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Twin transfusion syndrome: Successful in utero treatment with digoxin
197
ht. J. Gynaecol. Obstet., 1985, 23: 197-201 International Federation of Gynaecology & Obstetrics
TWIN TRANSFUSION SYNDROME: SUCCESSFUL IN UTERO TREATMENT WITH DIGOXIN
JULIAN E. DE LIAa, MAURICE G. EMERYb, SHERYL A. SHEAFORband
THOMAS A. JENNISON’
aDepartment of Obstetrics and Gynecology, Universityof Utah School of Medicine, bCollege of Pharmacy, Universityof Utah and ‘Department of Pathology, Universityof Utah School of Medicine, Salt Luke City, UT 84132 (USA) (Received October IOth, 1984) (Accepted January 19th, 1985)
Abstract DeLia, J. Emery M, Sheafor S, Jennison T (Department of Obstetrics and Gynecology, Department of Pathology, and College of Pharmacy, University of Utah School of Medicine, Salt Lake City, UT). Twin transfusion syndrome: successful in utero treatment with digoxin. Int J Gynaecol Obstet 23: 197-201, 1985 A pregnancy complicated by twin transfusion syndrome is presented. When signs of cardiac failure (edema, ascites and hydramnios) persisted in the recipient twin, maternaldigoxin therapy was instituted at 27 weeks’ gestation. The signs of failure resolved, and the twins were delivered electively by cesarean section at 34 weeks. At birth, the syndrome was confirmed by examination of the infants and placenta. Both infants survived. Digoxin therapy is recommended for fetal heart failure from circulatory overload in twin transfusion.
Keywords: Twins; Twin transfusion syndrome; Nonimmunologic hydrops; Digoxin. Introduction Vascular communications between placentas in monozygotic monochlorionic twins may lead to the twin transfusion syndrome resulting in discrepancies in fetal growth, hematocrit, hydropic changes and visceromegaly when blood is shunted between the in-
fants [2,13,19,21,221. During the past century, little has been added to the understanding or management of this peculiar cause of fetal compromise. Mortality rates as high as 70% generally result from the sequelae of circulatory overload in the recipient or exsanguination of the donor. Although mild cases can progress to term, only early intervention by preterm delivery favorably influences the outcome in severe cases [ 11 I. Because of passive transfer of digoxin across the placenta [ 71, it is possible to treat fetuses suffering from heart failure by administering the drug to the mother [9]. We report the successful treatment of heart failure in a fetus with twin transfusion syndrome by the maternal administration of digoxin. Case report This 29-year-old, gravida 2, para 1 woman had an uncomplicated pregnancy until approx. 22 weeks’ gestation when examination revealed a rapid interval growth of the uterus and a suspicion of two separate heartbeats. Two years previously the mother had delivered a normal infant at term without complications. Ultrasonography confirmed a twin pregnancy and polyhydramnios. The larger. presenting twin (twin A) had a biparietal diameter consistent with 23 weeks’ gestation and demonstrated scalp edema and ascites. Twin B was consistent with 2 1 weeks and lacked gross anomalies. The mother was Rh-positive with a negative indirect Coombs test. and a KleiItrt J Gpaecol Ohstet 23
198
De Lia et al.
hauer-Betke stain of her peripheral blood showed no fetal red cells. The prognosis and the significance of a probable twin transfusion syndrome were discussed with the parents. Four weeks later a repeat scan reported a normal interval growth with persistence of the discordance and progressive signs of cardiac failure in twin A (Fig. 1). On the basis of these findings, a decision was made to give digoxin to the mother in an effort to treat the heart failure in twin A. The experimental nature,of the therapy was explained to the parents, Oral digoxin, 1 mg ( 10 pg/kg) was administered as a loading dose, and the patient was maintained for the rest of the pregnancy on 0.375 mg daily dose.
