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Original Paper

Free Access

Demographic and Behavioral Predictors of Severe Fetomaternal Hemorrhage: A Case-Control Study

Stroustrup A.a-c · Plafkin C.c · Tran T.-A.c · Savitz D.A.d, e

Author affiliations

aDivision of Newborn Medicine, Department of Pediatrics, and bDepartment of Preventive Medicine, Icahn School of Medicine at Mount Sinai, and cIcahn School of Medicine at Mount Sinai, New York, N.Y., and Departments of dEpidemiology and eObstetrics and Gynecology, Brown University, Providence, R.I., USA

Corresponding Author

Annemarie Stroustrup, MD, MPH

Division of Newborn Medicine, Department of Pediatrics

Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1508

New York, NY 10029 (USA)

E-Mail annemarie.stroustrup@mssm.edu

Related Articles for ""

Neonatology 2016;109:248-254

Abstract

Background: Fetomaternal hemorrhage (FMH) signifies failure of the placental barrier with whole blood transfer. Fetal anemia following FMH is associated with significant morbidity and mortality. If FMH is identified early, fetal anemia can be treated to minimize adverse outcomes. Risk factors for FMH are not known, limiting efforts to provide targeted screening for FMH. Objective: To identify maternal and/or pregnancy characteristics associated with FMH that are recognizable prior to fetal morbidity. Methods: This is the first published case-control study of FMH. Cases were identified from a prospectively maintained database of all hospital births between 1988 and 2010. Each case was matched to 4 controls by date and time of birth, allowing for assessment of a wide range of clinical and demographic data. Logistic regression modeling was used to assess the association between demographic and clinical characteristics and the diagnosis of FMH. Results: A total of 23 mother-baby pairs impacted by FMH and 92 matched controls were evaluated. Compared to controls, case mothers were more likely to have private insurance and to work outside the home and at night during pregnancy. Cases were more likely to be delivered preterm, but preterm labor was not more common among cases. There was no difference in race/ethnicity of cases compared to controls. Conclusions: Severe FMH is associated with significant morbidity and mortality of the affected neonate. Women with FMH were more likely to work outside the home during pregnancy than women with normal pregnancies. This finding has implications for third-trimester screening of pregnant women who work in strenuous fields.

© 2016 S. Karger AG, Basel


Keywords

Case-control study · Fetomaternal hemorrhage · Neonatal anemia · Perinatal epidemiology ·


Introduction

Fetomaternal hemorrhage (FMH) is a poorly understood condition in which fetal whole blood crosses the placenta into the maternal circulation. This is most commonly a silent process in which a woman with a seemingly normal pregnancy does not experience symptoms related to the transfer of fetal blood [1]. The fetus, however, can face significant harm if blood loss is substantial. Small-volume fetal to maternal blood transfer can be detected following most births. Small-volume blood transfer is problematic only if maternal alloimmunization results [2]. Severe FMH, characterized by large-volume fetal blood loss, is associated with high rates of neonatal morbidity and mortality [1,3,4,5]. The clinical impact of FMH depends on the amount of blood transferred and the time frame over which the hemorrhage occurs [1,6,7]. Although recent data indicate that placental inflammation due to infection may be implicated in FMH [8], the pathophysiology of the condition is poorly understood.

FMH is most commonly diagnosed via the Kleihauer-Betke acid elution test or flow cytometry [9]. Both tests quantify fetal cells in a maternal blood sample. Retrospective studies in large populations document an incidence of FMH diagnosis of 1-2/10,000 live births [4,5,10]. The true incidence of clinically significant FMH is likely to be much higher, however, as FMH testing is underutilized in clinical practice [4,5,11]. Currently, testing for FMH after live birth occurs when significant fetal or neonatal anemia is recognized [1,2,12,13]. Symptomatic fetal or neonatal anemia - as evidenced by decreased fetal movement, sinusoidal fetal heart tracing, fetal or neonatal distress, or neonatal pallor - is a late consequence of severe FMH.

A number of risk factors have been suggested as predisposing factors for FMH (table 1). Of these, placental abruption, abdominal trauma, and the presence of placental tumors carry the most support in retrospective studies and are physiologically plausible. FMH must follow a breach of the trophoblast, and it is not difficult to see how abruption, trauma, or tumor invasion could be associated with fetal blood transfer. These risk factors are not present in the majority of cases of severe FMH, however, and commonly occur without FMH as a notable sequela [1,5,6,10,14,15,16]. No prospective epidemiological study of FMH has been completed in the general pregnant population, and predisposing factors for FMH are unknown in the vast majority of identified cases [1,2,15,16].

