Journal of Clinical Apheresis 6:230-233 (1991)
Management of Sickle Cell Anemia and Pregnancy Mabel Koshy, Darren Chisum, Laurence Burd, Armando Orlina, and Helen How Department of Medicine, University of Illinois (M.K., D.C.) and Michael Reese Hospital 8, Medical Center (Humana) (L.B., A.O.), Chicago; University of Tennessee (H.H.) There has been significant decrease in maternal morbidity and mortality of sickle cell disease patients during pregnancy due to better understanding of the pathophysiology of the disease and physiologic changes during pregnancy. Prophylactic blood transfusion does not appear to reduce complications in patients with sickle cell anemia. Patients with sickle hemoglobin C disease and with Sp thalassemia' have fewer complications but still need close monitoring. Blood transfusion therapy should be made available for medical and obstetrical complications to include increasing hypoxemia, progressive anemia, acut chest syndrome, twin pregnancy, splenic sequestration syndrome, preeclampsia, septicemia, or prior to general anesthesia and surgery. Blood transfusion therapy is associated with hepatitis, allergic reaction, alloimmunization, AIDS, and iron overload states. These aspects should be considered prior to using blood transfusion therapy. Excellent prenatal monitoring and aggressive intervention should be instituted when problems arise for the successful management of the pregnant patient with sickle cell disease. Prenatal diagnosis and cord blood screening should be made available for the infant. Appropriate pediatric referral and prophylactic penicillin is recommended for the infant with sickle cell disease.
Key words: maternal morbidity, prophylactic blood transfusion, pathophysiology
Studies conducted in the United States before 1970 indicated that maternal morbidity and mortality of patients with sickle cell anemia during pregnancy ranged from 3 to 48%. More recently there has been a marked reduction in the morbidity and mortality rates brought about probably through better undertanding of the pathophysiology of the disease and the physiologic changes that occur during pregnancy [ 1-51, In spite of the growing trend throughout the country to administer prophylactic transfusion for sickle cell disease (SCD) patients during pregnancy, it is not clear whether improvements reported were due to blood transfusion therapy or to satisfactory medical, obstetric, and neonatal care. The National Institutes of Health funded a randomized, prospective study on the use of prophylactic transfusion in SCD during pregnancy which evaluated the effects of transfusion in a comprehensive manner [6]. Two-hundred fifty-eight pregnant SCD patients entered the study. There were 69 abortions and the remaining 189 patients completed their pregnancy during the study period. Of the 100 patients with sickle cell anemia, 72 patients were randomized for either prophylactic transfusion or to serve as control. Twenty-eight patients did not qualify for randomization. Thirty-six patients received prophylactic transfusion, beginning at the early weeks of pregnancy and the remaining 36 received transfusion
0 1991 Wiley-Liss, Inc.
only for medical and/or obstetric complications. Sixtysix sickle hemoglobin C disease (SC) and 23 sickle beta thalassemia"" (Sp Thal) patients were given only emergency transfusion therapy. The prophylactic transfusion group maintained their hemoglobin concentration between 10 and l l g/dL and hemoglobin S below 35%. This was accomplished by either simple transfusion or partial exchange blood transfusion. In the control group, 44% received transfusion therapy for medical indications, similarly 48% of the non-randomized sickle cell anemia (SS) patients, 27% of the SC and 52% of the Sp Thal required blood transfusion therapy for emergencies. Premature delivery occurred in almost 40% of patients who received transfusion, and toxemia was noted in approximately 18% of patients. Four-hundred thirty-two units were used by the prophylactically transfused group, while the control group only received 108 units. Delayed transfusion reactions and alloimmunization occurred with the same frequency in patients who received blood transfusion therapy. Amongst the medical complications only pain crisis was significantly lower in the prophylactically transfused groups. Address reprint requests to Dr. M. Koshy, Department of Medicine. University of Illinois, 840 S. Wood Street (MIC 787), Chicago, 1L 60612.
