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3. Seubert DE, Puder KS, Goldmeier P, Gonik B. Colonoscopic release of the incarcerated gravid uterus. Obstet Gynecol 1999;94:792– 4. 4. Gibbons JM Jr, Paley WB. The incarcerated gravid uterus. Obstet Gynecol 1969;33:842–5. 5. Gottschalk EM, Siedentopf JP, Schoenborn I, Gartenschlaeger S, Dudenhausen JW, Henrick W. Prenatal sonographic and

Massive Fetomaternal Hemorrhage Secondary to Intrauterine Intravascular Transfusion Yae¨l Levy-Zauberman, MD, Agne`s Mailloux, Aminata Kane, MD, Vanina Castaigne, MD, Anne Cortey, MD, and Bruno Carbonne, MD

MD,

BACKGROUND: Small-volume fetomaternal hemorrhage is frequently observed after intrauterine transfusion. The Kleihauer-Betke test, the reference method for identifying fetomaternal hemorrhage, cannot be used after intrauterine transfusion, because the adult red blood cells used for transfusion cannot be distinguished from maternal red blood cells. CASE: Massive fetomaternal hemorrhage secondary to intrauterine transfusion led to fetal hemorrhagic stroke. We used a method based on blood group identification in the maternal blood to confirm and to quantify fetomaternal hemorrhage. CONCLUSION: Fetal stroke may result from severe hypovolemia and low cerebral blood flow caused by fetomaternal hemorrhage, rather than from fetal anemia itself. (Obstet Gynecol 2011;118:439–42) DOI: 10.1097/AOG.0b013e318212f935

I

ntrauterine transfusion is the reference treatment of fetal anemia caused by red cell alloimmunization. However, this invasive procedure is still associated with a fetal loss rate of approximately 1.5–3% per

From the Department of Obstetrics and Gynecology and Centre National de Re´fe´rence en He´mobiologie Pe´rinatale, Hoˆpital Saint-Antoine, Paris, France; and Assistance Publique – Hoˆpitaux de Paris, Universite´ Pierre et Marie Curie, Paris, France. Corresponding author: Pr. Bruno Carbonne, Department of Obstetrics and Gynecology, Hoˆpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; e-mail: bruno.carbonne@sat.aphp.fr. Financial Disclosure The authors did not report any potential conflicts of interest. © 2011 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/11

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MRI findings in a pregnancy complicated by uterine sacculation: case report and review of the literature. Ultrasound Obstet Gynecol 2008;32:582– 6. 6. Hess LW, Nolan TE, Martin RW, Martin JN, Wiser WL, Morrison JC. Incarceration of the retroverted gravid uterus: report of four patients managed with uterine reduction. South Med J 1989;82:310 –2.

procedure.1,2 Life-threatening complications for the fetus have been related to umbilical vein thrombosis, arterial vasospasm, bleeding at the puncture site of the cord, infection, premature rupture of the membranes, and preterm delivery.1 Fetal intravascular transfusion has been reported to be frequently associated with small volume fetomaternal hemorrhage without fetal consequences.3 We report a case of massive fetomaternal hemorrhage secondary to intrauterine transfusion leading to severe perinatal complications.

CASE A 24-year-old woman, group B, RhD-negative, pregnant with her second child, was referred to our center at 21 4/7 weeks of gestation for fetal hydrops. Her first pregnancy had been complicated with severe fetomaternal anti-RhD alloimmunization discovered during the third trimester. A cesarean delivery was performed at 32 weeks of gestation for abnormal fetal heart rate (FHR). The 1,970-g male neonate required intensive phototherapy and received a packed red cell transfusion after birth. At the beginning of the second pregnancy, the anti-RhD titer was 1/64 and the level was 95 international units/mL (19 micrograms/mL). Fetal surveillance with ultrasonography was performed every 2 weeks only, instead of the weekly monitoring usually performed in such situations. The woman was referred to our department at 21 4/7 weeks of gestation, when ultrasound scan revealed fetal ascites, pleural effusion, subcutaneous edema, and hydramnios. On arrival, the middle cerebral artery peak systolic velocity was 50 cm/sec (ie, 1.8 MoM). An intrauterine transfusion was performed immediately. The placenta was anterior, and umbilical vein puncture was transplacental. Fetal hemoglobin level before transfusion was 2.5 g/dL. The fetus was transfused with group O, RhD-negative blood, with extended crossmatch with maternal blood. Posttransfusion hemoglobin level was 11.5 g/dL. At 24 weeks, middle cerebral artery peak systolic velocity increased again at 60 cm/sec (1.95 MoM), but fetal hydrops had fully resolved. A second transplacental intrauterine transfusion was performed. Fetal hemoglobin was 4.1g/dL on blood sampling and was brought to 13.8 g/dL by the transfusion. A third intrauterine transfusion was performed at 27 3/7 weeks of gestation after a 2-day course of betamethasone, when middle cerebral artery peak systolic velocity increased again above 1.5 MoM. Pretransfusion and posttransfusion

