Original Article
Management of Rh-isoimmunised Pregnancies : Our Experience Lt Col D Arora*, Col TK Bhattacharyya+, Col SK Kathpalia#, Col SPS Kochar**, Gp Capt GS Sandhu, VSM,++ Lt Col BK Goyal## Abstract Background: The aim of this study was to assess the role of middle cerebral artery peak systolic velocity (MCA-PSV), as measured by doppler ultrasound, in detecting foetal anaemia in Rh- isoimmunised pregnancies. Intra-uterine foetal blood transfusion was performed in such anaemic foetuses to tide over the crisis of foetal immaturity till considered fit for extra-uterine survival. Methods: Rh-isoimmunised pregnancies reporting to a tertiary institute from 2003 to 2005, were screened by doppler ultrasound to estimate MCA-PSV to detect foetal anaemia. If the foetus developed MCA-PSV of more than 1.5 multiple of median (MoM) for the gestational age, foetal blood sampling through cordocentesis was performed to confirm foetal anaemia, followed by intrauterine foetal blood transfusion to all anaemic foetuses at the same sitting. Neonatal outcome was evaluated by recording gestational age at the time of delivery, duration of gestational time gained and need for blood transfusion in the neonatal period. Results : A total of thirteen isoimmunised pregnancies were evaluated. Three pregnancies did not require in-utero foetal blood transfusion. Twenty-one intrauterine foetal blood transfusions were performed in the remaining ten patients. Five received blood transfusion in the neonatal period. Intra uterine foetal death occurred in one grossly hydropic foetus and favourable neonatal outcome was recorded in the rest. Conclusion : The clinical outcome of these pregnancies justifies the use of doppler studies of MCA-PSV in detecting foetal anaemia and intra uterine foetal blood transfusion is the only hope of prolonging pregnancy and salvaging such foetuses. MJAFI 2007; 63 : 7-11 Key Words : Rh-isoimmunisation; Middle cerebral artery peak systolic velocity; Foetal anaemia; Foetal blood transfusion
Introduction aemolytic disease of the newborn, secondary to rhesus alloimmunisation was once a major contributor to perinatal morbidity and mortality. Today, rhesus immune globulin has markedly decreased the prevalence of this disease so much that less than three cases occur in every 1000 live births [1]. The rarity of this condition warrants referral to a maternal-foetal medicine specialist. Once sensitisation occurs, rhesus immune globulin is no longer effective. Maternal antibody titres cannot be used to screening foetal anaemia. Conventionally, serial amniocenteses were performed for spectrophotometric studies to detect foetal bilirubin by Δ OD450 for estimating foetal anaemia, based on the Liley’s reference chart. Serial peak middle cerebral artery velocities using doppler ultrasound have now become the mainstay of screening for foetal anaemia [2]. In anaemic foetuses remote from term, intrauterine foetal blood transfusion is usually necessary either intravenously, through ultrasound-directed puncture of
H
*
the umbilical vein or intraperitoneally. Perinatal survival rates of more than 90% have been reported in such foetuses. Development of hydrops foetalis, has however been reported to reduce the chance for a favourable outcome by up to 25%. Long term studies have revealed normal neurological outcomes in more than 90% of such anaemic foetuses treated with foetal blood transfusion. Material and Methods Starting January 2003, we offered serial foetal middle cerebral artery-peak systolic velocity (MCA-PSV) measurements only instead of ‘traditional management’ with serial amniocentesis to all Rh-isoimmunised patients who reported to this centre. Indirect coombs titre of equal to or more than 1:8 was considered an indication for doppler assessment. The maximum maternal antibody titer reached during the antenatal period was also recorded. Paternal antigen testing was performed for all cases. Doppler measurement of the MCA-PSV was performed in recumbent position [3]. The foetal vertex was visualised, and an axial plane that included the thalami and cavum septum
Reader, Maternal & Foetal Medicine Specialist, +Professor & Head, **Associate Professor & Gynaecologic Oncologist, ++Reader ( Obstetrics and Gynaecology), Armed Forces Medical College, Pune - 411040. #Senior Advisor (Obstetrics and Gynaecology), CH (Central Command), Lucknow. ##Classified Specialist (Obstetrics and Gynaecology), AH R & R, Delhi Cantt. Received : 11.7.2005; Accepted : 21.7.2006
8
pellucidum was obtained. The transducer was moved caudally until the circle of Willis was in view with colour flow doppler imaging. The middle cerebral artery (MCA) closest to the maternal skin was identified, and the angle of the ultrasound beam to the MCA blood flow was positioned as close to zero degrees as possible. The velocity measurements were made as close to the MCA origin from the circle of Willis as possible. Peak systolic velocity measurements were taken during periods of foetal quiescence (absent foetal breathing motion or foetal movements). The peak of the velocity waveform was measured. Multiple measurements were obtained during each ultrasound examination. The highest value obtained with an angle close to zero, was recorded as the peak systolic velocity (PSV). Serial ultrasound examinations for MCA-PSV were performed every one to three weeks depending on the antibody titre. Measurement for foetal growth was performed every four to six weeks and evidence of evolving foetal hydrops was evaluated at each ultrasound examination. If the MCA-PSV measured greater than 1.5 multiple of median (MoM) for gestational age, then the pregnancy was considered to be at risk of significant foetal anaemia [3]. All the foetuses with elevated MCA-PSV values and in the intrauterine transfusion zone on Mari et al chart [3], were offered foetal blood sampling. Intra uterine foetal blood transfusion was performed whenever foetal haemoglobin was less than 9 gm% or hematocrit was less than 30% for the foetuses with gestational age of less than 34 weeks [4]. If the gestational age was more than 34 weeks, delivery was considered in view of expected foetal lung maturity. Records were maintained for the gestational age at which evaluation for anaemia by MCA-PSV with doppler ultrasound was initiated, the total numbers of doppler studies of the middle cerebral artery performed, gestational age at which intra uterine foetal blood transfusion was performed and the number of intra uterine foetal blood transfusions done. The records were reviewed for the duration of gestational time gained and gestational age at delivery. After birth, the neonatologist considered the need for blood transfusion when neonatal haemoglobin was less than 8 gm%. Intra uterine foetal blood transfusion involves insertion of long spinal needle under ultrasound guidance in the umbilical vein to obtain foetal blood sample followed by transfusion. Three trained persons are required for this procedure, an experienced operator who performs the cannulation and monitors transfusion, an assistant who administers blood and a third who performs blood tests and calculations. Tocolysis and suitable antibiotics are administered before the procedure. The umbilical vein at its placental insertion site is used for transfusion. Frequently, placental position and foetal lie prevents safe access to the site of placental insertion of umbilical cord for transfusion. The alternative approach is to cannulate the umbilical vein in the free loop of umbilical cord or intra hepatic part of umbilical vein that requires piercing foetal abdomen with foetal paralysis.