Sickle Cell Disease and Pregnancy
In the randomized study, the only difference found between patients who received prophylactic blood transfusion and those who received blood transfusion only for medicaUobstetric indications was low incidence of pain crisis. The routine use for blood transfusion therapy for painful crisis does not appear to be justified given the known potential and possible life threatening complications of blood transfusion. At the termination of the cooperative study in 1986, the use of prophylactic blood transfusion therapy was discontinued as part of the treatment modality at our medical center, and patients with SCD continued to be monitored closely and received blood transfusion for medical and obstetrical indications. Between 1986 and 1990 there were 54 pregnancies among patients with SCD (Table I). Data on abortions during this period were not collected. Since the complications with twin pregnancies were significant, these were analyzed separately. There were 35 SS, 9 SC, 6 Sp Thal, and 4 SS with twin pregnancies. The average age of the mother was 24 years. There were no teenage pregnant mothers who had twin pregnancies. The lowest average gestational age and birthweight were among twin pregnancies. There was a high frequency of cesarean section among the SCD patients, due to our policy of a short trial of labor and early assisted delivery at the first signs of fetal distress [6-81. Twenty-six SS, 3 SC, 3 Sp Thal, and the 4 SS with twin pregnancy required blood transfusion therapy. The majority of indications was for preoperative preparation for a cesarean section (CS), and the remaining tranfusions were for the accepted medical indications of acute chest syndrome,
Table I. Sickle Cell Disease and Pregnancy, 1986-1990 Study: PRN Transfusion Theram*
Total No. of pregnancies Avg. age (years) Teenage pregnancies Avg. gestation (wk) Premature gestation Avg. birthweight (9) Cesarean scction Paticnts transfused Total No. of units Avg. No. of unitsipt. Maternal deaths lnfant deaths Maternal morbidity Pain crisis Acute chest syndrome Urinary tract infection Pre-eclampsia
ss
SC
35 24 3 31 I1 2,598 17 26 I12 4 0 0
9 23 3 39 2 3,089 3 3 12 4 I 0
6 23 1 38 2 2,680 3 4 16 4 0 0
4 26 0 29 4 1,051 3 4 26 6 0 3
18 5 6 5
5 0 2 2
3 3
2 I 1 2
Sp
Thai+"
SS"
1
1
*The figures represent Nos. and not percentages where applicable 'Twin pregnancy.
231
pre-eclampsia, and severe anemia. An average of 4 units of red blood cells (RBC) was transfused per patient. One SS patient received 20 units for severe pre-eclampsia, seizure disorder, and other persistent acute medical complications in spite of transfusion therapy. The 4 SS patients with twin pregnancies received prophylactic transfusion therapy when they reported to the Prenatal Clinic (12-24 weeks). One mother with twin pregnancy reported to the Prenatal Clinic at 24 weeks and was admitted with premature rupture of the membranes and lost both infants in spite of blood transfusion. One would speculate whether the outcome would have been different if earlier prenatal visits had been sought by the mother. The other single infant deaths occurred in the 2 remaining twin pregnancies at 28 and 29 weeks of gestation, respectively. There were no infant deaths in the SC, Sp Thal, and SS patients with single pregnancies. There was 1 maternal death in a patient with SC hemoglobinopathy who had only 1 prenatal visit at 20 weeks and was lost to follow-up. She was later transferred to the medical center at 36 weeks gestation, when she was agitated and obtunded, refused blood transfusion therapy, and sustained a cerebrovascular accident (CVA). She then received 2 units of RBC by partial exchange and underwent CS to save the fetus after brain death was established according to accepted criteria. Postmortem examination of the mother demonstrated bilateral brain infarcts; sagittal thrombosis; hemolytic anemia, elevated liver enzymes, and low platelets (HELLP Syndrome); and consumption coagulopathy. The infant had a good apgar score. We compared the obstetric maternal morbidity and mortality between the 2 studies of sickle cell anemia patients ( I 978-86 and 1986-90) against the normal African-American women without medical complications or hemoglobinopathy who delivered at our institution and the results are shown in Table 11. There was no maternal mortality recorded. Premature births occurred with increased frequency and prophylactic transfusion did not alter outcome. Similarly perinatal morbidity and mortality were increased among SS patients irrespective of types of transfusion therapy when compared to normal AA controls (Table 111). Among sickle cell anemia related complications, pain crisis appears to be present with increased frequency (Table IV). Some of these painful events were mild and would have been managed by outpatient and oral analgesic treatment, but were admitted because of the concurrent pregnancy. During the 1986-1990 study period the acute chest syndrome included a11 cases of pneumonia, congestive heart failure, and any patient with pulmonary infiltrate and fever that persisted over 102°F for more than 3 hours. Severe anemia was diagnosed when the admitting
232
Koshy et al. TABLE 11. Comparison of Maternal Morbidity and Mortality (SS Patients) Between the Randomized Study Normal AA and Post Randomization Study* 1978-1986 Cooperative Study Trdnsfusion Control Normal" -~
1986-1990 SSIPRN ..
