Sickle cell : Hemoglobinopathies Pathophysiology and relationship to

SHELDON E. BAUM, D.O. Detroit, Michigan

The treatment of a patient with (sickle cell ) , SA hemoglobin (sickle requires cell trait), SC hemoglobin (sickle cell C dis- ease) , and STH hemoglobin (sickle cell thalas- consideration of the pathophysiology semia disease). of all its various manifestations. The Varying percentages of S hemoglobin are physician must be aware of the present in the homozygous and heterozygous risks involved when pregnancy is states. In the homozygous state, the abnormal superimposed. In this article the author hemoglobin is generally in excess of 60 per reviews the pathophysiology of sickle cell cent. In the heterozygous state, type S hemo- globin constitutes usually 20 to 40 per cent of disease and its effect on reproduction. the cell hemoglobin, the remainder being nor- While fertility apparently is reduced mal. Sickle cell disease may also exist in in- in sickle cell anemia, this is not so termediate forms in conjunction with other in the other sickle cell diseases. abnormal hemoglobins. The pregnant patient with a sickle cell Adult hemoglobin (type A) is composed of alpha and beta chains of amino acids. Fetal requires close hemoglobin (type F) , is composed of alpha supervision and exacting care during and gamma chains. At birth, F hemoglobin the pregnancy, delivery, and postpartum normally comprises 90 per cent of the blood, period. Two cases are reported. the remainder being type A hemoglobin. Usu- One involved sickle cell anemia ally by 6 to 8 months of age type A hemoglobin associated with pregnancy; delivery predominates in the normal infant, compris- ing 90 to 99 per cent of the blood. With ab- was followed by a series of grand mal normal hemoglobin, there is substitution in seizures. The other involved sickle cell the beta-amino-acid chain at the number six trait complicated at the time of position. In sickle cell hemoglobin (S hemo- pregnancy and illustrates that the globin) , valine is substituted for glutamic acid. pregnant patient with sickle cell Lysine is substituted at the same position to trait may have increased problems of result in hemoglobin C, which does not sickle.3 In sickle cell disease, there is a correlation pregnancy as well as greater problems between the seriousness and nature of clinical of sickle cell disease. symptomatology and the percentage of abnor- mal hemoglobin.2 It is generally felt that the "sickle cell prep" Sickle cell anemia is a congenital hemolytic is a good test which may be done easily to anemia which is generally fatal before the age identify sickling of erythrocytes. One must of thirty. Although the disease occurs pre- realize that this test may be positive in absence dominantly in Negroes, it has also been re- of hemoglobin S and negative in peripheral ported in persons with no Negro ancestry. 2 It blood of patients with severe disease. Thus, is characterized by the presence of an abnormal for exact identification of hemoglobin abnor- hemoglobin, type S, which is carried on auto- mality, hemoglobin electrophoresis is neces- somal intermediate chromosomes rather than sary. on X chromosomes. There are four major types The physiochemical properties of the hemo- of S hemoglobin combinations: SS hemoglobin globin in persons with the are