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fetal hemoglobin levels were 5.1 g/dL and 16.0 g/dL, respectively. The fourth transfusion was performed at 30 1/7 weeks of gestation, after a second course of corticosteroids. Because the accuracy of middle cerebral artery peak systolic velocity decreases in case of repeated intrauterine transfusions, the transfusion was performed despite levels remaining below 1.5 MoM. The decision was made on the basis of an expected drop in fetal hemoglobin of 3 g/dL per week from the fetal hemoglobin level obtained at the end of the previous intrauterine transfusion. The procedure was uneventful, with a single transplacental puncture to the umbilical vein using a 20-gauge needle. No evidence of arterial puncture or vascular laceration was found. No change in the FHR and no abnormal streaming from the umbilical vein were observed during or after the procedure. Fetal hemoglobin level was 9.5 g/dL before transfusion and 17.5 g/dL afterward. Transfusion and middle cerebral artery peak systolic velocity data are summarized in Table 1. The following morning, FHR monitoring displayed a sinusoidal pattern with moderate tachycardia at 160 beats per minute, suggesting recurrent fetal anemia. Although middle cerebral artery peak systolic velocity remained below 1.5 MoM, at 56 cm/sec an emergency cesarean delivery was performed because of persisting sinusoidal FHR. The amniotic fluid was clear and blood-free. A live male fetus weighing 1,500 g was delivered. One-minute Apgar score was 2, and he required immediate tracheal intubation and artificial ventilation. Umbilical artery blood pH was 7.37, pCO2 was 35 mm Hg, base excess was ⫺4.6 mmol/L, and lactates were 4.9 mmol/L. Umbilical vein hemoglobin level was 7.0 g/dL, corresponding to a more than 10 g/dL drop in hemoglobin in less than 24 hours. The neonate received immediate red blood cell transfusion and was transferred to the neonatal intensive care unit. The blood-free amniotic fluid ruled out intra-amniotic bleeding secondary to the umbilical cord puncture. A massive fetomaternal hemorrhage was thus the only likely explanation for this drop in fetal Hb. Kleihauer-Betke test was not informative because the fetus had been transfused previously with O RhD-negative adult red cells. Pathologic examination, with special focus on the umbilical cord insertion, revealed no anomaly of the placenta and umbil-

ical vessels. Our laboratory tested maternal blood for the presence of a double population of red cells: with a blood sample from the mother placed on an identification card DiaClon ABO/Rh for newborns (DiaMed), the group B RhD-negative red blood cells from the mother could be identified, as well as O RhD-negative red blood cells from the fetal circulation. This test consists of four gels containing antibodies against A, B, A and B, and RhD antigens, respectively. The blood sample is placed on top of the gel and centrifuged. The red cells are stopped in the gel when they express the antigen corresponding to the antibody. If not, they progress to the bottom of the gel. The blood group identification card demonstrating a double population of red cells in maternal blood is displayed in Figure 1. When compared with a control group, this corresponded to a volume of 300 fetal red cells per 10,000 maternal red cells (ie, a fetal bleeding volume of approximately 150 mL). During his stay in the neonatal intensive care unit, the neonate developed moderate multiorgan dysfunction, with renal failure, elevated liver enzymes, and disseminated intravascular coagulation. He received another red cell transfusion, platelets, and frozen plasma transfusion. He also was on continuous phototherapy for severe jaundice. On day 1, transfontanellar ultrasonography was considered normal. Repeated ultrasound scan on day 3 revealed a right parietal stroke with ischemic and hemorrhagic features, along with subependymal hemorrhage. Magnetic resonance imaging confirmed the diagnosis of stroke, with several sites of intracranial hemorrhage (Fig. 2). The neonate’s clinical evolution was rapidly favorable; he was extubated on day 3 and was transferred to intermediate neonatal care for the subsequent 2 weeks. He was discharged from the hospital on day 19 with a normal clinical neurologic examination. Ongoing follow-up at 18 months of age is deemed satisfactory, with no clinically detectable motor or cognitive impairment.