-
~
-~
-
~~~
Number of patients Materndl mortality Gestational age dt birth (wk) Multiple births (%) Preterm labor (%) Placenta previa (%) Abruptio placenta (%) Toxemia of pregnancy Cesarean section (%)
~~
36 0 36 8 39 3 6 17 22
8,981 0 40 2 17 04 05 4 14
36 0 38 3 17 0 3 22 28
39 0 37 12 38 NA NA 17 50
*SS/PRN After discontinuation of cooperative study, SS patients on prn transfusion NA available "African-American patients without hemoglobinopathy, anemia, diabetes, chronic hypertension
=
not
TABLE 111. Comparison of Perinatal Morbidity and Mortality Between the Randomized Study, 1978-1986 (SS), Normal (AA) and PRN Transfusion Study, 1986-1990 (SS) ("/.)
1978-1986 (SS) ~
~~~
~~~
Stillbirth Neonatal death Perinatal mortality Birthweight (g) Intrauterine growth retardation
Normal
Transfusion -.
Control
1980-1986
10 0 10 2,495 14
5 0 5 2,652 18
2 1 3 3,006 9
SSIPRN 1986- 1990
~
-~
5 5 10 2,531 17
"African-American patients without hemoglobinopathy, anemia, diabetes, or chronic hypertension.
TABLE IV. Comparison of Sickle Cell Anemia Related Complications in the Cooperative Study, 1978-1986, and the PRN Transfusion Study, 1986-1990 1978-1986 study
Pain crisis Seizure disorder Headaches Splenic sequestration Acute chest syndrome Congestive heart failure Severe anemia Pyelonephritis Urinary tract infection Nephrotic syndrome Chronic renal failure Cholecystitis
Transfusion
Control
1986- 1990 SSiPRN
14 3 3 0 6 3 3 3 6 3 0 0
50 3 3 3 8 3 8 3 17 3 3 6
51 2 3 0 15" NA* 5 2 17 0 0 0
* NA = not analyzed separately-included in acute chest syndrome. 'Combined total of pneumonia, congestive heart failure and pulmonary infiltrate with fever.