Arora et al
The volume of blood transfusion is determined by pretransfusion foetal hematocrit, the estimated foetoplacental blood volume for the gestational age and the hematocrit of the donor blood. Nomograms have been worked out based on these parameters to provide an estimation of volume of donor blood required to raise the foetal hematocrit to 40% [5]. At the end of the procedure one ml of foetal blood is aspirated to estimate post-transfusion foetal hematocrit. The blood is transfused at a rate of 10 ml per minute in 5-10 ml aliquots. During the procedure the flow of blood as a cascade is continuously visualised on the ultrasound screen that confirms correct needle placement. The foetal heart rate is periodically checked to look for foetal bradycardia. The onset of foetal bradycardia warrants abandoning the procedure to prevent cardiac overload and arrest. We used a free-hand technique rather than a needle guide to allow independent movement of the ultrasound transducer for periodic visualization of the foetal heart. The blood used is adult O Rh D negative blood ideally not more than 72 hours old, cross matched with maternal blood and screened for hepatitis B and C, cytomegalovirus and human immunodeficiency virus (HIV). To prevent graft versus host complications, the donor blood is passed through leucocyte depletion filters followed by irradiation to remove white blood cells. The donor blood cells are packed to a hematocrit of 75 – 85% to minimise volume. Top up transfusions as compared to exchange transfusions are quicker and reduce risk of needle displacement, bacterial contamination and umbilical vein thrombosis. The second transfusion should not be performed later than two weeks after the first. In cases of severe foetal anaemia, grossly hydropic foetuses or in cases where the first transfusion was small, the second transfusion may be required after a week. The mean fall of hematocrit is around 1% per day but wide variation between the first and second transfusion is possible[6]. The foetal loss during the procedure ranges from 4- 14%. The risk is more, if foetal blood transfusion is given before 20 weeks of gestation [6]. Transient foetal bradycardia is commenest and occurs in 8% of cases. The potentially fatal complications for the foetus are cord accidents like cord haematoma, umbilical artery spasm, haemorrhage from the cannulation site, thromboembolism and overloading of foetal circulation. Worsening degree of maternal sensitisation, chorioamnionitis, premature rupture of membranes and preterm labour are also possible while performing the procedure [7]. If the foetus receives more than three transfusions, foetal circulation will only show the transfused adult blood group O Rh D negative. The foetal erythropoiesis is suppressed and can remain suppressed up to six months postnatally, which should be monitored by regular haemoglobin estimation in the neonate. Top up transfusion may be necessary till resumption of erythropoiesis. These neonates do not have increased risk of compromise at birth and attain normal growth. There is also no neurodevelopmental abnormality on long term follow up [8]. MJAFI, Vol. 63, No. 1, 2007
Rh-isoimmunised Pregnancies
Results Thirteen Rh-isoimmunised antenatal patients with affected foetuses, met the criteria for inclusion in the study. The earliest gestational age at first MCA-PSV measurement was 18.5 weeks in the study group. The mean number of MCA-PSV studies per patient were 7.8. The highest Rh-D antibody titer was 1 in 1024, in an isoimmunised mother with hydropic foetus. In our study group, four foetuses had hydrops. Of the 13 pregnancies that were complicated by Rh isoimmunisation, 12 foetuses were Rh-D antigen positive. One foetus was RhD antigen negative with high maternal anti-D titre due to anamnestic reaction (Table 1). A total of 22 cordocentesis were performed on 13 foetuses. The lowest foetal haemoglobin was 1.7 g / dl, found in a foetus affected by Rh isoimmunisation at 24.3 weeks of gestation (Table 2). Of these 13 isoimmunised pregnancies 12 foetuses had a live birth. A total of 21 intra uterine foetal blood transfusions were performed on these 13 anaemic foetuses. The average gestational age at delivery was 35.1 weeks. The maximum time interval between initiation of foetal blood transfusion to delivery was 7.4 weeks. Three neonates required exchange transfusion in the neonatal period for increasing hyperbilirubinemia. Two neonates required top up transfusion in the neonatal period for maintaining the haemoglobin status. One of these neonates, who had received a top up transfusion, was also administered immunoglobulin to prevent hyperbilirubinemia.