COMMENT Intrauterine intravascular transfusion, although a well-established procedure, still bears a risk of severe perinatal complications, with an estimated fetal loss rate of approximately 1.5–3% per procedure.1–3 Fetomaternal hemorrhage is another well-known yet in-

Table 1. Details of Middle Cerebral Artery Peak Systolic Velocity and Fetal Hemoglobin Levels Before and After Intrauterine Transfusions and at Birth Gestational Age (wk) 21 24 27 30 30

5/7 1/7 3/7 2/7 3/7 (birth)

Middle Cerebral Artery Peak Systolic Fetal Hemoglobin Level Before Fetal Hemoglobin Level After Velocity Before Intrauterine Transfusion Intrauterine Transfusion Intrauterine Transfusion (cm/s) (g/dL) (g/dL) 50 (1.8MoM) 60 (1.9MoM) 50 (1.4MoM) 48 (1.2MoM) 56 (1.4 MoM) (before delivery)

2.5 4.1 5.1 9.5 7.0 (at birth)

11.5 13.8 16.0 17.5 NA

MoM, multiples of the median; NA, not applicable.

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Fig. 2. Brain magnetic resonance imaging of the neonate on day 18. Right fronto-parietal hemorrhagic stroke features can be seen on sagittal view (arrow). Fig. 1. Blood group identification card demonstrating a double population of red blood cells in the mother’s blood. Panel 1 is a control O RhD-positive blood sample; panel 2 is a control B RhD-negative blood sample; panel 3 is a blood sample from the patient, showing predominant B RhD-negative blood from the mother and a small contingent of O RhD-negative red blood cells from the fetal circulation at the bottom of the tube (arrows). Levy-Zauberman. Fetomaternal Hemorrhage. Obstet Gynecol 2011.

constant consequence of intrauterine transfusion. Nicolini et al3 estimated the mean fetal blood loss from fetomaternal hemorrhage to be 2.4 mL during intrauterine transfusion, corresponding to 3.1% of the total fetoplacental blood volume. In the case of an anterior placenta, transplacental access to the umbilical cord vein has been shown to be safer than transamniotic puncture.1 However, this route is at higher risk for fetomaternal hemorrhage than transamniotic puncture in posterior placentas.3 In the present case, a massive fetomaternal hemorrhage occurred after transplacental intrauterine transfusion. A drop of more than 10 g/dL in fetal hemoglobin occurred within less than 24 hours after the procedure, with an estimated fetal bleeding volume of around 150 mL. Although this complication would be less likely using a transamniotic cord puncture without transplacental passage, intrauterine transfusion would also be technically more difficult by this route and the risk of hemorrhage into the amniotic fluid at the puncture

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site would be higher.1 The risk– benefit ratio remains in favor of a direct transplacental puncture of the vein. The diagnosis of fetomaternal hemorrhage is classically confirmed by Kleihauer-Betke test. In the reported case, the test was not informative because the fetus had already been transfused on three occasions with adult red cells. No fetal red cells could be detected by Kleihauer-Betke test in posttransfusion fetal blood or in maternal blood. It has been shown that fetomaternal hemorrhage could be suggested by a rise in alpha-feto-protein levels in maternal blood.3,4 We did not perform alpha-feto-protein measurements; however, we could a posteriori demonstrate the presence of a double population of adult red cells in maternal blood using a test for blood group determination: the group B RhD-negative red cells from the mother, and group O RhD-negative red cells from an adult donor coming from the fetal circulation after fetomaternal hemorrhage. This technique also allows an approximate quantitation of the volume of fetomaternal hemorrhage but it can be used only in cases where the mother’s blood group is not the same as the donor’s blood group, that is, group O. The severity of fetomaternal hemorrhage was suggested by the observation of severe FHR abnormalities on the day after intrauterine transfusion. When sinusoidal FHR pattern was observed, we tried