Table 1

Previously suggested risk factors associated with FMH

http://www.karger.com/WebMaterial/ShowPic/493568

Early recognition of large-volume FMH can significantly reduce morbidity and mortality. Intrauterine transfusions, early operative delivery, and aggressive neonatal transfusion are viable options to prevent tissue hypoxia and end organ damage due to anemia [1,3,17,18,19]. Universal screening for FMH is not practical due to the cost of laboratory testing. As the clinical and epidemiological risk factors for FMH are unknown, targeted testing cannot be undertaken.

In this study, we investigated the risk factors for FMH using a retrospective case-control approach. We hypothesize that distinct epidemiological and/or early clinical predictors of FMH can be identified. Our goal was to define a subpopulation of pregnant women who could benefit from targeted early screening for FMH and intervention prior to long-term adverse fetal/neonatal events related to severe anemia.

Methods

This is a retrospective case-control study. Case participants were defined as live-birth mother-baby pairs where FMH was diagnosed by Kleihauer-Betke testing during the immediate postpartum period demonstrating 0.1 ml or more of fetal blood in a maternal blood specimen. Cases were identified from a database of clinical information prospectively maintained for all patients admitted to the level I-IV newborn nurseries at our institution, as described previously [4]. Neonates with hematocrit 1 standard deviation (SD) below the mean for gestational age within the first 4 h of life were considered to have congenital anemia. The medical records for these patients were reviewed to identify those with associated FMH. Controls were selected from the general birth population at our institution. They were selected in a 4:1 ratio to cases by day and hour of birth; controls were the 2 births immediately prior to and immediately following the case subject. Cases and controls were born at our urban quaternary care medical center between January 1, 1988 and December 31, 2010. Medical records from the index pregnancy and perinatal admission were abstracted for a broad range of demographic and clinical information. All diagnoses included in the analyses were determined to be present if an attending physician note or problem list in the maternal obstetric or neonatal medical record noted the condition. Maternal diagnoses present during the index pregnancy, maternal procedures performed within 17 weeks of delivery (the lifespan of a fetal reticulocyte in the maternal circulation [20]), and all neonatal diagnoses and procedures present during the birth hospitalization were included in analyses. Our hospital records included detailed demographic information on factors including age, race, insurance provider, and employment type and status.

Descriptive statistics included means ± SD for normally distributed data and medians (with interquartile range, IQR) for skewed data. Student's t test, Pearson's χ2 test, Fisher's exact test, or the Wilcoxon rank-sum test were performed as appropriate. Correlations were assessed with Spearman's ρ. Bivariable logistic regression was used to obtain odds ratios and 95% confidence intervals (CI) for the association between individual case status and risk factor variables. Multivariable logistic regression was performed, including potential causative factors significant in bivariable analyses. A 2-tailed α level of 0.05 was used for significance. For the calculation of odds ratios involving cells with 0 observations, the 0.5 zero-cell correction was applied [21]. Statistical analyses were conducted using SPSS software, version 22 (IBM, Armonk, N.Y., USA). This study was approved by the Mount Sinai Program for the Protection of Human Subjects.

Results

Of 124,738 eligible mother-baby pairs, 23 (1.8 per 10,000) were diagnosed with FMH. Table 2 shows demographic and clinical information about the pregnancy that was known before the onset of labor or became apparent during labor and delivery. There were no differences in maternal race, age, or maternal hemoglobin or hematocrit prior to delivery between cases and controls. There was no significant difference in either the number of twin pregnancies or the incidence of invasive procedures during pregnancy (including amniocentesis and cephalic version) between cases and controls. Mothers of cases and controls were equally likely to have diabetes during pregnancy, experience physical trauma or vaginal bleeding during pregnancy, or have pre-eclampsia, hypercoagulability, urinary tract infection, placental tumors or chorioamnionitis. There was no difference in the incidence of uterine anomaly, fibroids, or oligohydramnios between cases and controls. The use of drugs or tobacco reported during pregnancy was similar between the two groups. As reported in previous studies of FMH, abnormal fetal heart tracing, specifically sinusoidal fetal heart tracing, and placental abruption were more common in cases than controls (p = 0.005 to p = 0.043). Female gender of the fetus was also weakly associated with FMH (p = 0.045). Cases were more likely than controls to be born via emergent Cesarean delivery and to require resuscitation in the delivery room (p < 0.001). They had lower Apgar scores at 1 and 5 min (p < 0.001). Cases were delivered at an earlier median gestational age than controls: 37.1 (35.0-39.5) versus 39.3 (38.3-40.3) weeks, and were more likely to be delivered preterm (less than 37 weeks' gestational age) than controls (p < 0.001). The median birth weight of cases was therefore lower than that of controls: 2.75 (2.35-3.21) versus 3.42 (3.20-3.67), but small for gestational age birth was not more common among cases.