Discussion The reliability of MCA-PSV in detecting foetal anaemia as a non invasive tool has been revealed earlier by Mari et al [3]. Intra uterine foetal blood transfusion is a procedure that requires expertise and experience. It is the only way to salvage the affected foetuses from certain intra uterine death and to gain crucial time before delivery to allow for foetal lung maturity. Isoimmunised pregnancies are at an increased risk of developing foetal anaemia, hydrops and stillbirth. Pregnancies at risk for haemolytic disease conventionally underwent serial amniocentesis for spectrophotometric measurement of bilirubin as an evidence of foetal haemolysis and anaemia [3]. To minimise invasive procedures and determine the optimal timing of intervention, a number of studies were performed to evaluate reliability and usefulness of noninvasive parameters [9]. Foetal hydrops is a late marker for foetal anaemia and is associated with a very high risk of perinatal morbidity and death. No other ultrasound markers predicts foetal anaemia consistently or at an early stage of foetal affection [3,9]. Mari et al [3] reported that MCA-PSV greater than 1.5 MoM for gestational age reliably detects foetal anaemia. This has also been found in our group of patients who underwent cordocentesis for foetal blood sampling only, when MJAFI, Vol. 63, No. 1, 2007
9 Table 1 Antenatal Evaluation Case No.
Highest Rh D antibody titer during antenatal period
I II III IV (Hydrops) V VI VII (Hydrops) VIII (Hydrops) IX X# XI XII (Hydrops) XIII
1 1 1 1 1 1 1 1 1 1 1 1 1
in in in in in in in in in in in in in
128 64 256 512 128 64 256 512 16 256 8 1024 512
Gestational age at initiation of MCA-PSV (in weeks)
Total number of MCA-PSV estimation
26.1 22.3 18.5 24.3 21.4 27.3 22.5 22.0 29.4 34.0 35.3 22.2 28.1
8 7 13 1 * 8 7 11 13 6 2 1 17 7
* This grossly hydropic foetus developed severe bradycardia intraoperatively while receiving intra-uterine foetal blood transfusion and finally had intra-uterine foetal death the next day. # This foetus was Rh D negative as revealed on foetal blood sampling and indirect coombs test (ICT) was positive due to anamnestic reaction. Table 2 Correlation of middle cerebral artery peak systolic velocity to foetal hemoglobin on cordocentesis Case No. Cordocentesis MCA-PSV Gestational age Foetal Hb values at the time of by (in cm / sec) cordocentesis cordocentesis (in weeks) (in gram %) I
1 2 3 II 4 III 5 6 7 IV (Hydrops) 8 V 9 VI 10 VII (Hydrops) 1 1 12 13 VIII (Hydrops) 1 4 15 16 XI 17 XII (Hydrops) 1 8 19 20 21 XIII 22
66 73 81 90 76 69 73 72 68 83 93 68 69 71 67 74 69 105 54 64 72 62
29.5 31.3 34.2 34.5 29.1 31.4 33.5 24.4 33.2 33.5 30.1 31.4 33.6 28.2 30 32.5 34 26.3 27.3 31.2 33.2 29.2
7.2 8.1 7.9 6.9 6.5 7.8 8.1 1.7 7.4 5.9 @ 4.8 7.7 8.2 @ 5.0 7.2 7.9 @ 10.5 2.4 8.7 8.0 5.0 9.6@
@ Neonate received top up / exchange transfusion
MCA-PSV value was found to be more than 1.5 MoM for the gestational age (Table 2). In our series we support findings of Mari et al, except in one foetus whose
10
Arora et al
blood group was Rh D negative. The MCA-PSV values in this foetus were borderline for foetal anaemia. The mother of this foetus had history of previous two perinatal losses. Foetal blood sampling in this case revealed blood group negative for Rh D antigen and Rh D titres were raised probably due to an anamnestic reaction. Amniocentesis and foetal blood sampling are associated with risks including infection, pregnancy loss, preterm labour, preterm premature rupture of membranes, chorioamnionitis, worsening of isoimmunization and foetal bradycardia. The risk of complications after amniocentesis and foetal blood sampling is approximately 1% and 1-2%, respectively [10]. We encountered one minor complication of umbilical vein counter puncture during the procedure of intra uterine foetal blood transfusion. This resolved spontaneously without any adverse foetal sequelae. In our study, the hydropic foetuses were detected to have haemoglobin equal to or less than 5 g/dl. However,
Fig. 1 : Intrauterine blood transfusion in progress