Two weeks after initiating therapy, repeat sonography showed appropriate growth of the twins and resolution of the edema and ascites in twin A (Fig. 2). Serial scans and digoxin levels were followed until the 34th week of gestation when a diagnostic amniocentesis of the sac of twin A revealed lung maturation (lecithin/sphingomyelin ratio, 2.36; phosphatidylglycerol, positive). An elective cesarean section was chosen as the method of delivery because the uterus was overdistended from the persistent hydramnios, the presenting twin was floating, and both premature infants were in unstable lies. At the time of surgery, amniotic fluid, umbilical cord and maternal venous blood
Fig. 1. Ultrasound scan of twin A at approx. 28 weeks demonstrating scalp edema (A) and ascites (B).
Fig. 2. Ultrasound scan of twin A obtained at approx. 32 weeks demonstrating the resolution of the scalp edema (A) and ascites (B) after digoxin therapy.
Int J Gynaecol Obstet 23
in utero digoxin treatment of twin transfusion
samples were obtained and analyzed for digoxin levels. Injection of the placenta with milk verified a single 2 mm vascular communication (arterio-venous) and common villous district. Histologic examination of the dividing membranes revealed diamniotic monochorionic placentation. Twin A weighed 1690 g and had Apgar scores of 6 and 7 at 1 and 5 min, respectively. His initial hematocrit was 67%; and he had hypertension, mild respiratory distress, cardiomegaly and hepatomegaly attributed to circulatory overload. In addition, a defect in his right thigh was noted with shortening of the leg. This was thought to be due to aseptic necrosis secondary to a hyperviscosity thrombosis early in pregnancy. Since all signs of cardiac overload improved after reduction transfusion, digoxin was discontinued. Twin B weighed 1570 g and had Apgar scores of 1 and 5, thought to be due to transient asphyxia which responded to usual resuscitative efforts. He had an initial hematocrit of 57% and no gross abnormalities. After 6 days both twins were discharged from the intensive care nursery in good condition. Results
Calculations of the loading and maintenance dose of digoxin were made from Jelliffe’s nomogram [ 121 based on our patient’s weight (100 kg) and estimated creatinine clearance in pregnancy of 125 ml/min. The maternal serum concentration increased from 0.6 ng/ml 2 weeks after initiating therapy to 1 ng/ml at delivery. Measurements of creatinine clearance were made at 2 and 4 weeks of therapy and were found to be 172 ml/min and 142 ml/min, respectively. Drug accumulation due to a decline in glomerular filtration rate explains the progressive rise in the steady-state serum concentration. No adjustments in dosage were made because of sonographic evidence of improvement in fetal cardiovascular status. No cardiac toxicity was observed in the mother during treatment. Digoxin determinations were made 6-8 h
Tt+ble 1. Digoxin concentrations
199
at birth. Digoxin r&ml
Maternal serum Twin A cord blood Twin A amniotic fluid Twin B cord blood Twin B amniotic fluid
1 .oo 0.71 1.57 0.63 1.53
after the last dose and were measured by a fluorescent polarization immunoassay (TDX, Abbott Diagnostics). Recently Graves and associates 18,231 reported a digoxin-like immunoequivalent substance in neonates and pregnant women using four radioimmunoassay techniques in the absence of digoxin therapy. Therefore, we studied crossreacting substances in cord blood and neonatal controls. Our assay demonstrated only minimal interference (0.06 ng/ml vs. 0.2 ng/ml) when compared to a standard RIA for digoxin. The levels of digoxin obtained at delivery are summarized in Table I. The patient’s last dose was administered 6 h prior to delivery. Discussion
The twin transfusion syndrome (TTS) invariably occurs as a result of shunting of blood through vascular anastomoses in monochorionic placentas. The time of gestation this occurs, the duration and amount of transfusion is variable. The syndrome may date from fetal angiogenesis [6] or may not occur until delivery when an acute interfetal blood transfer may result in marked hemoglobin differences without stigmata associated with chronic TTS [131. The actual incidence of TTS is unknown. Tan et al. I22], reported TTS in 7% of 482 surviving twin pairs. Benirschke [ 1] reported tde syndrome in 5% of 200 consecutive sets of twins past 20 weeks’ gestation. Rausen et al. [ 19 1, reported 19 cases (15%) with sufficient evidence to warrant the diagnosis in 130 monochorial twin pregnancies where one fetus weighed more than 500 g. Only 13 of the 38 fetuses in this report survived the perinatal Int J Gynaecol Obstet 23
200
De Lia et al.