1268/98 different from those of the hemoglobin in by obliterative vascular lesions.5 Joint and normal persons. This abnormal hemoglobin bone pain, leg cramps, and cerebral signs are crystallizes on deoxygenation and goes back frequent. Leg ulcers, cardiac hypertrophy, and into solution on oxygenation. The crystals resultant congestive heart failure are also formed within the erythrocytes distort their prominent. Hepatomegaly and splenomegaly membranes, causing the erythrocytes to as- may be seen in the early stages, but later the sume multi-pointed or "sickle," shapes. The spleen becomes smaller because of progressive degree of cellular distortion is greater and fibrosis and siderotic nodule formation. The sickling occurs more readily in persons with peripheral smear reveals sickled cells as well larger amounts of abnormal hemoglobin. Crys- as oval and target cells and occasional nu- tallization of hemoglobin within the erythro- cleated erythrocytes. The bone marrow is cyte is associated with increased viscosity of found to be hypercellular. General character- the blood. The resultant circulatory stasis then istics of are found: Jaundice predisposes to anoxia and thus exaggeration with increased bilirubin values and increase of the sickling process. Hypoxia causes injury in percentage of reticulocytes. In sickle cell to the vascular and parenchymal cells and disease, erythrocyte production is not acceler- initiates vascular occlusive processes, intra- ated until the hemoglobin falls to about 9.0 vascular coagulation, and parenchymal degen- grams/100 ml. erative changes and necrosis.5 Fertility appears to be reduced in women There is increased turnover of iron in all of with sickle cell anemia. Hendrickse and Wat- the sickle cell states, with decreased half-life son-Williams 7 stated that many of them do of the erythrocyte.6 Half-life of the erythrocyte not survive to reproductive age, especially in in patients with SS hemoglobin is 2 to 15 days, areas where intercurrent disease and dietary as compared to the normal of 120 days. Most inadequacies take many lives. Puberty may be patients with SS and SC hemoglobin have in- delayed many years in those not treated. There creased iron stores and circulating iron. In is no evidence that fertility is reduced in persons with SA and STH hemoglobin, iron hemoglobin SC disease, sickle cell , deficiency anemia is not uncommon. Some de- sickle cell high fetal hemoglobin disease, hemo- gree of erythropoiesis is present in all forms. globin C disease, or in sickle cell trait. In patients with sickle cell trait, the S hemo- Hemoglobinopathies and pregnancy globin returns more slowly than A hemoglobin during an acute illness. For this reason, these Sickle cell trait patients may have negative sickle cell prepara- The incidence of sickle cell trait in pregnant tions during an acute illness or after acute women was 7.9 per cent in a large series re- blood loss. ported by Adams and co-workers, 5 whose as- Patients with sickle cell anemia usually sumption was that it occurs with the same have manifestations of the disease in infancy. frequency in pregnancy as in the general popu- Chronic anemia and jaundice are present lation. Carriers of the sickle cell trait usually throughout life. Generally, these persons are do not suffer from sickling phenomena and able to tolerate very low hematocrit values they ordinarily go through life unaffected. without symptoms. Often death occurs during Pregnancy in these patients neither activates childhood or in early adult life. The recurrent blood destruction nor precipitates the anemic febrile and painful illnesses ("crises") from state. The incidence of toxemia is increased in which these persons suffer are best explained these patients, but the exact cause is not

1269/99 Journal AOA/vol. 68, August 1969 Sickle cell hemoglobinopathies

known. According to Adams and co-workers, anemia and a second pregnancy has one chance it is probable that there are mild vascular in four of dying. Adams and co-workers stated changes in the trait which are similar to those that it is the accepted opinion that gravidity in sickle cell anemia. Fetal mortality is also and parity are reduced in sickle cell anemia found to be increased. In cases of severe and that life expectancy is probably shortened oxygen deprivation sickle cell trait may be by the first pregnancy. the cause of sudden, unexplained death. When pregnancy is superimposed upon The increased incidence of pyelonephritis sickle cell anemia, the latter is aggravated. may be related to renal papillary damage. There is a gradual drop in the hemoglobin Harrow and co-workers 5 demonstrated roent- values, the lowest value being reached at about genographic papillary defects caused by papil- 32 to 34 weeks of gestation. The values may lary necrosis in patients with SA hemoglobin. be extremely low at this time, necessitating The necrosis is produced by hemostasis and transfusion. The drop follows the pattern of the resultant small infarctions of renal pa- physiologic variation characteristic of hemo- pillae. This condition, which results in painless globin values in normal pregnancy, except hematuria, may necessitate nephrectomy. Sick- that the drop is faster and more profound. ling occurs more readily in the renal papillae The anemia is a major problem in the preg- because of the increased osmolarity caused by nant patient and is related to shortened eryth- a countercurrent mechanism and the decreased rocyte survival. In the non-pregnant state, the oxygen tension. Oxygen tension is lowest in extra demand for folic acid can usually be met the renal papillae and greatest in the renal by dietary means, but once pregnancy is super- cortex.5 The combination of functional urinary imposed the demand is considerably increased tract obstruction secondary to hydronephrosis by the requirements of the growing fetus. If and hydroureter induced by pregnancy, plus the diet is not supplemented with folic acid, the renal papillae damage, can be expected erythropoiesis may become megaloblastic.1° to result in increased susceptibility of these When this occurs, the severity of the anemia women to pyelonephritis. In the greater per- increases rapidly and is very likely to be fatal centage of cases, anemia is not present or may unless exchange transfusions are done. Severe be mild, but occasionally for some unknown anemia is readily prevented by folic acid ad- reason it may be profound. ministration throughout pregnancy. According to Hendrickse and Watson-Williams,7 mild Sickle cell anemia anemia (hemoglobin 6.0 grams/100 ml. or The combination of pregnancy and sickle cell above) apparently causes no major problems; anemia produces a hazard which must be thor- they stated that blood transfusions are gener- oughly understood. Patients with this disease ally contraindicated unless the hemoglobin may die suddenly with or without apparent value falls below 6.0 grams/100 ml. or opera- cause during the period of gestation (espe- tive delivery is anticipated. cially during the last trimester), during labor, Acute erythrocyte sequestration may occur or in the puerperium. The complications which at any time in the pregnant patient with sickle may confront these patients are greater than cell anemia, resulting in the rapid develop- those associated with normal gestation. Of ment of profound anemia, which may threaten particular significance is the resultant marked life. Although it may occur earlier in preg- increase in maternal and fetal mortality. Ac- nancy this complication is most likely in the cording to Ricks, 1 a woman with sickle cell last trimester. Its occurrence at this time, in