the foetuses in the study group of Nicolaides et al [11] tolerated anaemia up to 4 g/dl or less without developing hydrops. In our series, one hydropic foetus suffered intra uterine foetal death. The mother of this severely anaemic foetus reported at 24.3 weeks gestation. This foetus had bad prognostic signs of gross scalp oedema, subcutaneous oedema and cardiac dilatation. Cordocentesis revealed very low haemoglobin of 1.7 gm%. This foetus was transfused less than half of the calculated volume of packed red blood cells to prevent cardiac overload. The foetus could not withstand even reduced transfusion and developed intra operative bradycardia. The transfusion was abandoned. Ultrasound evaluation on the next day revealed intra uterine foetal death. Intra uterine foetal transfusion was administered to all foetuses having haemoglobin of less than 8.2 g/dl. This was in order to maintain the foetal hematocrit of 40% for a favourable perinatal outcome [5]. We have been able to salvage 12 out of 13 affected foetuses. An average delivery age of 35.1 weeks was achieved in this study (Table 3). The maximum gestational time gained was 7.4 weeks in a foetus with hydrops (case XI). However in another patient (case II), we performed foetal transfusion just before delivery for preventing exchange transfusion in the neonatal period. The intra uterine foetal blood transfusion prevents premature deliveries and intra uterine foetal demise due to severe anaemia. The risk of neonatal exchange transfusion is reduced, but not completely eliminated despite MCAPSV being normal. The rate of rise of neonatal bilirubin levels determines the need for exchange transfusion in the neonatal period [1]. MCA-PSV offers a reliable non-invasive modality for determining the foetal anaemic status in isoimmunised pregnancies. It guides the timing of intra uterine
Table 3 Perinatal outcome Case No
I II III IV (Hydrops) V VI VII (Hydrops) VIII (Hydrops) IX X XI XII (Hydrops) XIII
Earliest estimated gestational age at abnormal MCA-PSV (in weeks/days)
Estimated gestational age at delivery (in weeks/days)
Total number of intrauterine foetal blood transfusion performed
Initiation of foetal transfusion and delivery interval (in weeks/ days)
Total number of exchange/top up transfusion in the neonate
28.5 34.5 27.2 24.3 22.4 31.5 27.5 26.3 Nil Nil Nil 26.3 28.2
35.1 35.3 34.3 IUFD 35 36.4 34.2 34 37.5 36.2 37 34 33.6
3 1 3 1 1 1 3 3 Nil Nil Nil 4 1
5.3 0.5 5.2 Nil 1.5 2.6 4.1 5.5 7.4 4.4
Nil Nil Nil IUFD Nil 1 (Top up) 1 (Exch) 1 (Exch) Nil 1 (Exch) Nil Nil 1 (Top up + I G) MJAFI, Vol. 63, No. 1, 2007
Rh-isoimmunised Pregnancies
transfusions, aids in monitoring the post transfusion period and helps in optimizing delivery timing to near term. Conflicts of Interest None identified References 1. McLean LK, Hedriana HL, Lanouette JM, Hanns C, Haesslein. A retrospective review of isoimmunised pregnancies managed by middle cerebral artery peak systolic velocity. American Journal of Obstetrics and Gynecology 2004; 190: 1732-8. 2. Detti L, Mari G, Akiyama M, Cosmi Erich, Moise Jr K J, Stefor T, Conaway M, Deter R. Longitudinal assessment of the middle cerebral artery peak systolic velocity in healthy foetuses and in foetuses at risk for anaemia. American Journal of Obstetrics and Gynecology 2002; 937-9. 3. Mari G. The collaborative group for diagnosis of foetal anaemia with doppler ultrasonography. Noninvasive diagnosis by doppler ultrasonography of foetal anaemia due to maternal red-cell alloimmunisation. N Engl J Med 2000; 342:9-14. 4. Weiner CP, Heilskov J, Pelzer G, Grant S, Wenstrom K, Williamson RA. Normal values for human umbilical venous and amniotic fluid pressures and their alteration by foetal disease. American Journal of Obstetrics and Gynecology 1989; 161: 714-7. 5. Nicolaides KH, Soothill PW, Rodeck CH, CLewell W. Rh
MJAFI, Vol. 63, No. 1, 2007
11 disease: Intravascular foetal blood transfusion by cordocentesis. Foetal Therapy 1986; 1: 185-92. 6. Rodeck CH, Deans A. Red cell alloimmunisation. In: Rodeck CH, Whittle MJ, editors. Foetal medicine: Basic science and clinical practice.1st ed. London: Churchill Livingstone, 1999; 785-04. 7. Weiner CP, Williamson RA, Wenstrom KD, Sipes SL, Wideness JA, Grant SS, Estle L. Management of foetal hemolytic disease by cordocentesis. American Journal of Obstetrics and Gynecology 1991; 165: 1302-7. 8. Doyle LW, Kelly EA, Richards EJ, Ford GW, Callanan C. Sensorineural outcome at two years for survivors of erythroblastosis treated with foetal intravascular transfusion. Obstet Gynecol 1993; 81: 931-5. 9. Divakaran TG, Waugh J, Clark TJ, Khan KS, Whittle MF, Kilby MD. Noninvasive techniques to detect foetal anaemia because of red blood cell alloimmunisation: A systematic review. Obstet Gynecol 2001; 98: 509-17. 10. Daffos F, Capella-Pavlovsky M, Forestier F. Foetal blood sampling during pregnancy with use of a needle guided by ultrasound: A study of 606 consecutive cases. American Journal of Obstetrics and Gynecology 1985; 153: 655-60. 11. Nicolaides KH, Thilaganathan B, Rodeck CH, Mibashan. Erythroblastosis and reticulocytosis in anemic fetuses. American Journal of Obstetrics and Gynecology 1988; 159: 1063-5.
