population that was tested for cause without in utero death (n=15). Massive fetomaternal hemorrhage in the indicated testing is associated with a significantly poor outcome: preterm delivery (53.3% versus 10.3%; P<.01), transfer to neonatal intensive care unit (NICU) (69.2% versus 0%; P<.001), and neonatal transfusion (38.5% versus 0%; P<.05).
Fetomaternal hemorrhage prognosis was related to the fetal transfused volume corrected for estimated fetal weight (milligrams per kilogram) (Table 2). For each cutoff volume (20, 40, 80 mL/kg), fetal and neonatal adverse outcomes were increased compared with the combined classes of lower transfused volumes (P<.05). Twenty-three patients (48%) had a transfused volume of 20 mL/kg or greater (approximately one quarter of the total fetal blood volume6,7). Above this cutoff volume, we observed an increased risk of fetal death (26.1% versus 0%; P=.01), induced preterm delivery (17.4% versus 0%; P=.04), transfer to NICU (34.8% versus 0.04%; P=.01), and neonatal transfusion (21.7% versus 0%; P=.02).
The objective of our study was to assess the prognosis of massive fetomaternal hemorrhage over an 8-year period. We found that the prognosis of massive fetomaternal hemorrhage is associated with the fetal volume transfused. Above a threshold volume of 20 mL/kg, the number of complications increases, including fetal death, preterm delivery, transfer to intensive care unit, and neonatal anemia requiring transfusion. Long-term follow-up showed that none of the 31 children had neurological sequelae imputable to fetomaternal hemorrhage.
There are few studies reporting large numbers of women and their infants affected by fetomaternal hemorrhage. Few examine the relationship between antenatal presentation and outcome of neonates with massive fetomaternal hemorrhage. We reviewed our experience with massive fetomaternal hemorrhage with the aim of evaluating the prognosis of this pathology. Because the number of cases is small, studies about fetomaternal hemorrhage are difficult to conduct. Moreover, assessment of the outcome is limited by the large variation of intensity and kinetic of fetomaternal hemorrhage. Our series studied 48 cases, which represents a relative significant number compared with previously published data.
With a cutoff volume of 20 mL, the crude incidence of massive fetomaternal hemorrhage was estimated at approximately 1.1 per 1,000 births in our study (95% CI 0.8–1.4). This rate is lower than the previously published data. Sebring and Polesky2 reported a frequency of 3.0 per 1,000 births, that is, three times higher than in our study, with a stricter definition of fetomaternal hemorrhage (threshold 30 mL). De Almeida and Bowman1 found a rate similar to ours (0.9 per 1,000 births) but used a transfused volume much higher than we did (cutoff point 80 mL or more).
We hypothesize that the frequency of massive fetomaternal hemorrhage may be underestimated in our study. Indeed, the Kleihauer screening was ordered routinely only for patients with a Rh-negative phenotype (approximately 15% of the pregnant women in our region). If we calculate the incidence of massive fetomaternal hemorrhage among the 6,777 Rh-negative patients who gave birth during the study period—as De Almeida and Bowman1 did before us—there were still 31 cases of massive fetomaternal hemorrhage and the corrected incidence is estimated at 4.6 per 1,000 live births (95% CI 3.1–6.5). If we set the threshold volume at 30 mL, we would observe 26 Rh-negative patients, for a frequency of massive fetomaternal hemorrhage of 3.8 per 1,000 (95% CI 2.5–5.6), similar to the results observed by Sebring and Polesky.2 Finally, in considering the most severe massive fetomaternal hemorrhage (cutoff point 80 mL or greater), the incidence would have been very close to the incidence observed by De Almeida and Bowman1 (0.7, 95% CI 0.2–0.7, versus 0.9 per 1,000 births). Thus, when we use the same cutoff volume or the same denominators, our estimates are similar to the previously published studies. We acknowledge that these rates are certainly below the real frequency of fetomaternal hemorrhage during pregnancy, because the Kleihauer test performed at birth cannot always detect fetomaternal hemorrhage that occurred several weeks earlier.2
The incidence of fetal death among the cases of massive fetomaternal hemorrhage in our series was similar to that in the literature for the same volumes.1–3 In our study, as in the literature, the percentage of fetal death from fetomaternal hemorrhage increases with the fetal volume transfused, up to 33.3% for a volume of 80 mL or more. Our study found a prevalence of massive fetomaternal hemorrhage of 1.6% among the fetal deaths (95% CI 0.6–3.4). These results lead us to recommend a Kleihauer test in all cases of unexplained fetal death. Overall, this disease caused approximately one death per 10,000 births in our study (0.013%, 95% CI 0.0–0.03. This incidence is slightly less than that found by other authors, who report that massive fetomaternal hemorrhage causes fetal death in 0.02–0.04% of births and causes roughly 4% of all fetal deaths.8–10 We observe that the incidence of fetal death by massive fetomaternal hemorrhage is lowest for the most recent studies: 0.04% of births in Laube and Schauberger in 1982,8 0.03% in Marions and Thomassen in 1991,9 0.02% in Samadi et al in 1999,10 and, finally, 0.01% in our study. We hypothesize that this may indicate improved diagnosis and obstetric management of massive fetomaternal hemorrhage over time.