hemoglobin dropped by 30% from the stable nonpregnant state. Symptomatic urinary tract infection was treated with antibiotics as an outpatient. Two patients had pyelonephritis and required hospitalization. When the outcome of the current study (1986- 1990) was compared to that of the randomized study (19781986), that of Powars, and of a larger co-operative study of Smith (1979- 1988) et al. (personal communication), there was no difference in the mean birthweight, gestational age, or percentage of premature delivery [5,17]. DISCUSSION
SCD patients contemplating pregnancy should be informed of the availability of prenatal diagnosis [9] and about the serious complications which occur to them as well as to the children, both before and after birth. They should be made aware of the fact that there is a great variability in clinical severity of the disease which could be influenced by genetic factors [lo-121. Some investigators find that the severity and symptoms of sickle cell anemia vary greatly among different individuals. Some spend a lifetime with debilitating complications necessi-
Sickle Cell Disease and Pregnancy
tating frequent hospitalization while others appear to have no complications at all. Modifying factors include concentration of fetal hemoglobin. An elevated fetal hemoglobin concentration interferes with the tendency for polymerization and thus ameliorates the clinical symptoms. Other factors are the various beta gene haplotypes. These include the central African Republic or Carr haplotype with severe clinical disease, the Benin haplotype with intermediate severity, the Atlantic West Africans, Senegal haplotype with mild disease, and sickle cell anemia that has been described among Saudi Arabians, Iranians, and Indians with very mild manifestations [ 10,13,14]. Similarly the presence of alpha thalassemia, found in approximately 30% of SCD patients, alters the expression of the disease. Beta thalassemia also alters the manifestations of SCD. Patients with Sp Thal’ have a milder clinical course and fewer complications as compared to the Sp Thal” patients who may have similar complications as those with sickle cell anemia. Finally, the presence of other hemoglobins also alters the clinical presentation, the most common association being with hemoglobin C, and patients with both types of hemoglobin have a usually milder clinical course. Perinatal mortality and morbidity in present patients with sickle cell anemia are increased when compared with a group of 8,98 1 normal African-American patients who delivered at Michael Reese Hospital and Medical Center during the cooperative study period, and who had no evidence of anemia, hypertension, or diabetes. Pre-term delivery, abruptio placenta, placenta previa, and toxemia are high in patients with sickle cell anemia. We were unable to detect any improvement in the survival of the mother or fetus that was due to prophylactic blood transfusion. Nonetheless, pregnant patients with sickle cell anemia and their infants are at considerable risk as evidenced by the increased recurrence of pregnancy complications, and fetal and neonatal outcome. They require meticulous prenatal care, early detection, and aggressive management of medical and obstetrical complications. This should be approached by an obstetrics/hematology team. Twin pregnancies appear to be associated with major complications; patients should be encouraged to seek prenatal care in the first trimester, and prophylactic blood transfusion therapy should be instituted. Patients with SC and Sp thalassemia need to be observed closely, and transfusion therapy should be recommended for clinical indications. Prophylactic transfusion should be discouraged. Blood transfusion therapy is associated with increased incidence of hepatitis, iron overload, alloimmunization, allergic reaction, and acquired immunodeficiency. Nonetheless these issues should be addressed prior to establishing criteria for prophylactic transfusion as therapy for pregnant patients
233
with SCD. Until effective anti-sickling agents become available, supportive management and excellent prenatal care will continue to play an important role in the management of pregnancy in patients with sickle cell disease 115,161. ACKNOWLEDGMENTS
Thanks are due to Pamela Moore for all secretarial assistance. REFERENCES 1. In Charache S , Lubin B, Reid CD (eds): Cooperative Study of
2.
3.
4. 5. 6.
7. 8.
9. 10. I I.
12.
13.
14.
15.
16.
17.