Management of Rh-isoimmunised Pregnancies : Our Experience Lt Col D Arora*, Col TK Bhattacharyya+, Col SK Kathpalia#, Col SPS Kochar**, Gp Capt GS Sandhu, VSM,++ Lt Col BK Goyal## Abstract Background: The aim of this study was to assess the role of middle cerebral artery peak systolic velocity (MCA-PSV), as measured by doppler ultrasound, in detecting foetal anaemia in Rh- isoimmunised pregnancies. Intra-uterine foetal blood transfusion was performed in such anaemic foetuses to tide over the crisis of foetal immaturity till considered fit for extra-uterine survival. Methods: Rh-isoimmunised pregnancies reporting to a tertiary institute from 2003 to 2005, were screened by doppler ultrasound to estimate MCA-PSV to detect foetal anaemia. If the foetus developed MCA-PSV of more than 1.5 multiple of median (MoM) for the gestational age, foetal blood sampling through cordocentesis was performed to confirm foetal anaemia, followed by intrauterine foetal blood transfusion to all anaemic foetuses at the same sitting. Neonatal outcome was evaluated by recording gestational age at the time of delivery, duration of gestational time gained and need for blood transfusion in the neonatal period. Results : A total of thirteen isoimmunised pregnancies were evaluated. Three pregnancies did not require in-utero foetal blood transfusion. Twenty-one intrauterine foetal blood transfusions were performed in the remaining ten patients. Five received blood transfusion in the neonatal period. Intra uterine foetal death occurred in one grossly hydropic foetus and favourable neonatal outcome was recorded in the rest. Conclusion : The clinical outcome of these pregnancies justifies the use of doppler studies of MCA-PSV in detecting foetal anaemia and intra uterine foetal blood transfusion is the only hope of prolonging pregnancy and salvaging such foetuses. MJAFI 2007; 63 : 7-11 Key Words : Rh-isoimmunisation; Middle cerebral artery peak systolic velocity; Foetal anaemia; Foetal blood transfusion
Introduction aemolytic disease of the newborn, secondary to rhesus alloimmunisation was once a major contributor to perinatal morbidity and mortality. Today, rhesus immune globulin has markedly decreased the prevalence of this disease so much that less than three cases occur in every 1000 live births [1]. The rarity of this condition warrants referral to a maternal-foetal medicine specialist. Once sensitisation occurs, rhesus immune globulin is no longer effective. Maternal antibody titres cannot be used to screening foetal anaemia. Conventionally, serial amniocenteses were performed for spectrophotometric studies to detect foetal bilirubin by Δ OD450 for estimating foetal anaemia, based on the Liley’s reference chart. Serial peak middle cerebral artery velocities using doppler ultrasound have now become the mainstay of screening for foetal anaemia [2]. In anaemic foetuses remote from term, intrauterine foetal blood transfusion is usually necessary either intravenously, through ultrasound-directed puncture of
H
*
the umbilical vein or intraperitoneally. Perinatal survival rates of more than 90% have been reported in such foetuses. Development of hydrops foetalis, has however been reported to reduce the chance for a favourable outcome by up to 25%. Long term studies have revealed normal neurological outcomes in more than 90% of such anaemic foetuses treated with foetal blood transfusion. Material and Methods Starting January 2003, we offered serial foetal middle cerebral artery-peak systolic velocity (MCA-PSV) measurements only instead of ‘traditional management’ with serial amniocentesis to all Rh-isoimmunised patients who reported to this centre. Indirect coombs titre of equal to or more than 1:8 was considered an indication for doppler assessment. The maximum maternal antibody titer reached during the antenatal period was also recorded. Paternal antigen testing was performed for all cases. Doppler measurement of the MCA-PSV was performed in recumbent position [3]. The foetal vertex was visualised, and an axial plane that included the thalami and cavum septum
Reader, Maternal & Foetal Medicine Specialist, +Professor & Head, **Associate Professor & Gynaecologic Oncologist, ++Reader ( Obstetrics and Gynaecology), Armed Forces Medical College, Pune - 411040. #Senior Advisor (Obstetrics and Gynaecology), CH (Central Command), Lucknow. ##Classified Specialist (Obstetrics and Gynaecology), AH R & R, Delhi Cantt. Received : 11.7.2005; Accepted : 21.7.2006
8
pellucidum was obtained. The transducer was moved caudally until the circle of Willis was in view with colour flow doppler imaging. The middle cerebral artery (MCA) closest to the maternal skin was identified, and the angle of the ultrasound beam to the MCA blood flow was positioned as close to zero degrees as possible. The velocity measurements were made as close to the MCA origin from the circle of Willis as possible. Peak systolic velocity measurements were taken during periods of foetal quiescence (absent foetal breathing motion or foetal movements). The peak of the velocity waveform was measured. Multiple measurements were obtained during each ultrasound examination. The highest value obtained with an angle close to zero, was recorded as the peak systolic velocity (PSV). Serial ultrasound examinations for MCA-PSV were performed every one to three weeks depending on the antibody titre. Measurement for foetal growth was performed every four to six weeks and evidence of evolving foetal hydrops was evaluated at each ultrasound examination. If the MCA-PSV measured greater than 1.5 multiple of median (MoM) for gestational age, then the pregnancy was considered to be at risk of significant foetal anaemia [3]. All the foetuses with elevated MCA-PSV values and in the intrauterine transfusion zone on Mari et al chart [3], were offered foetal blood sampling. Intra uterine foetal blood transfusion was performed whenever foetal haemoglobin was less than 9 gm% or hematocrit was less than 30% for the foetuses with gestational age of less than 34 weeks [4]. If the gestational age was more than 34 weeks, delivery was considered in view of expected foetal lung maturity. Records were maintained for the gestational age at which evaluation for anaemia by MCA-PSV with doppler ultrasound was initiated, the total numbers of doppler studies of the middle cerebral artery performed, gestational age at which intra uterine foetal blood transfusion was performed and the number of intra uterine foetal blood transfusions done. The records were reviewed for the duration of gestational time gained and gestational age at delivery. After birth, the neonatologist considered the need for blood transfusion when neonatal haemoglobin was less than 8 gm%. Intra uterine foetal blood transfusion involves insertion of long spinal needle under ultrasound guidance in the umbilical vein to obtain foetal blood sample followed by transfusion. Three trained persons are required for this procedure, an experienced operator who performs the cannulation and monitors transfusion, an assistant who administers blood and a third who performs blood tests and calculations. Tocolysis and suitable antibiotics are administered before the procedure. The umbilical vein at its placental insertion site is used for transfusion. Frequently, placental position and foetal lie prevents safe access to the site of placental insertion of umbilical cord for transfusion. The alternative approach is to cannulate the umbilical vein in the free loop of umbilical cord or intra hepatic part of umbilical vein that requires piercing foetal abdomen with foetal paralysis.