period. By extrapolating these studies we estimate that the number of twin fetuses that succumb to TTS to be approx. 2200 annually in the United States alone. With the exception of the sequelae of the transfusion, most of the fetuses are normal and therefore represent a tragic loss of life. The pregnancies that offer the best chance for in utero therapeutic intervention are those that develop signs of chronic TTS in the second trimester. Twin transfusion syndrome frequently presents as our case with hydrops and hydramnios in an affected twin at midpregnancy [ 3 I. Poor outcome subsequently results from either intrauterine death or premature labor and delivery when expectant management is utilized [2,3,17,19,24]. Immediate delivery, on the other hand, severely jeopardizes the infants due to immaturity. Medical management of the cardiac compromise with digoxin until maturity is achieved is an attractive therapeutic option, especially if it can be accomplished with minimal risk to both mother and fetus. Digoxin was selected to treat the fetussince it is known to enter the umbilical circulation soon after its appearance in maternal blood [7]. In addition, there have been several reports of fetuses with congestive heart failure from supraventricular arrhythmias successfully treated by maternal administration of the drug [9, lo]. Digoxin in cord blood has been reported to be less than [ 51, equal to [ 201, and greater than [ 101 simultaneously obtained maternal levels. These differences can be explained in part by a time-dependent slow distribution of digoxin to and from the fetal compartment. Fouron [ 71 demonstrated that although digoxin passively diffuses across the placenta, an 8-lo-day lag time is observed before equilibrium is achieved. Our levels at delivery, however, still showed lower fetal concentrations (63%-7 1%) for the twins after 6 weeks of therapy. The exact therapeutic levels necessary to treat cardiac failure from circulatory overload in the fetus are unknown. Recent evidence from neonates suggests that the therapeutic
effect of digoxin is achieved at serum levels similar to adults [20]. Comparing systolic time intervals to plasma concentrations, a positive effect on myocardial contractility is observed at 0.5 ng/ml with maximum effects observed between 1 to 2 ng/ml [4]. Based on the observed response in our case, we assume that the therapeutic levels were achieved in the fetus while the maternal levels were between 0.6 and 1 ng/ml. With the demonstration of the immunoreactive digoxin-like substance in pregnant women with standard digoxin assays, loading and maintenance doses of digoxin may be best determined by calculations derived from the mother’s body weight. creatinine clearance, and evidence of therapeutic effect rather than absolute digoxin levels, until this problem is resolved. Before initiating digoxin therapy, the diagnosis should be confirmed by eliminating other causes of non-immunologic hydrops .fetalis. At least 36 additional causes or associations of non-immunologic hydrops have been identified and TTS accounts for approx. 13% of cases [ IS]. Brennan et al. [3], suggest that the diagnosis of TTS can be established using ultrasonographic criteria which include: ( 1) a significant disparity in size, with like-sex fetuses, (2) two separate umbilical cords with disparity in size or in number of vessels, (3) disparity in the size of the amniotic sacs, (4) a single placenta with disparity of echogenicity of cotyledons supplying the two cords. and (5) evidence of hydrops or congestive cardiac failure in either fetus. There are recent reports of sonographicallydocumented ascites, scalp edema and hydramnios in which the abnormality resolved spontaneously. Mueller-Heubach and Mazer [ 161 observed two cases of transient fetal ascites in singleton pregnancies at 24 and 27 weeks which disappeared at 30 and 34 weeks. respectively. Normal fetuses were subsequently delivered with no apparent explanation for the ascites. Platt et al. [ 191. reported a case demonstrating ascites. scalp edema and hydramnios in a singleton at 26 weeks with subsequent resolution of all abnormalities by term.