the Clinical Course of Sickle Cell Discase: Management and Therapy of Sickle Cell Disease: NIH Publication No. 89-21 17. Bethesda, Maryland, U.S. Department of Health and Human Services, Public Health Service, Revised Septcmber 1989. Davies SC, Brozovic M: Sickle cell anemia: the prcsentation, management and prophylaxis of sickle cell disease. Blood Rev 3:29, 1989. Koshy M: Update in sickle cell disease. In Rake1 RE (ed): “Conn’s Current Therapy” Philadclphia: W.B. Saunders Co., Harcourt Brace Jovanovich, Inc., 1991, pp 318-322. Koshy M, Ashenhurst J: Management of pregnancy in sickle cell anemia. Tex Rep Biol Mcd 40:273, 1980-1981. Powars DR, Sandhu M, Niland-Weiss J , et al.: Pregnancy in sickle cell disease. Obstet Gynecol 67:217, 1986. Koshy M, Burd L, Wallace D, et al.: Prophylactic red ccll transfusion in pregnant patients with sickle cell disease. N Engl J Med 319:1447, 1988. Koshy M, Burd L: Management of pregnancy in sickle cell syndromes. Hematol Oncol Clin North Am 5(3):585-596, 1991. Finer P, Blair J, Rowe P: Epidural analgesia in the management of labor pain and sickle cell crisis-a case report. Anesthesiology 68:799, 1988. Chang JC, Kan YW: A sensitive new prenatal test for sicklc cell anemia. N EngI J Med 307:30, 1982. Hdrkncss D: Sickle cell trait revisited. Am J Med 87:330N, 1984. Nagel RL, Fabry ME, Pagnier J , et al.: Haematologically and genetically distinct forms of sickle cell anemia in Africa: the sencgal type and the benin type. N Engl J Med 312:880, 1985. Ojwang PJ, Ogada T. Beris P, et al.: Haplotypc and giobin gene analyses in sickle cell anemia patients from Kenya. Br J Haematol 65:211, 1987. Miller BA, Salameh M. Ahmed M, et al.: High fetal hemoglobin production in sickle ccll anemia in thc eastern province of Saudi Arabia is genetically determined. Blood 67: 1404, 1986. Powars DR, Weiss JN. Chan LS, et al.: Is therc a thrcshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 63:912, 1984. Anyaegbunam A, Langer 0, Brustman L, et al.: The application of uterine and umbilical artery velocimetry to the antenatal supervision of pregnancies complicated by maternal sickle hcmoglobinopathies. Am J Obstet Gynecol 159:544, 1988. Sadovsky E, Polishuk WZ: Fetal movements in utero: nature, assessment, prognostic value. time of delivery. Obstet Gynecol 50:49, 1977. Smith J, et al.: Cooperative Study of the Clinical Course of Sickle Cell Disease: Prcgnancy Outcome, 1978- 1988. (Analysis in progress, NIH #HHS N01-HB-97062).
Management of Sickle Cell Anemia and Pregnancy Mabel Koshy, Darren Chisum, Laurence Burd, Armando Orlina, and Helen How Department of Medicine, University of Illinois (M.K., D.C.) and Michael Reese Hospital 8, Medical Center (Humana) (L.B., A.O.), Chicago; University of Tennessee (H.H.) There has been significant decrease in maternal morbidity and mortality of sickle cell disease patients during pregnancy due to better understanding of the pathophysiology of the disease and physiologic changes during pregnancy. Prophylactic blood transfusion does not appear to reduce complications in patients with sickle cell anemia. Patients with sickle hemoglobin C disease and with Sp thalassemia' have fewer complications but still need close monitoring. Blood transfusion therapy should be made available for medical and obstetrical complications to include increasing hypoxemia, progressive anemia, acut chest syndrome, twin pregnancy, splenic sequestration syndrome, preeclampsia, septicemia, or prior to general anesthesia and surgery. Blood transfusion therapy is associated with hepatitis, allergic reaction, alloimmunization, AIDS, and iron overload states. These aspects should be considered prior to using blood transfusion therapy. Excellent prenatal monitoring and aggressive intervention should be instituted when problems arise for the successful management of the pregnant patient with sickle cell disease. Prenatal diagnosis and cord blood screening should be made available for the infant. Appropriate pediatric referral and prophylactic penicillin is recommended for the infant with sickle cell disease.
Key words: maternal morbidity, prophylactic blood transfusion, pathophysiology
Studies conducted in the United States before 1970 indicated that maternal morbidity and mortality of patients with sickle cell anemia during pregnancy ranged from 3 to 48%. More recently there has been a marked reduction in the morbidity and mortality rates brought about probably through better undertanding of the pathophysiology of the disease and the physiologic changes that occur during pregnancy [ 1-51, In spite of the growing trend throughout the country to administer prophylactic transfusion for sickle cell disease (SCD) patients during pregnancy, it is not clear whether improvements reported were due to blood transfusion therapy or to satisfactory medical, obstetric, and neonatal care. The National Institutes of Health funded a randomized, prospective study on the use of prophylactic transfusion in SCD during pregnancy which evaluated the effects of transfusion in a comprehensive manner [6]. Two-hundred fifty-eight pregnant SCD patients entered the study. There were 69 abortions and the remaining 189 patients completed their pregnancy during the study period. Of the 100 patients with sickle cell anemia, 72 patients were randomized for either prophylactic transfusion or to serve as control. Twenty-eight patients did not qualify for randomization. Thirty-six patients received prophylactic transfusion, beginning at the early weeks of pregnancy and the remaining 36 received transfusion
0 1991 Wiley-Liss, Inc.