Only four studies have examined the neonatal prognosis of massive fetomaternal hemorrhage.1–4 Morbidity appears to range between 2% and 12%, depending on the cutoff volume. No neurological sequelae imputable to fetomaternal hemorrhage were observed in our study. We observed no neonatal deaths, an observation that conflicts with other studies that report mortality between 11% and 13% in cases of massive fetomaternal hemorrhage.1–3 Kecskes4 found that 19% of neonatal deaths were the result of fetomaternal hemorrhage but considered only infants transferred to the intensive care unit. Three reasons could explain the absence of neonatal deaths or sequelae in our series. First, a zero percentage of morbidity and mortality has a wide confidence interval (95% CI 0.0–8.4) because of the small number of cases in our series. Second, past studies covered longer periods between 1966 and 2000, with different diagnosis and management of fetal and neonatal anemia over time. Finally, Kecskes4 found that initial neonatal hemoglobin of 4 g/dL or less was associated with an increased risk of poor outcome. In our population, neonatal hemoglobin was always greater (mean hemoglobin 9.1±3.3 g/dL, range 4.8–15.4).
To our knowledge, the published data on the long-term prognosis of children born after massive fetomaternal hemorrhage are poor, and the consequences of such anemia on the fetal brain are unknown. These studies are made difficult by the rarity of recognized cases and the difficulty in follow-up of these children. Prognosis has been only reported for 20 individual cases of massive fetomaternal hemorrhage.3 Fourteen were described by De Almeida and Bowman,1 and only one child had a quadriplegia due to fetomaternal hemorrhage (7.1%). In our study, the outcome of the 31 children born after severe fetomaternal hemorrhage was assessed from data routinely collected in their health records, and no sequelae were observed, despite a mean transfused volume of 24.1±20.9 mL/kg. We are aware that our study is based on a relatively small number of cases, with a high percentage of children lost to follow-up and a wide confidence interval for the frequency of sequelae (95% CI 0.0–11.6). The high percentage of children lost to follow-up (26%) is consistent with the data for systematic follow-up of children in France. (The percentage lost to follow-up is currently almost 37% at 9 months and 52% at 24 months.11) Nonetheless, the patients lost to follow-up had transfused volumes similar to those of the patients who were followed. In addition, we did not observe sequelae in any patients, even among those who had the highest volumes of fetal blood transfused.
In our study, we corrected the volume transfused for estimated fetal weight and for the whole fetal blood volume, which increases progressively throughout the pregnancy. The fetal blood volume is approximately between 80 and 90 mL/kg. Thus, depending on the gestational age at onset of fetomaternal hemorrhage, the volume of transfused blood will represent a more or less important part of circulating fetal blood volume. In our study, a transfusion of more than 25% of fetal blood volume (20 mL/kg) was associated with a significantly increased risk of fetal death, induced preterm delivery, neonatal transfer to intensive care unit, and neonatal transfusion. An experimental study in lambs demonstrated that the fetus is able to tolerate acute blood loss of up to 40% of total blood volume. However long-term outcome was not studied in this work.12 Nonetheless, it appears useful to correct the transfused volume for estimated fetal weight. The cutoff point of 20 mL/kg appeared to be a predictive factor for complications in our study. The absence of long-term neurological sequelae in the liveborn children allows us to provide parents with relatively reassuring information, even though long-term sequelae have been described1,3 and cannot be totally ruled out by our study. The major limitation of the evaluation of the prognosis of this pathology is the nondiagnosis of undetected fetomaternal hemorrhage that occurred during the prenatal course. These results lead us to recommend a Kleihauer test in all cases of unexplained fetal death, fetal distress, decreased fetal movements, nonimmune hydrops fetalis, neonatal shock, and nonhemolytic neonatal anemia.