Table 2

Demographic and clinical factors known prior to or immediately following birth

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Mothers of cases were more likely to work during pregnancy (p = 0.036) and to work at night (p = 0.035). As some of the case mothers were night shift medical workers, work specifically in the medical field was evaluated, but this was not a significant predictor of FMH. Private insurance was also associated with a diagnosis of FMH (p = 0.012). Maternal employment status during pregnancy was correlated with the use of private insurance (ρ = 0.7) and with Caucasian ethnicity (ρ = 0.4). Multivariable models adjusting for noncorrelated factors implicated in univariable analyses confirmed a significant association between maternal work during pregnancy and FMH (table 3).

Table 3

Multivariable logistic regression modeling of demographic and clinical factors associated with FMH known prior to birth

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Table 4 shows clinical outcome information for cases and controls pertaining to the neonatal clinical course. As expected based on delivery room characteristics, cases were more likely than controls to be admitted to the neonatal intensive care unit (NICU) as opposed to the level I nursery (p < 0.001). Mean hemoglobin at NICU admission was 7.2 ± 2.8 mg/dl for cases and 16.8 ± 2.4 mg/dl for controls (p < 0.001). Case neonates were significantly more likely to undergo invasive procedures and had more frequent diagnoses of respiratory distress syndrome, hypotension, and persistence of the fetal circulation than controls (p < 0.001 to p = 0.002). Cases were more likely to die in the neonatal period than controls (p = 0.03).

Table 4

Neonatal characteristics of FMH-impacted pregnancies compared to controls

http://www.karger.com/WebMaterial/ShowPic/493565

Discussion

Previous attempts to define the epidemiology of FMH have relied on large administrative databases without access to detailed case level clinical and demographic data, have focused exclusively on Rh-women carrying Rh+ fetuses, and/or have focused on infant outcomes rather than prenatal risk factor identification [5,6,10,14]. Additional reports of FMH are limited to case studies and small series, and have not broadened our understanding of predisposing clinical or demographic factors for the majority of cases of FMH [7,16,22]. A recent study of placental pathology indicating that placental inflammation may play a role in FMH [8] provides a promising novel lead that deserves further evaluation for clinical significance.

We report a case-control study of FMH based on 23 years of experience with FMH at our institution. Our population demonstrated an incidence of FMH consistent with previous large population-based studies [5,10]. Although based on a modest number of cases of FMH, this study clarifies previously noted associations between FMH and race and socioeconomic status [5]. Specifically, at our institution, where a racially diverse patient population is cared for by a single neonatology group, we found no evidence of an association between race and FMH. We did, however, find statistically significant associations between FMH and the correlated factors of maternal employment and private insurance. The effect size for this association was strongest in multivariable analysis adjusted for preterm delivery and gender of the fetus. Although the association between night shift work and FMH was not significant in the multivariable analysis, this may be related to the small number of night shift workers examined in this study. In aggregate, our findings raise the possibility that strenuous work during pregnancy may be a risk factor for FMH. Previous studies of FMH have shown that abdominal trauma, a rare event during pregnancy, is associated with FMH. It is possible that, in some situations, women who undertake physically demanding work during pregnancy may be at risk for FMH by a similar mechanism.

Previous studies of FMH have not considered employment status or employment hours in analyses. Maternal employment status may have been an unmeasured confounder in previous studies of FMH. Although maternal work history is not often recorded in administrative databases, we had access to this information in our chart abstraction. In contrast, race and insurance payer, which are correlated with each other and with employment status, are often recorded in administrative databases such as those used in previous population-based studies of FMH. If private insurance status served as a marker of maternal employment rather than as a marker of socioeconomic status broadly, the previously noted association between socioeconomic status and FMH may represent misclassification of an actual association between maternal work history and FMH. In our study, we had access to specific information on maternal employment, and could separate women who worked during pregnancy from those who were homemakers, students, or unemployed but nonetheless covered by private insurance.