In utero digoxin treatment of twin transfusion 201
No explanation was determined by an extensive workup. Lubinsky and Rapoport [ 141 reported the spontaneous resolution of ascites, scalp edema and hydramnios in a monochorionic twin. In their case it was the suspected donor that demonstrated the transient fetal hydrops at 22 weeks which cleared by 32 weeks’ gestation. The possibility exists, therefore, that the hydrops noted in our case could have resolved coincidentally at the time the digoxin was begun. We believe this is unlikely based on the findings at birth and the predominance of reports of similar midtrimester findings which resulted in poor outcomes in the absence of treatment. Therefore, we recommend the use of cardiac glycosides in suspected TTS when one fetus has signs of cardiac failure. References
6 7 8
9
10
Benirschke K: Twin placenta in perinatal mortality. NY State J Med 61: 1499, 1964. Benirschke K. Chung KK: Multiple pregnancy (first of two parts). N Engl J Med 288: 1276, 1973. Brennan JN, Diwan RV, Rosen MG et al.: Fetofetal transfusion syndrome: prenatal ultrasonographic diagnosis. Radiology 143: 535,1982. Buch J, Waldoff S: Classical concentration response relationship between serum digoxin level and contractility indices. Dan Med Bull 27; 287, 1980. Chan V, Tse TF, Wong V: Transfer of digoxin across the placenta and into breast milk. Br J Obstet Gynaecol 85: 605,1978. Corney G, Ahern W: The placental transfusion syndrome in monozygous twins. Arch Dis Child 40: 264, 1965. Fouron JC: Dynamics of the placental transfer of digoxin in the dog. Biol Neonate 2.3: 116, 1973. Graves SW, Valdes R, Brown BA et al.: Endogenous digoxin-immunoreactive substance in human pregnancies, J Clin Endocrinol Metab 58: 748, 1984. Harrigan JT, Kangos JJ. Sikka A et al.: Successful treatment of fetal congestive heart failure secondary to tachycardia. N Engl J Med 304: 1527,198l. Heaton FC, Vaughan R: Intrauterine supraventricular tachycardia: Cardioversion with maternal digoxin. Obstet Gynecol60: 749, 1982.
11 Hutchison AA, Drew JH, Yu VY et al.: Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol.59: 347,1982. 12 Jelliffe RW, Brooker G: A nomogram for disoxin therapy Am J Med 57: 63,1974. 13 Klebe JG, Ingomar CJ: The fetoplacental circulation during parturition illustrated by the interfetal transfusion syndrome. Pediatrics 49: 112,1972. 14 Lubinsky M, Rapoport P: Transient fetal hydrops and “prune belly” in one identical female twin. N Engl J Med308: 256,1983. 15 Machin GA: Differential diagnosis of hydrops fetalis. Am J Med Genet 9: 341,198l. 16 Meuller-Heuback E,Mazer J: Sonographically documented disappearance of fetal ascites. Obstet Gynecol 61: 253, 1983. 17 Moore CM, McAdams AJ, Sutherland J: Intrauterine disseminated intravascular coagulation: a syndrome of multiple pregnancy with a dead twin fetus. J Pediatr 14: 523, 1969. 18 Pinsky WW, Jacobsen JR, Gillette PC et al.: Dosage of digoxin in premature infants. J Pediatr 96: 639, 1979. 19 Platt LD, Collea JV, Joseph DM: Transitory fetal ascites: an ultrasound diagnosis. Am J Obstet Gynecol132: 906, 1978. 20 Rogers MC, Willerson JT,Goldblatt A et al.: Serum digoxin concentration in the human fetus, neonate and Infant. N Engl J Med 287: 1010,1972. 21 Sekiya S,Hafez ES: Physiomorphology of twin transfusion syndrome: a study of 86 twin gestations. Obstet Gynecol 50: 288,1977. 22 Tan KL, Tan R, Tan SH et al.: The twin transfusion syndrome: clinical observations on 35 affected pairs. Clin Pediatr 18: 111,1979. 23 Valdes R, Graves SW, Brown BA et al.: Endogenous substance in newborn infants causing false positive digoxin measurements. J Pediatr 102: 947, 1983. 24 Wittman BK, Baldwin VJ, Nichol B: Antenatal diagnosis of twin transfusion syndrome by ultrasound. Obstet Gynecol58: 123, 1981.