Arora et al
The volume of blood transfusion is determined by pretransfusion foetal hematocrit, the estimated foetoplacental blood volume for the gestational age and the hematocrit of the donor blood. Nomograms have been worked out based on these parameters to provide an estimation of volume of donor blood required to raise the foetal hematocrit to 40% [5]. At the end of the procedure one ml of foetal blood is aspirated to estimate post-transfusion foetal hematocrit. The blood is transfused at a rate of 10 ml per minute in 5-10 ml aliquots. During the procedure the flow of blood as a cascade is continuously visualised on the ultrasound screen that confirms correct needle placement. The foetal heart rate is periodically checked to look for foetal bradycardia. The onset of foetal bradycardia warrants abandoning the procedure to prevent cardiac overload and arrest. We used a free-hand technique rather than a needle guide to allow independent movement of the ultrasound transducer for periodic visualization of the foetal heart. The blood used is adult O Rh D negative blood ideally not more than 72 hours old, cross matched with maternal blood and screened for hepatitis B and C, cytomegalovirus and human immunodeficiency virus (HIV). To prevent graft versus host complications, the donor blood is passed through leucocyte depletion filters followed by irradiation to remove white blood cells. The donor blood cells are packed to a hematocrit of 75 – 85% to minimise volume. Top up transfusions as compared to exchange transfusions are quicker and reduce risk of needle displacement, bacterial contamination and umbilical vein thrombosis. The second transfusion should not be performed later than two weeks after the first. In cases of severe foetal anaemia, grossly hydropic foetuses or in cases where the first transfusion was small, the second transfusion may be required after a week. The mean fall of hematocrit is around 1% per day but wide variation between the first and second transfusion is possible[6]. The foetal loss during the procedure ranges from 4- 14%. The risk is more, if foetal blood transfusion is given before 20 weeks of gestation [6]. Transient foetal bradycardia is commenest and occurs in 8% of cases. The potentially fatal complications for the foetus are cord accidents like cord haematoma, umbilical artery spasm, haemorrhage from the cannulation site, thromboembolism and overloading of foetal circulation. Worsening degree of maternal sensitisation, chorioamnionitis, premature rupture of membranes and preterm labour are also possible while performing the procedure [7]. If the foetus receives more than three transfusions, foetal circulation will only show the transfused adult blood group O Rh D negative. The foetal erythropoiesis is suppressed and can remain suppressed up to six months postnatally, which should be monitored by regular haemoglobin estimation in the neonate. Top up transfusion may be necessary till resumption of erythropoiesis. These neonates do not have increased risk of compromise at birth and attain normal growth. There is also no neurodevelopmental abnormality on long term follow up [8]. MJAFI, Vol. 63, No. 1, 2007
Rh-isoimmunised Pregnancies
Results Thirteen Rh-isoimmunised antenatal patients with affected foetuses, met the criteria for inclusion in the study. The earliest gestational age at first MCA-PSV measurement was 18.5 weeks in the study group. The mean number of MCA-PSV studies per patient were 7.8. The highest Rh-D antibody titer was 1 in 1024, in an isoimmunised mother with hydropic foetus. In our study group, four foetuses had hydrops. Of the 13 pregnancies that were complicated by Rh isoimmunisation, 12 foetuses were Rh-D antigen positive. One foetus was RhD antigen negative with high maternal anti-D titre due to anamnestic reaction (Table 1). A total of 22 cordocentesis were performed on 13 foetuses. The lowest foetal haemoglobin was 1.7 g / dl, found in a foetus affected by Rh isoimmunisation at 24.3 weeks of gestation (Table 2). Of these 13 isoimmunised pregnancies 12 foetuses had a live birth. A total of 21 intra uterine foetal blood transfusions were performed on these 13 anaemic foetuses. The average gestational age at delivery was 35.1 weeks. The maximum time interval between initiation of foetal blood transfusion to delivery was 7.4 weeks. Three neonates required exchange transfusion in the neonatal period for increasing hyperbilirubinemia. Two neonates required top up transfusion in the neonatal period for maintaining the haemoglobin status. One of these neonates, who had received a top up transfusion, was also administered immunoglobulin to prevent hyperbilirubinemia.