Our study also addressed the role of race and ethnicity in FMH. Our institution has a diverse patient mix; our study population was 40% Black or Hispanic. All patients admitted to our institution's NICU are cared for by the same physician group with uniform diagnostic and practice guidelines regardless of race or health insurance status. In this environment, the previously seen association between race and FMH was not significant. This supports our hypothesis that previously seen associations between race and FMH in population-based studies relying on administrative data were related to access to care and geographic practice patterns rather than to biology [5].

Our study also clarifies a previously documented association between preterm birth and FMH [5]. As we found no association between preterm labor and FMH, we suggest that preterm birth in our case population may have been a consequence of FMH in which fetal distress prompted early delivery. This is in contrast to a possible association between spontaneous preterm birth and FMH.

As a single-center retrospective study, our analyses have certain limitations. The absolute number of FMH cases seen was small, so some analyses were underpowered. Although racially and socioeconomically diverse, our urban patient population may not be fully representative of other patient populations. As in most published studies of FMH, the diagnosis of FMH in our study relied on a clinical diagnosis made in real time. As demonstrated in table 4, our cases therefore represent the more severe, more clinically significant end of the FMH spectrum. Further prospective study is needed to evaluate the risk factors we propose in the broad population of pregnancies impacted by FMH.

Conclusion

We found a significant association between a mother's work history during pregnancy and the diagnosis of clinically significant FMH in the perinatal period. If supported in larger studies, this finding would have important ramifications regarding both the limitations of strenuous work during pregnancy and targeted screening for FMH among working women. Since the cost of life-long care for survivors of severe FMH is high, a laboratory screening strategy based on work history may be both feasible and cost-effective. As severe FMH is a rare condition, either a large multicenter prospective study or an international registry of cases may be needed to fully evaluate the associations proposed in the present study. Although there is no doubt that the majority of women can work safely during pregnancy, increased awareness of the possibility of FMH among women with demanding work schedules, particularly those involving night shifts, could aid early diagnosis by targeted prenatal FMH testing and early intervention to avoid significant fetal/neonatal morbidity and mortality in those cases where FMH occurs.

Acknowledgment

This study was supported by grant UL1TR000069 from the National Center for Advancing Translational Sciences, National Institutes of Health (KL2RR029885 to Dr. Stroustrup).

Disclosure Statement

The authors have no conflicts of interest to disclose.