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to confirm fetal anemia by immediately performing a middle cerebral artery peak systolic velocity, the reference method for the diagnosis of fetal anemia.5 We have previously shown that middle cerebral artery peak systolic velocity measurement was accurate in the diagnosis of fetal anemia resulting from fetomaternal hemorrhage.6 However, in this previously published case, fetomaternal hemorrhage was a low-rate, chronic hemorrhage. In the present case, although middle cerebral artery peak systolic velocity increased from 1.2 MoM to 1.4 MoM in less than 24 hours, it did not reach the cutoff value of 1.5 MoM. We hypothesize that fetomaternal hemorrhage was extremely acute and that it was responsible for fetal hypovolemic shock. In such a situation, few changes in fetal hematocrit occur at the beginning of hemorrhage. Increased blood velocity in chronic fetal anemia has been reported to result from decreased fetal blood viscosity, increased venous return, increased preload, and increased cardiac output. In the present case, the rapid bleeding did probably not allow blood viscosity to decrease at the time when middle cerebral artery peak systolic velocity measurement was performed. The consequences observed on the fetal or neonatal brain may seem surprising because the neonatal hemoglobin level was 7.0 g/dL, whereas much lower fetal hemoglobin levels had been observed at the time of previous intrauterine transfusions, without any sign of poor fetal tolerance, either on ultrasonography or on FHR monitoring. Brain damage with chronic anemia was previously observed in case of extremely severe and prolonged fetal anemia.7 In the present case, we believe that the fetal stroke was caused by severe hypovolemia and low cerebral blood flow as a result of fetomaternal hemorrhage, rather than by fetal anemia, in a way similar to what is observed in the surviving twin in monochorionic pregnancies.8 None of the main other causes of perinatal stroke, that is, perinatal asphyxia or infection, was found in the neonate. Thombocytopenia resulting from dissemi-

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nated intravascular coagulation may have contributed to the hemorrhagic pattern of the stroke. This case demonstrates that a massive, life-threatening fetomaternal hemorrhage may occur after an uneventful intrauterine transfusion. Such complication, when extremely acute, may not be identified by ultrasonography and middle cerebral artery peak systolic velocity measurement. Fetal heart rate monitoring remains an important means of fetal surveillance within the first hours after an intravascular invasive procedure. REFERENCES 1. Van Kamp IL, Klumper FJ, Oepkes D, Meerman RH, Scherjon SA, Vandenbussche FP, et al. Complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization. Am J Obstet Gynecol 2005;192: 171–7. 2. Carbonne B, Castaigne-Meary V, Cynober E, Gougeul-Tesnie`re V, Cortey A, Soulie´ JC, et al. Use of peak systolic velocity of the middle cerebral artery in the management of fetal anemia due to fetomaternal erythrocyte alloimmunization [in French]. J Gynecol Obstet Biol Reprod (Paris) 2008;37:163–9. 3. Nicolini U, Kochenour NK, Greco P, Letsky EA, Johnson RD, Contreras M, et al. Consequences of fetomaternal haemorrhage after intrauterine transfusion. BMJ 1988;297:1379 – 81. 4. Hay DL, Barrie JU, Davison GB, Buttery BW, Horacek I, Pepperell RJ, et al. The relation between maternal serum alpha-fetoprotein levels and fetomaternal haemorrhage. Br J Obstet Gynaecol 1979;86:516 –20. 5. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ Jr, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. N Engl J Med 2000;342:9 –14. 6. Friszer S, Cortey A, Pierre F, Carbonne B. Using middle cerebral artery peak systolic velocity to time serial in utero transfusions in fetomaternal hemorrhage. Obstet Gynecol 2010;115:1036 – 8. 7. Carbonne B, Nguyen A, Cynober E, Castaigne V, Cortey A, Brossard Y. Prenatal diagnosis of anoxic cerebral lesions caused by profound fetal anemia secondary to maternal red blood cell alloimmunization. Obstet Gynecol 2008;112(2 pt 2):442– 4. 8. Fusi L, McParland P, Fisk N, Nicolini U, Wigglesworth J. Acute twin-twin transfusion: a possible mechanism for braindamaged survivors after intrauterine death of a monochorionic twin. Obstet Gynecol 1991;78(3 pt 2):517–20.

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