only for medical and/or obstetric complications. Sixtysix sickle hemoglobin C disease (SC) and 23 sickle beta thalassemia"" (Sp Thal) patients were given only emergency transfusion therapy. The prophylactic transfusion group maintained their hemoglobin concentration between 10 and l l g/dL and hemoglobin S below 35%. This was accomplished by either simple transfusion or partial exchange blood transfusion. In the control group, 44% received transfusion therapy for medical indications, similarly 48% of the non-randomized sickle cell anemia (SS) patients, 27% of the SC and 52% of the Sp Thal required blood transfusion therapy for emergencies. Premature delivery occurred in almost 40% of patients who received transfusion, and toxemia was noted in approximately 18% of patients. Four-hundred thirty-two units were used by the prophylactically transfused group, while the control group only received 108 units. Delayed transfusion reactions and alloimmunization occurred with the same frequency in patients who received blood transfusion therapy. Amongst the medical complications only pain crisis was significantly lower in the prophylactically transfused groups. Address reprint requests to Dr. M. Koshy, Department of Medicine. University of Illinois, 840 S. Wood Street (MIC 787), Chicago, 1L 60612.
Sickle Cell Disease and Pregnancy
In the randomized study, the only difference found between patients who received prophylactic blood transfusion and those who received blood transfusion only for medicaUobstetric indications was low incidence of pain crisis. The routine use for blood transfusion therapy for painful crisis does not appear to be justified given the known potential and possible life threatening complications of blood transfusion. At the termination of the cooperative study in 1986, the use of prophylactic blood transfusion therapy was discontinued as part of the treatment modality at our medical center, and patients with SCD continued to be monitored closely and received blood transfusion for medical and obstetrical indications. Between 1986 and 1990 there were 54 pregnancies among patients with SCD (Table I). Data on abortions during this period were not collected. Since the complications with twin pregnancies were significant, these were analyzed separately. There were 35 SS, 9 SC, 6 Sp Thal, and 4 SS with twin pregnancies. The average age of the mother was 24 years. There were no teenage pregnant mothers who had twin pregnancies. The lowest average gestational age and birthweight were among twin pregnancies. There was a high frequency of cesarean section among the SCD patients, due to our policy of a short trial of labor and early assisted delivery at the first signs of fetal distress [6-81. Twenty-six SS, 3 SC, 3 Sp Thal, and the 4 SS with twin pregnancy required blood transfusion therapy. The majority of indications was for preoperative preparation for a cesarean section (CS), and the remaining tranfusions were for the accepted medical indications of acute chest syndrome,
Table I. Sickle Cell Disease and Pregnancy, 1986-1990 Study: PRN Transfusion Theram*
Total No. of pregnancies Avg. age (years) Teenage pregnancies Avg. gestation (wk) Premature gestation Avg. birthweight (9) Cesarean scction Paticnts transfused Total No. of units Avg. No. of unitsipt. Maternal deaths lnfant deaths Maternal morbidity Pain crisis Acute chest syndrome Urinary tract infection Pre-eclampsia
ss
SC
35 24 3 31 I1 2,598 17 26 I12 4 0 0
9 23 3 39 2 3,089 3 3 12 4 I 0
6 23 1 38 2 2,680 3 4 16 4 0 0
4 26 0 29 4 1,051 3 4 26 6 0 3
18 5 6 5
5 0 2 2
3 3
2 I 1 2
Sp
Thai+"
SS"
1
1
*The figures represent Nos. and not percentages where applicable 'Twin pregnancy.