Discussion The reliability of MCA-PSV in detecting foetal anaemia as a non invasive tool has been revealed earlier by Mari et al [3]. Intra uterine foetal blood transfusion is a procedure that requires expertise and experience. It is the only way to salvage the affected foetuses from certain intra uterine death and to gain crucial time before delivery to allow for foetal lung maturity. Isoimmunised pregnancies are at an increased risk of developing foetal anaemia, hydrops and stillbirth. Pregnancies at risk for haemolytic disease conventionally underwent serial amniocentesis for spectrophotometric measurement of bilirubin as an evidence of foetal haemolysis and anaemia [3]. To minimise invasive procedures and determine the optimal timing of intervention, a number of studies were performed to evaluate reliability and usefulness of noninvasive parameters [9]. Foetal hydrops is a late marker for foetal anaemia and is associated with a very high risk of perinatal morbidity and death. No other ultrasound markers predicts foetal anaemia consistently or at an early stage of foetal affection [3,9]. Mari et al [3] reported that MCA-PSV greater than 1.5 MoM for gestational age reliably detects foetal anaemia. This has also been found in our group of patients who underwent cordocentesis for foetal blood sampling only, when MJAFI, Vol. 63, No. 1, 2007
9 Table 1 Antenatal Evaluation Case No.
Highest Rh D antibody titer during antenatal period
I II III IV (Hydrops) V VI VII (Hydrops) VIII (Hydrops) IX X# XI XII (Hydrops) XIII
1 1 1 1 1 1 1 1 1 1 1 1 1
in in in in in in in in in in in in in
128 64 256 512 128 64 256 512 16 256 8 1024 512
Gestational age at initiation of MCA-PSV (in weeks)
Total number of MCA-PSV estimation
26.1 22.3 18.5 24.3 21.4 27.3 22.5 22.0 29.4 34.0 35.3 22.2 28.1
8 7 13 1 * 8 7 11 13 6 2 1 17 7
* This grossly hydropic foetus developed severe bradycardia intraoperatively while receiving intra-uterine foetal blood transfusion and finally had intra-uterine foetal death the next day. # This foetus was Rh D negative as revealed on foetal blood sampling and indirect coombs test (ICT) was positive due to anamnestic reaction. Table 2 Correlation of middle cerebral artery peak systolic velocity to foetal hemoglobin on cordocentesis Case No. Cordocentesis MCA-PSV Gestational age Foetal Hb values at the time of by (in cm / sec) cordocentesis cordocentesis (in weeks) (in gram %) I
1 2 3 II 4 III 5 6 7 IV (Hydrops) 8 V 9 VI 10 VII (Hydrops) 1 1 12 13 VIII (Hydrops) 1 4 15 16 XI 17 XII (Hydrops) 1 8 19 20 21 XIII 22
66 73 81 90 76 69 73 72 68 83 93 68 69 71 67 74 69 105 54 64 72 62
29.5 31.3 34.2 34.5 29.1 31.4 33.5 24.4 33.2 33.5 30.1 31.4 33.6 28.2 30 32.5 34 26.3 27.3 31.2 33.2 29.2
7.2 8.1 7.9 6.9 6.5 7.8 8.1 1.7 7.4 5.9 @ 4.8 7.7 8.2 @ 5.0 7.2 7.9 @ 10.5 2.4 8.7 8.0 5.0 9.6@
@ Neonate received top up / exchange transfusion
MCA-PSV value was found to be more than 1.5 MoM for the gestational age (Table 2). In our series we support findings of Mari et al, except in one foetus whose
10
Arora et al
blood group was Rh D negative. The MCA-PSV values in this foetus were borderline for foetal anaemia. The mother of this foetus had history of previous two perinatal losses. Foetal blood sampling in this case revealed blood group negative for Rh D antigen and Rh D titres were raised probably due to an anamnestic reaction. Amniocentesis and foetal blood sampling are associated with risks including infection, pregnancy loss, preterm labour, preterm premature rupture of membranes, chorioamnionitis, worsening of isoimmunization and foetal bradycardia. The risk of complications after amniocentesis and foetal blood sampling is approximately 1% and 1-2%, respectively [10]. We encountered one minor complication of umbilical vein counter puncture during the procedure of intra uterine foetal blood transfusion. This resolved spontaneously without any adverse foetal sequelae. In our study, the hydropic foetuses were detected to have haemoglobin equal to or less than 5 g/dl. However,
Fig. 1 : Intrauterine blood transfusion in progress