References

  1. Wylie BJ, D'Alton ME: Fetomaternal hemorrhage. Obstet Gynecol 2010;115:1039-1051.
    External Resources
  2. Sebring ES, Polesky HF: Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects. Transfusion 1990;30:344-357.
  3. Lindenburg IT, Smits-Wintjens VE, van Klink JM, et al: Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. Am J Obstet Gynecol 2012;206:141, e1-8.
  4. Stroustrup A, Plafkin C, Savitz DA: Impact of physician awareness on diagnosis of fetomaternal hemorrhage. Neonatology 2014;105:250-255.
  5. Stroustrup A, Trasande L: Demographics, clinical characteristics and outcomes of neonates diagnosed with fetomaternal haemorrhage. Arch Dis Child Fetal Neonatal Ed 2012;97:F405-F410.
  6. de Almeida V, Bowman JM: Massive fetomaternal hemorrhage: Manitoba experience. Obstet Gynecol 1994;83:323-328.
    External Resources
  7. Singh P, Swanson T: Acute and chronic fetal anemia as a result of fetomaternal hemorrhage. Case Rep Obstet Gynecol 2014;2014:296463.
  8. Scholz C, Hermann C, Kachler A, et al: Association of placental inflammation with fetomaternal hemorrhage and loss of placental mucin-1. Arch Gynecol Obstet 2012;285:605-612.
  9. de Wit H, Nabbe KC, Kooren JA, et al: Reference values of fetal erythrocytes in maternal blood during pregnancy established using flow cytometry. Am J Clin Pathol 2011;136:631-636.
  10. Christensen RD, Lambert DK, Baer VL, et al: Severe neonatal anemia from fetomaternal hemorrhage: report from a multihospital health-care system. J Perinatol 2013;33:429-434.
  11. Stroustrup A, Plafkin C: A pilot prospective study of fetomaternal hemorrhage identified by anemia in asymptomatic neonates. J Perinatol, in press.
  12. Lubusky M, Simetka O, Studnickova M, Prochazka M, Ordeltova M, Vomackova K: Fetomaternal hemorrhage in normal vaginal delivery and in delivery by cesarean section. Transfusion 2012;52:1977-1982.
  13. Meleti D, De Oliveira LG, Araujo Junior E, et al: Evaluation of passage of fetal erythrocytes into maternal circulation after invasive obstetric procedures. J Obstet Gynaecol Res 2013;39:1374-1382.
  14. David M, Smidt J, Chen FC, Stein U, Dudenhausen JW: Risk factors for fetal-to-maternal transfusion in Rh D-negative women - results of a prospective study on 942 pregnant women. J Perinat Med 2004;32:254-257.
  15. Giacoia GP: Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv 1997;52:372-380.
  16. Laube DW, Schauberger CW: Fetomaternal bleeding as a cause for ‘unexplained' fetal death. Obstet Gynecol 1982;60:649-651.
    External Resources
  17. Lindenburg IT, van Klink JM, Smits-Wintjens VE, van Kamp IL, Oepkes D, Lopriore E: Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review. Prenat Diagn 2013;33:815-822.
  18. Stefanovic V, Paavonen J, Halmesmaki E, et al: Two intrauterine rescue transfusions in treatment of severe fetomaternal hemorrhage in the early third trimester. Clin Case Rep 2013;1:59-62.
  19. van Klink JM, Koopman HM, Oepkes D, Walther FJ, Lopriore E: Long-term neurodevelopmental outcome after intrauterine transfusion for fetal anemia. Early Hum Dev 2011;87:589-593.
  20. Dziegiel MH, Koldkjaer O, Berkowicz A: Massive antenatal fetomaternal hemorrhage: evidence for long-term survival of fetal red blood cells. Transfusion 2005;45:539-544.
  21. Sweeting MJ, Sutton AJ, Lambert PC: What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;23:1351-1375.
  22. Madu AE: Massive idiopathic feto-maternal transfusion associated with dilatation of umbilical vein: case report and review of literature. J Matern Fetal Neonatal Med 2013;26:1076-1081.
  23. Merz WM, Patzwaldt F, Fimmers R, Stoffel-Wagner B, Gembruch U: Fetomaternal hemorrhage in the second trimester. J Perinat Med 2012;40:353-357.
  24. Cardwell MS: Fetomaternal hemorrhage. When to suspect, how to manage. Postgrad Med 1987;82:127-130.
    External Resources
  25. Glasser L, West JH, Hagood RM: Incompatible fetomaternal transfusion with maternal intravascular lysis. Transfusion 1970;10:322-325.
  26. Meleti D, Caetano AC, Boute T, et al: Assessment of fetomaternal hemorrhage by Kleihauer-Betke test, flow cytometry and alpha-fetoprotein after invasive obstetric procedures. Clin Exp Obstet Gynecol 2012;39:303-306.
    External Resources
  27. Scholz C, Kachler A, Hermann C, et al: Flowcytometric assessment of fetomaternal hemorrhage during external cephalic version at term. J Perinat Med 2009;37:334-337.
  28. Rose PG, Strohm PL, Zuspan FP: Fetomaternal hemorrhage following trauma. Am J Obstet Gynecol 1985;153:844-847.
  29. Santamaria M, Benirschke K, Carpenter PM, Baldwin VJ, Pritchard JA: Transplacental hemorrhage associated with placental neoplasms. Pediatr Pathol 1987;7:601-615.

Author Contacts

Annemarie Stroustrup, MD, MPH

Division of Newborn Medicine, Department of Pediatrics

Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1508

New York, NY 10029 (USA)

E-Mail annemarie.stroustrup@mssm.edu


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: August 19, 2015
Accepted: November 02, 2015
Published online: February 10, 2016
Issue release date: June 2016