Address for reprints: Julian E. De Lia, M.D. Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City, UT 84132 USA
ht. J. Gynaecol. Obstet., 1985, 23: 197-201 International Federation of Gynaecology & Obstetrics
TWIN TRANSFUSION SYNDROME: SUCCESSFUL IN UTERO TREATMENT WITH DIGOXIN
JULIAN E. DE LIAa, MAURICE G. EMERYb, SHERYL A. SHEAFORband
THOMAS A. JENNISON’
aDepartment of Obstetrics and Gynecology, Universityof Utah School of Medicine, bCollege of Pharmacy, Universityof Utah and ‘Department of Pathology, Universityof Utah School of Medicine, Salt Luke City, UT 84132 (USA) (Received October IOth, 1984) (Accepted January 19th, 1985)
Abstract DeLia, J. Emery M, Sheafor S, Jennison T (Department of Obstetrics and Gynecology, Department of Pathology, and College of Pharmacy, University of Utah School of Medicine, Salt Lake City, UT). Twin transfusion syndrome: successful in utero treatment with digoxin. Int J Gynaecol Obstet 23: 197-201, 1985 A pregnancy complicated by twin transfusion syndrome is presented. When signs of cardiac failure (edema, ascites and hydramnios) persisted in the recipient twin, maternaldigoxin therapy was instituted at 27 weeks’ gestation. The signs of failure resolved, and the twins were delivered electively by cesarean section at 34 weeks. At birth, the syndrome was confirmed by examination of the infants and placenta. Both infants survived. Digoxin therapy is recommended for fetal heart failure from circulatory overload in twin transfusion.
Keywords: Twins; Twin transfusion syndrome; Nonimmunologic hydrops; Digoxin. Introduction Vascular communications between placentas in monozygotic monochlorionic twins may lead to the twin transfusion syndrome resulting in discrepancies in fetal growth, hematocrit, hydropic changes and visceromegaly when blood is shunted between the in-
fants [2,13,19,21,221. During the past century, little has been added to the understanding or management of this peculiar cause of fetal compromise. Mortality rates as high as 70% generally result from the sequelae of circulatory overload in the recipient or exsanguination of the donor. Although mild cases can progress to term, only early intervention by preterm delivery favorably influences the outcome in severe cases [ 11 I. Because of passive transfer of digoxin across the placenta [ 71, it is possible to treat fetuses suffering from heart failure by administering the drug to the mother [9]. We report the successful treatment of heart failure in a fetus with twin transfusion syndrome by the maternal administration of digoxin. Case report This 29-year-old, gravida 2, para 1 woman had an uncomplicated pregnancy until approx. 22 weeks’ gestation when examination revealed a rapid interval growth of the uterus and a suspicion of two separate heartbeats. Two years previously the mother had delivered a normal infant at term without complications. Ultrasonography confirmed a twin pregnancy and polyhydramnios. The larger. presenting twin (twin A) had a biparietal diameter consistent with 23 weeks’ gestation and demonstrated scalp edema and ascites. Twin B was consistent with 2 1 weeks and lacked gross anomalies. The mother was Rh-positive with a negative indirect Coombs test. and a KleiItrt J Gpaecol Ohstet 23
198
De Lia et al.
hauer-Betke stain of her peripheral blood showed no fetal red cells. The prognosis and the significance of a probable twin transfusion syndrome were discussed with the parents. Four weeks later a repeat scan reported a normal interval growth with persistence of the discordance and progressive signs of cardiac failure in twin A (Fig. 1). On the basis of these findings, a decision was made to give digoxin to the mother in an effort to treat the heart failure in twin A. The experimental nature,of the therapy was explained to the parents, Oral digoxin, 1 mg ( 10 pg/kg) was administered as a loading dose, and the patient was maintained for the rest of the pregnancy on 0.375 mg daily dose.