the foetuses in the study group of Nicolaides et al [11] tolerated anaemia up to 4 g/dl or less without developing hydrops. In our series, one hydropic foetus suffered intra uterine foetal death. The mother of this severely anaemic foetus reported at 24.3 weeks gestation. This foetus had bad prognostic signs of gross scalp oedema, subcutaneous oedema and cardiac dilatation. Cordocentesis revealed very low haemoglobin of 1.7 gm%. This foetus was transfused less than half of the calculated volume of packed red blood cells to prevent cardiac overload. The foetus could not withstand even reduced transfusion and developed intra operative bradycardia. The transfusion was abandoned. Ultrasound evaluation on the next day revealed intra uterine foetal death. Intra uterine foetal transfusion was administered to all foetuses having haemoglobin of less than 8.2 g/dl. This was in order to maintain the foetal hematocrit of 40% for a favourable perinatal outcome [5]. We have been able to salvage 12 out of 13 affected foetuses. An average delivery age of 35.1 weeks was achieved in this study (Table 3). The maximum gestational time gained was 7.4 weeks in a foetus with hydrops (case XI). However in another patient (case II), we performed foetal transfusion just before delivery for preventing exchange transfusion in the neonatal period. The intra uterine foetal blood transfusion prevents premature deliveries and intra uterine foetal demise due to severe anaemia. The risk of neonatal exchange transfusion is reduced, but not completely eliminated despite MCAPSV being normal. The rate of rise of neonatal bilirubin levels determines the need for exchange transfusion in the neonatal period [1]. MCA-PSV offers a reliable non-invasive modality for determining the foetal anaemic status in isoimmunised pregnancies. It guides the timing of intra uterine
Table 3 Perinatal outcome Case No
I II III IV (Hydrops) V VI VII (Hydrops) VIII (Hydrops) IX X XI XII (Hydrops) XIII
Earliest estimated gestational age at abnormal MCA-PSV (in weeks/days)
Estimated gestational age at delivery (in weeks/days)
Total number of intrauterine foetal blood transfusion performed
Initiation of foetal transfusion and delivery interval (in weeks/ days)
Total number of exchange/top up transfusion in the neonate
28.5 34.5 27.2 24.3 22.4 31.5 27.5 26.3 Nil Nil Nil 26.3 28.2
35.1 35.3 34.3 IUFD 35 36.4 34.2 34 37.5 36.2 37 34 33.6
3 1 3 1 1 1 3 3 Nil Nil Nil 4 1
5.3 0.5 5.2 Nil 1.5 2.6 4.1 5.5 7.4 4.4
Nil Nil Nil IUFD Nil 1 (Top up) 1 (Exch) 1 (Exch) Nil 1 (Exch) Nil Nil 1 (Top up + I G) MJAFI, Vol. 63, No. 1, 2007
Rh-isoimmunised Pregnancies
transfusions, aids in monitoring the post transfusion period and helps in optimizing delivery timing to near term. Conflicts of Interest None identified References 1. McLean LK, Hedriana HL, Lanouette JM, Hanns C, Haesslein. A retrospective review of isoimmunised pregnancies managed by middle cerebral artery peak systolic velocity. American Journal of Obstetrics and Gynecology 2004; 190: 1732-8. 2. Detti L, Mari G, Akiyama M, Cosmi Erich, Moise Jr K J, Stefor T, Conaway M, Deter R. Longitudinal assessment of the middle cerebral artery peak systolic velocity in healthy foetuses and in foetuses at risk for anaemia. American Journal of Obstetrics and Gynecology 2002; 937-9. 3. Mari G. The collaborative group for diagnosis of foetal anaemia with doppler ultrasonography. Noninvasive diagnosis by doppler ultrasonography of foetal anaemia due to maternal red-cell alloimmunisation. N Engl J Med 2000; 342:9-14. 4. Weiner CP, Heilskov J, Pelzer G, Grant S, Wenstrom K, Williamson RA. Normal values for human umbilical venous and amniotic fluid pressures and their alteration by foetal disease. American Journal of Obstetrics and Gynecology 1989; 161: 714-7. 5. Nicolaides KH, Soothill PW, Rodeck CH, CLewell W. Rh
MJAFI, Vol. 63, No. 1, 2007
11 disease: Intravascular foetal blood transfusion by cordocentesis. Foetal Therapy 1986; 1: 185-92. 6. Rodeck CH, Deans A. Red cell alloimmunisation. In: Rodeck CH, Whittle MJ, editors. Foetal medicine: Basic science and clinical practice.1st ed. London: Churchill Livingstone, 1999; 785-04. 7. Weiner CP, Williamson RA, Wenstrom KD, Sipes SL, Wideness JA, Grant SS, Estle L. Management of foetal hemolytic disease by cordocentesis. American Journal of Obstetrics and Gynecology 1991; 165: 1302-7. 8. Doyle LW, Kelly EA, Richards EJ, Ford GW, Callanan C. Sensorineural outcome at two years for survivors of erythroblastosis treated with foetal intravascular transfusion. Obstet Gynecol 1993; 81: 931-5. 9. Divakaran TG, Waugh J, Clark TJ, Khan KS, Whittle MF, Kilby MD. Noninvasive techniques to detect foetal anaemia because of red blood cell alloimmunisation: A systematic review. Obstet Gynecol 2001; 98: 509-17. 10. Daffos F, Capella-Pavlovsky M, Forestier F. Foetal blood sampling during pregnancy with use of a needle guided by ultrasound: A study of 606 consecutive cases. American Journal of Obstetrics and Gynecology 1985; 153: 655-60. 11. Nicolaides KH, Thilaganathan B, Rodeck CH, Mibashan. Erythroblastosis and reticulocytosis in anemic fetuses. American Journal of Obstetrics and Gynecology 1988; 159: 1063-5.