231
pre-eclampsia, and severe anemia. An average of 4 units of red blood cells (RBC) was transfused per patient. One SS patient received 20 units for severe pre-eclampsia, seizure disorder, and other persistent acute medical complications in spite of transfusion therapy. The 4 SS patients with twin pregnancies received prophylactic transfusion therapy when they reported to the Prenatal Clinic (12-24 weeks). One mother with twin pregnancy reported to the Prenatal Clinic at 24 weeks and was admitted with premature rupture of the membranes and lost both infants in spite of blood transfusion. One would speculate whether the outcome would have been different if earlier prenatal visits had been sought by the mother. The other single infant deaths occurred in the 2 remaining twin pregnancies at 28 and 29 weeks of gestation, respectively. There were no infant deaths in the SC, Sp Thal, and SS patients with single pregnancies. There was 1 maternal death in a patient with SC hemoglobinopathy who had only 1 prenatal visit at 20 weeks and was lost to follow-up. She was later transferred to the medical center at 36 weeks gestation, when she was agitated and obtunded, refused blood transfusion therapy, and sustained a cerebrovascular accident (CVA). She then received 2 units of RBC by partial exchange and underwent CS to save the fetus after brain death was established according to accepted criteria. Postmortem examination of the mother demonstrated bilateral brain infarcts; sagittal thrombosis; hemolytic anemia, elevated liver enzymes, and low platelets (HELLP Syndrome); and consumption coagulopathy. The infant had a good apgar score. We compared the obstetric maternal morbidity and mortality between the 2 studies of sickle cell anemia patients ( I 978-86 and 1986-90) against the normal African-American women without medical complications or hemoglobinopathy who delivered at our institution and the results are shown in Table 11. There was no maternal mortality recorded. Premature births occurred with increased frequency and prophylactic transfusion did not alter outcome. Similarly perinatal morbidity and mortality were increased among SS patients irrespective of types of transfusion therapy when compared to normal AA controls (Table 111). Among sickle cell anemia related complications, pain crisis appears to be present with increased frequency (Table IV). Some of these painful events were mild and would have been managed by outpatient and oral analgesic treatment, but were admitted because of the concurrent pregnancy. During the 1986-1990 study period the acute chest syndrome included a11 cases of pneumonia, congestive heart failure, and any patient with pulmonary infiltrate and fever that persisted over 102°F for more than 3 hours. Severe anemia was diagnosed when the admitting
232
Koshy et al. TABLE 11. Comparison of Maternal Morbidity and Mortality (SS Patients) Between the Randomized Study Normal AA and Post Randomization Study* 1978-1986 Cooperative Study Trdnsfusion Control Normal" -~
1986-1990 SSIPRN ..
-
~
-~
-
~~~
Number of patients Materndl mortality Gestational age dt birth (wk) Multiple births (%) Preterm labor (%) Placenta previa (%) Abruptio placenta (%) Toxemia of pregnancy Cesarean section (%)
~~
36 0 36 8 39 3 6 17 22
8,981 0 40 2 17 04 05 4 14
36 0 38 3 17 0 3 22 28
39 0 37 12 38 NA NA 17 50
*SS/PRN After discontinuation of cooperative study, SS patients on prn transfusion NA available "African-American patients without hemoglobinopathy, anemia, diabetes, chronic hypertension
=
not
TABLE 111. Comparison of Perinatal Morbidity and Mortality Between the Randomized Study, 1978-1986 (SS), Normal (AA) and PRN Transfusion Study, 1986-1990 (SS) ("/.)
1978-1986 (SS) ~
~~~
~~~
Stillbirth Neonatal death Perinatal mortality Birthweight (g) Intrauterine growth retardation
Normal
Transfusion -.
Control
1980-1986
10 0 10 2,495 14
5 0 5 2,652 18
2 1 3 3,006 9
SSIPRN 1986- 1990
~
-~
5 5 10 2,531 17
"African-American patients without hemoglobinopathy, anemia, diabetes, or chronic hypertension.