1270/100 labor, or in the puerperium is usually associ- suggested that repeated transfusions during ated with a bone pain crisis. However, it may the last trimester may reduce the incidence of occur in labor unaccompanied by crisis and crises by decreasing the number of abnormal as a terminal event in severe megaloblastic cells.74,75 anemia. One may anticipate the event by moni- Marrow embolism developing during a bone toring the hemoglobin values every 4 hours at crisis is another fatal complication. It usually the time of greatest risk. Hendrickse and as- follows infarction in one of the long bones sociates stated that exchange transfusion is and fat droplets can be identified in the cir- indicated if the hemoglobin drops by more culating blood. A definite syndrome termed than 2.0 grams/100 ml. in 24 hours or below "pseudotoxemia" apparently precedes embol- 6.0 grams/100 ml. There is no evidence that ism. This syndrome is characterized by the de- crises are associated with an increased severity velopment of systolic hypertension and album- of anemia or a higher reticulocyte count. In- inuria during a bone pain crisis. "The patient creased hemolysis can thus be ruled out as a soon becomes increasingly dyspneic and anx- common cause of crises. The association of ious-looking and death may follow."7 This con- crises with pyrexial transfusion reactions has dition can thus be easily confused with toxemia been noted.11,12 of pregnancy. Attacks of severe bone pain, abdominal pain, One can readily understand that the inci- and intracranial crisis are probably caused by dence of toxemia in pregnant patients with intravascular sickling, leading to stagnation in sickle cell anemia is increased if he considers the capillaries and resulting infarction of the that they are both vaso-obliterative disorders area. Bone pain crises are more frequent and characterized by endothelial proliferation and more severe in complicated by alterations in vascular permeability. In both sickle cell anemia than by SC hemoglobin dis- diseases there are occlusive vascular phenom- ease. Bone pain crises occur more often in the ena, thromboses, hypoxia, and focal necrosis. pregnant state than in the non-pregnant state. Anoxia is probably the factor initiating the Although many factors including hypoxia, in- vascular damage. In toxemia of pregnancy, fection, and trauma may be responsible for vasospasm of the arterioles leads to anoxia; in initiating a bone crisis, "the common denomi- sickle cell anemia, the anemia and the stasis nators are sickled cells, increased viscosity, produced by sickled cells leads to anoxia. From circulatory stasis, hypoxia, vasospasm, dehy- this point on the two processes are very simi- dration, hemoconcentration, and acidosis."" lar. Proteinuria, pedal edema, cephalalgia, The reason for the increase of such crises dur- visual disturbances, and convulsions may be ing the last trimester is not known. Shaw" found in both conditions. As a rule, patients showed that a prolonged fall in bone blood with sickle cell anemia exhibit cardiac hyper- flow and marrow pressure followed the injec- trophy and systolic murmurs, which are not tion of Pituitrin in cats. Hendrickse and Wat- common in patients with toxemia. Hyperten- son-Williams7 considered the possibility that sion is an important sign of toxemia but is not "the effect of the posterior pituitary in initiat- a manifestation of sickle cell anemia.5 ing labor might, as a side effect, result in A common finding at autopsy is the marked lowered marrow pressure and bone blood flow, sickling of erythrocytes in the maternal sin- and thus in marrow infarction," stating that uses of the placenta with no or minimal sick- this possibility at least suggests caution in the ling in the fetal blood vessels." According to use of oxytocics in these patients. It has been Fujikura and Froehlich," "When the placenta