Two weeks after initiating therapy, repeat sonography showed appropriate growth of the twins and resolution of the edema and ascites in twin A (Fig. 2). Serial scans and digoxin levels were followed until the 34th week of gestation when a diagnostic amniocentesis of the sac of twin A revealed lung maturation (lecithin/sphingomyelin ratio, 2.36; phosphatidylglycerol, positive). An elective cesarean section was chosen as the method of delivery because the uterus was overdistended from the persistent hydramnios, the presenting twin was floating, and both premature infants were in unstable lies. At the time of surgery, amniotic fluid, umbilical cord and maternal venous blood
Fig. 1. Ultrasound scan of twin A at approx. 28 weeks demonstrating scalp edema (A) and ascites (B).
Fig. 2. Ultrasound scan of twin A obtained at approx. 32 weeks demonstrating the resolution of the scalp edema (A) and ascites (B) after digoxin therapy.
Int J Gynaecol Obstet 23
in utero digoxin treatment of twin transfusion
samples were obtained and analyzed for digoxin levels. Injection of the placenta with milk verified a single 2 mm vascular communication (arterio-venous) and common villous district. Histologic examination of the dividing membranes revealed diamniotic monochorionic placentation. Twin A weighed 1690 g and had Apgar scores of 6 and 7 at 1 and 5 min, respectively. His initial hematocrit was 67%; and he had hypertension, mild respiratory distress, cardiomegaly and hepatomegaly attributed to circulatory overload. In addition, a defect in his right thigh was noted with shortening of the leg. This was thought to be due to aseptic necrosis secondary to a hyperviscosity thrombosis early in pregnancy. Since all signs of cardiac overload improved after reduction transfusion, digoxin was discontinued. Twin B weighed 1570 g and had Apgar scores of 1 and 5, thought to be due to transient asphyxia which responded to usual resuscitative efforts. He had an initial hematocrit of 57% and no gross abnormalities. After 6 days both twins were discharged from the intensive care nursery in good condition. Results
Calculations of the loading and maintenance dose of digoxin were made from Jelliffe’s nomogram [ 121 based on our patient’s weight (100 kg) and estimated creatinine clearance in pregnancy of 125 ml/min. The maternal serum concentration increased from 0.6 ng/ml 2 weeks after initiating therapy to 1 ng/ml at delivery. Measurements of creatinine clearance were made at 2 and 4 weeks of therapy and were found to be 172 ml/min and 142 ml/min, respectively. Drug accumulation due to a decline in glomerular filtration rate explains the progressive rise in the steady-state serum concentration. No adjustments in dosage were made because of sonographic evidence of improvement in fetal cardiovascular status. No cardiac toxicity was observed in the mother during treatment. Digoxin determinations were made 6-8 h
Tt+ble 1. Digoxin concentrations
199
at birth. Digoxin r&ml
Maternal serum Twin A cord blood Twin A amniotic fluid Twin B cord blood Twin B amniotic fluid
1 .oo 0.71 1.57 0.63 1.53
after the last dose and were measured by a fluorescent polarization immunoassay (TDX, Abbott Diagnostics). Recently Graves and associates 18,231 reported a digoxin-like immunoequivalent substance in neonates and pregnant women using four radioimmunoassay techniques in the absence of digoxin therapy. Therefore, we studied crossreacting substances in cord blood and neonatal controls. Our assay demonstrated only minimal interference (0.06 ng/ml vs. 0.2 ng/ml) when compared to a standard RIA for digoxin. The levels of digoxin obtained at delivery are summarized in Table I. The patient’s last dose was administered 6 h prior to delivery. Discussion
The twin transfusion syndrome (TTS) invariably occurs as a result of shunting of blood through vascular anastomoses in monochorionic placentas. The time of gestation this occurs, the duration and amount of transfusion is variable. The syndrome may date from fetal angiogenesis [6] or may not occur until delivery when an acute interfetal blood transfer may result in marked hemoglobin differences without stigmata associated with chronic TTS [131. The actual incidence of TTS is unknown. Tan et al. I22], reported TTS in 7% of 482 surviving twin pairs. Benirschke [ 1] reported tde syndrome in 5% of 200 consecutive sets of twins past 20 weeks’ gestation. Rausen et al. [ 19 1, reported 19 cases (15%) with sufficient evidence to warrant the diagnosis in 130 monochorial twin pregnancies where one fetus weighed more than 500 g. Only 13 of the 38 fetuses in this report survived the perinatal Int J Gynaecol Obstet 23
200
De Lia et al.