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 4

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


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References

  1. Wylie BJ, D'Alton ME: Fetomaternal hemorrhage. Obstet Gynecol 2010;115:1039-1051.
    External Resources
  2. Sebring ES, Polesky HF: Fetomaternal hemorrhage: incidence, risk factors, time of occurrence, and clinical effects. Transfusion 1990;30:344-357.
  3. Lindenburg IT, Smits-Wintjens VE, van Klink JM, et al: Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. Am J Obstet Gynecol 2012;206:141, e1-8.
  4. Stroustrup A, Plafkin C, Savitz DA: Impact of physician awareness on diagnosis of fetomaternal hemorrhage. Neonatology 2014;105:250-255.
  5. Stroustrup A, Trasande L: Demographics, clinical characteristics and outcomes of neonates diagnosed with fetomaternal haemorrhage. Arch Dis Child Fetal Neonatal Ed 2012;97:F405-F410.
  6. de Almeida V, Bowman JM: Massive fetomaternal hemorrhage: Manitoba experience. Obstet Gynecol 1994;83:323-328.
    External Resources
  7. Singh P, Swanson T: Acute and chronic fetal anemia as a result of fetomaternal hemorrhage. Case Rep Obstet Gynecol 2014;2014:296463.
  8. Scholz C, Hermann C, Kachler A, et al: Association of placental inflammation with fetomaternal hemorrhage and loss of placental mucin-1. Arch Gynecol Obstet 2012;285:605-612.
  9. de Wit H, Nabbe KC, Kooren JA, et al: Reference values of fetal erythrocytes in maternal blood during pregnancy established using flow cytometry. Am J Clin Pathol 2011;136:631-636.
  10. Christensen RD, Lambert DK, Baer VL, et al: Severe neonatal anemia from fetomaternal hemorrhage: report from a multihospital health-care system. J Perinatol 2013;33:429-434.
  11. Stroustrup A, Plafkin C: A pilot prospective study of fetomaternal hemorrhage identified by anemia in asymptomatic neonates. J Perinatol, in press.
  12. Lubusky M, Simetka O, Studnickova M, Prochazka M, Ordeltova M, Vomackova K: Fetomaternal hemorrhage in normal vaginal delivery and in delivery by cesarean section. Transfusion 2012;52:1977-1982.
  13. Meleti D, De Oliveira LG, Araujo Junior E, et al: Evaluation of passage of fetal erythrocytes into maternal circulation after invasive obstetric procedures. J Obstet Gynaecol Res 2013;39:1374-1382.
  14. David M, Smidt J, Chen FC, Stein U, Dudenhausen JW: Risk factors for fetal-to-maternal transfusion in Rh D-negative women - results of a prospective study on 942 pregnant women. J Perinat Med 2004;32:254-257.
  15. Giacoia GP: Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv 1997;52:372-380.
  16. Laube DW, Schauberger CW: Fetomaternal bleeding as a cause for ‘unexplained' fetal death. Obstet Gynecol 1982;60:649-651.
    External Resources
  17. Lindenburg IT, van Klink JM, Smits-Wintjens VE, van Kamp IL, Oepkes D, Lopriore E: Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review. Prenat Diagn 2013;33:815-822.
  18. Stefanovic V, Paavonen J, Halmesmaki E, et al: Two intrauterine rescue transfusions in treatment of severe fetomaternal hemorrhage in the early third trimester. Clin Case Rep 2013;1:59-62.
  19. van Klink JM, Koopman HM, Oepkes D, Walther FJ, Lopriore E: Long-term neurodevelopmental outcome after intrauterine transfusion for fetal anemia. Early Hum Dev 2011;87:589-593.
  20. Dziegiel MH, Koldkjaer O, Berkowicz A: Massive antenatal fetomaternal hemorrhage: evidence for long-term survival of fetal red blood cells. Transfusion 2005;45:539-544.
  21. Sweeting MJ, Sutton AJ, Lambert PC: What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;23:1351-1375.
  22. Madu AE: Massive idiopathic feto-maternal transfusion associated with dilatation of umbilical vein: case report and review of literature. J Matern Fetal Neonatal Med 2013;26:1076-1081.
  23. Merz WM, Patzwaldt F, Fimmers R, Stoffel-Wagner B, Gembruch U: Fetomaternal hemorrhage in the second trimester. J Perinat Med 2012;40:353-357.
  24. Cardwell MS: Fetomaternal hemorrhage. When to suspect, how to manage. Postgrad Med 1987;82:127-130.
    External Resources
  25. Glasser L, West JH, Hagood RM: Incompatible fetomaternal transfusion with maternal intravascular lysis. Transfusion 1970;10:322-325.
  26. Meleti D, Caetano AC, Boute T, et al: Assessment of fetomaternal hemorrhage by Kleihauer-Betke test, flow cytometry and alpha-fetoprotein after invasive obstetric procedures. Clin Exp Obstet Gynecol 2012;39:303-306.
    External Resources
  27. Scholz C, Kachler A, Hermann C, et al: Flowcytometric assessment of fetomaternal hemorrhage during external cephalic version at term. J Perinat Med 2009;37:334-337.
  28. Rose PG, Strohm PL, Zuspan FP: Fetomaternal hemorrhage following trauma. Am J Obstet Gynecol 1985;153:844-847.
  29. Santamaria M, Benirschke K, Carpenter PM, Baldwin VJ, Pritchard JA: Transplacental hemorrhage associated with placental neoplasms. Pediatr Pathol 1987;7:601-615.
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