TABLE IV. Comparison of Sickle Cell Anemia Related Complications in the Cooperative Study, 1978-1986, and the PRN Transfusion Study, 1986-1990 1978-1986 study
Pain crisis Seizure disorder Headaches Splenic sequestration Acute chest syndrome Congestive heart failure Severe anemia Pyelonephritis Urinary tract infection Nephrotic syndrome Chronic renal failure Cholecystitis
Transfusion
Control
1986- 1990 SSiPRN
14 3 3 0 6 3 3 3 6 3 0 0
50 3 3 3 8 3 8 3 17 3 3 6
51 2 3 0 15" NA* 5 2 17 0 0 0
* NA = not analyzed separately-included in acute chest syndrome. 'Combined total of pneumonia, congestive heart failure and pulmonary infiltrate with fever.
hemoglobin dropped by 30% from the stable nonpregnant state. Symptomatic urinary tract infection was treated with antibiotics as an outpatient. Two patients had pyelonephritis and required hospitalization. When the outcome of the current study (1986- 1990) was compared to that of the randomized study (19781986), that of Powars, and of a larger co-operative study of Smith (1979- 1988) et al. (personal communication), there was no difference in the mean birthweight, gestational age, or percentage of premature delivery [5,17]. DISCUSSION
SCD patients contemplating pregnancy should be informed of the availability of prenatal diagnosis [9] and about the serious complications which occur to them as well as to the children, both before and after birth. They should be made aware of the fact that there is a great variability in clinical severity of the disease which could be influenced by genetic factors [lo-121. Some investigators find that the severity and symptoms of sickle cell anemia vary greatly among different individuals. Some spend a lifetime with debilitating complications necessi-
Sickle Cell Disease and Pregnancy
tating frequent hospitalization while others appear to have no complications at all. Modifying factors include concentration of fetal hemoglobin. An elevated fetal hemoglobin concentration interferes with the tendency for polymerization and thus ameliorates the clinical symptoms. Other factors are the various beta gene haplotypes. These include the central African Republic or Carr haplotype with severe clinical disease, the Benin haplotype with intermediate severity, the Atlantic West Africans, Senegal haplotype with mild disease, and sickle cell anemia that has been described among Saudi Arabians, Iranians, and Indians with very mild manifestations [ 10,13,14]. Similarly the presence of alpha thalassemia, found in approximately 30% of SCD patients, alters the expression of the disease. Beta thalassemia also alters the manifestations of SCD. Patients with Sp Thal’ have a milder clinical course and fewer complications as compared to the Sp Thal” patients who may have similar complications as those with sickle cell anemia. Finally, the presence of other hemoglobins also alters the clinical presentation, the most common association being with hemoglobin C, and patients with both types of hemoglobin have a usually milder clinical course. Perinatal mortality and morbidity in present patients with sickle cell anemia are increased when compared with a group of 8,98 1 normal African-American patients who delivered at Michael Reese Hospital and Medical Center during the cooperative study period, and who had no evidence of anemia, hypertension, or diabetes. Pre-term delivery, abruptio placenta, placenta previa, and toxemia are high in patients with sickle cell anemia. We were unable to detect any improvement in the survival of the mother or fetus that was due to prophylactic blood transfusion. Nonetheless, pregnant patients with sickle cell anemia and their infants are at considerable risk as evidenced by the increased recurrence of pregnancy complications, and fetal and neonatal outcome. They require meticulous prenatal care, early detection, and aggressive management of medical and obstetrical complications. This should be approached by an obstetrics/hematology team. Twin pregnancies appear to be associated with major complications; patients should be encouraged to seek prenatal care in the first trimester, and prophylactic blood transfusion therapy should be instituted. Patients with SC and Sp thalassemia need to be observed closely, and transfusion therapy should be recommended for clinical indications. Prophylactic transfusion should be discouraged. Blood transfusion therapy is associated with increased incidence of hepatitis, iron overload, alloimmunization, allergic reaction, and acquired immunodeficiency. Nonetheless these issues should be addressed prior to establishing criteria for prophylactic transfusion as therapy for pregnant patients
233
with SCD. Until effective anti-sickling agents become available, supportive management and excellent prenatal care will continue to play an important role in the management of pregnancy in patients with sickle cell disease 115,161. ACKNOWLEDGMENTS
Thanks are due to Pamela Moore for all secretarial assistance. REFERENCES 1. In Charache S , Lubin B, Reid CD (eds): Cooperative Study of
2.
3.
4. 5. 6.
7. 8.
9. 10. I I.
12.
13.
14.
15.
16.
17.
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