period. By extrapolating these studies we estimate that the number of twin fetuses that succumb to TTS to be approx. 2200 annually in the United States alone. With the exception of the sequelae of the transfusion, most of the fetuses are normal and therefore represent a tragic loss of life. The pregnancies that offer the best chance for in utero therapeutic intervention are those that develop signs of chronic TTS in the second trimester. Twin transfusion syndrome frequently presents as our case with hydrops and hydramnios in an affected twin at midpregnancy [ 3 I. Poor outcome subsequently results from either intrauterine death or premature labor and delivery when expectant management is utilized [2,3,17,19,24]. Immediate delivery, on the other hand, severely jeopardizes the infants due to immaturity. Medical management of the cardiac compromise with digoxin until maturity is achieved is an attractive therapeutic option, especially if it can be accomplished with minimal risk to both mother and fetus. Digoxin was selected to treat the fetussince it is known to enter the umbilical circulation soon after its appearance in maternal blood [7]. In addition, there have been several reports of fetuses with congestive heart failure from supraventricular arrhythmias successfully treated by maternal administration of the drug [9, lo]. Digoxin in cord blood has been reported to be less than [ 51, equal to [ 201, and greater than [ 101 simultaneously obtained maternal levels. These differences can be explained in part by a time-dependent slow distribution of digoxin to and from the fetal compartment. Fouron [ 71 demonstrated that although digoxin passively diffuses across the placenta, an 8-lo-day lag time is observed before equilibrium is achieved. Our levels at delivery, however, still showed lower fetal concentrations (63%-7 1%) for the twins after 6 weeks of therapy. The exact therapeutic levels necessary to treat cardiac failure from circulatory overload in the fetus are unknown. Recent evidence from neonates suggests that the therapeutic
effect of digoxin is achieved at serum levels similar to adults [20]. Comparing systolic time intervals to plasma concentrations, a positive effect on myocardial contractility is observed at 0.5 ng/ml with maximum effects observed between 1 to 2 ng/ml [4]. Based on the observed response in our case, we assume that the therapeutic levels were achieved in the fetus while the maternal levels were between 0.6 and 1 ng/ml. With the demonstration of the immunoreactive digoxin-like substance in pregnant women with standard digoxin assays, loading and maintenance doses of digoxin may be best determined by calculations derived from the mother’s body weight. creatinine clearance, and evidence of therapeutic effect rather than absolute digoxin levels, until this problem is resolved. Before initiating digoxin therapy, the diagnosis should be confirmed by eliminating other causes of non-immunologic hydrops .fetalis. At least 36 additional causes or associations of non-immunologic hydrops have been identified and TTS accounts for approx. 13% of cases [ IS]. Brennan et al. [3], suggest that the diagnosis of TTS can be established using ultrasonographic criteria which include: ( 1) a significant disparity in size, with like-sex fetuses, (2) two separate umbilical cords with disparity in size or in number of vessels, (3) disparity in the size of the amniotic sacs, (4) a single placenta with disparity of echogenicity of cotyledons supplying the two cords. and (5) evidence of hydrops or congestive cardiac failure in either fetus. There are recent reports of sonographicallydocumented ascites, scalp edema and hydramnios in which the abnormality resolved spontaneously. Mueller-Heubach and Mazer [ 161 observed two cases of transient fetal ascites in singleton pregnancies at 24 and 27 weeks which disappeared at 30 and 34 weeks. respectively. Normal fetuses were subsequently delivered with no apparent explanation for the ascites. Platt et al. [ 191. reported a case demonstrating ascites. scalp edema and hydramnios in a singleton at 26 weeks with subsequent resolution of all abnormalities by term.
In utero digoxin treatment of twin transfusion 201
No explanation was determined by an extensive workup. Lubinsky and Rapoport [ 141 reported the spontaneous resolution of ascites, scalp edema and hydramnios in a monochorionic twin. In their case it was the suspected donor that demonstrated the transient fetal hydrops at 22 weeks which cleared by 32 weeks’ gestation. The possibility exists, therefore, that the hydrops noted in our case could have resolved coincidentally at the time the digoxin was begun. We believe this is unlikely based on the findings at birth and the predominance of reports of similar midtrimester findings which resulted in poor outcomes in the absence of treatment. Therefore, we recommend the use of cardiac glycosides in suspected TTS when one fetus has signs of cardiac failure. References
6 7 8
9
10
Benirschke K: Twin placenta in perinatal mortality. NY State J Med 61: 1499, 1964. Benirschke K. Chung KK: Multiple pregnancy (first of two parts). N Engl J Med 288: 1276, 1973. Brennan JN, Diwan RV, Rosen MG et al.: Fetofetal transfusion syndrome: prenatal ultrasonographic diagnosis. Radiology 143: 535,1982. Buch J, Waldoff S: Classical concentration response relationship between serum digoxin level and contractility indices. Dan Med Bull 27; 287, 1980. Chan V, Tse TF, Wong V: Transfer of digoxin across the placenta and into breast milk. Br J Obstet Gynaecol 85: 605,1978. Corney G, Ahern W: The placental transfusion syndrome in monozygous twins. Arch Dis Child 40: 264, 1965. Fouron JC: Dynamics of the placental transfer of digoxin in the dog. Biol Neonate 2.3: 116, 1973. Graves SW, Valdes R, Brown BA et al.: Endogenous digoxin-immunoreactive substance in human pregnancies, J Clin Endocrinol Metab 58: 748, 1984. Harrigan JT, Kangos JJ. Sikka A et al.: Successful treatment of fetal congestive heart failure secondary to tachycardia. N Engl J Med 304: 1527,198l. Heaton FC, Vaughan R: Intrauterine supraventricular tachycardia: Cardioversion with maternal digoxin. Obstet Gynecol60: 749, 1982.
11 Hutchison AA, Drew JH, Yu VY et al.: Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol.59: 347,1982. 12 Jelliffe RW, Brooker G: A nomogram for disoxin therapy Am J Med 57: 63,1974. 13 Klebe JG, Ingomar CJ: The fetoplacental circulation during parturition illustrated by the interfetal transfusion syndrome. Pediatrics 49: 112,1972. 14 Lubinsky M, Rapoport P: Transient fetal hydrops and “prune belly” in one identical female twin. N Engl J Med308: 256,1983. 15 Machin GA: Differential diagnosis of hydrops fetalis. Am J Med Genet 9: 341,198l. 16 Meuller-Heuback E,Mazer J: Sonographically documented disappearance of fetal ascites. Obstet Gynecol 61: 253, 1983. 17 Moore CM, McAdams AJ, Sutherland J: Intrauterine disseminated intravascular coagulation: a syndrome of multiple pregnancy with a dead twin fetus. J Pediatr 14: 523, 1969. 18 Pinsky WW, Jacobsen JR, Gillette PC et al.: Dosage of digoxin in premature infants. J Pediatr 96: 639, 1979. 19 Platt LD, Collea JV, Joseph DM: Transitory fetal ascites: an ultrasound diagnosis. Am J Obstet Gynecol132: 906, 1978. 20 Rogers MC, Willerson JT,Goldblatt A et al.: Serum digoxin concentration in the human fetus, neonate and Infant. N Engl J Med 287: 1010,1972. 21 Sekiya S,Hafez ES: Physiomorphology of twin transfusion syndrome: a study of 86 twin gestations. Obstet Gynecol 50: 288,1977. 22 Tan KL, Tan R, Tan SH et al.: The twin transfusion syndrome: clinical observations on 35 affected pairs. Clin Pediatr 18: 111,1979. 23 Valdes R, Graves SW, Brown BA et al.: Endogenous substance in newborn infants causing false positive digoxin measurements. J Pediatr 102: 947, 1983. 24 Wittman BK, Baldwin VJ, Nichol B: Antenatal diagnosis of twin transfusion syndrome by ultrasound. Obstet Gynecol58: 123, 1981.
Address for reprints: Julian E. De Lia, M.D. Department of Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City, UT 84132 USA