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separates from the uterine wall, the resulting pathy are completely asymptomatic prior to hypoxia creates a natural sickling prepara- pregnancy and will present themselves with tion of the trapped erythrocytes with the normal hematocrit values. Some event in preg- placenta." Anderson and co-workers" postu- nancy may cause sickling of the erythrocytes lated that erythrostasis of sickled erythrocytes with subsequent anemia and sludging of the in the uterine and decidual arterioles, by bring- cells in the smaller vascular channels. These ing about diminished chorio-decidual blood women may then develop all the complications flow and placental insufficiency, may be re- associated with sickle cell anemia. 2° Crises sponsible for the observed lower birth weight are usually mild and infrequent, but they may of infants born to women with sickle cell ane- be severe. Pulmonary infarctions from fat em- mia. Curzen" described a case of sickle cell boli are more common than in sickle cell ane- disease in pregnancy which required hyster- mia. Curtis2° suggested that these patients are ectomy immediately after cesarean section. more seriously affected than those with sickle The uterus was noted to have "a most unusual cell anemia, just the opposite of the situation consistency, the upper segment being extra- outside of pregnancy. This particular point ordinarily thin and feeling like a pouch of is quite controversial in the literature. 18.2° Mc- leather." Microscopically, the myometrium Curdy21 reported that a group of patients with showed hyaline degeneration. The small ves- sickle cell C disease had a greater frequency sels were stuffed with sickled erythrocytes. of pyelonephritis, postpartum hemorrhage, and "The general impression was of a low-grade, pneumonitis. Splenomegaly is seen here as slowly progressive necrosis of the inner myo- compared to the small fibrotic spleen of sickle metrium associated with sickle-cell disease." cell anemia. Significant in hemoglobin SC The bony structure of the patient with sickle disease is the recurring pattern of maternal cell anemia should be of concern to the obste- mortality characterized by rapid and progres- trician. The typical patient is tall and asthen- sive embolization to the lungs. Laros 22 report- ic. 16 She has narrow shoulders, narrow hips, ed that in a group of 29 fatal cases of sickle and long thin legs. Studies by Anderson and cell C disease bone marrow infarction with Busby" indicate that the typical pelvis is an marrow and fat embolization was the most anthropoid type with convergent side walls frequent cause of death, with megaloblastic and prominent ischial spines. Frequently, there anemia a close second. is decalcification of the pelvic bones. The ver- tebrae are flattened and aseptic necrosis of Treatment the head of the femur is not uncommon. Con- In treating any patient with sickle cell disease tracted pelves are probably more common with one must be concerned with all the aspects of sickle cell anemia because of faulty bone de- its pathology. Good standard prenatal care velopment. There is general agreement that is of utmost importance. Supplemental vita- bony changes depend on the severity and dur- mins should be given. McCurdy 21 recommended ation of sickle cell anemia. 5 Because of the a regimen of folic acid in doses of 1 to 5 mg./ possibility of these structural changes, pelvi- day. There is generally no need for additional metry studies should be done on all patients iron. Patients should be watched for the de- prior to delivery. velopment of pyelonephritis with periodic urine cultures. Periodic hematologic studies Sickle cell C disease should be done to determine the effect of preg- Many of the women with this hemoglobino- nancy on the disease. Since it has been found

1272/102 that the incidence of bone pain crisis in chil- that repeated transfusions will cause iron to dren is reduced by the prophylactic adminis- be deposited as hemosiderin in organs of the tration of antibiotics, their use in labor and body. By depressing erythropoiesis, transfu- during bone pain crisis is indicated. ? Heparin sions inhibit the formation of sickle cells. is used during bone pain crisis in the last Therefore, when transfused cells have dissi- month of pregnancy, with the clotting time pated, anemia of even greater severity may maintained at more than 17 minutes. The se- develop. verity or duration of the crisis is not affected The selection of a proper anesthetic is a very by heparin administration but embolization is important aspect of the management of these prevented. If delivery is by cesarean section, patients. The slightest anoxemia may be fatal, protamine sulfate is administered just before even in those who have the sickle cell trait. the procedure to restore the normal clotting General anesthesia is thus hazardous in these time, and heparinization is repeated 30 min- deliveries. Adams and co-workers5 stated that utes after delivery. Oxygen should be given caudal and spinal anesthesia should not be to help thwart anoxia. Infection, , used because of the likelihood that sudden metabolic acidosis, dehydration, hypoxia, and drops in blood pressure will occur with resul- trauma are all factors responsible for bone tant cerebral anoxia. Anoxia will in turn pro- pain crises and must be avoided. Prolonged duce cerebral thromboses and the outcome will and difficult labor must be prevented. Cesarean be serious, or perhaps fatal. Thus, pudendal section should be used exclusively for obstetric block or local infiltration may be the method indications. of choice. Heavy sedation should be avoided. Many authors have reported the use of ex- One must remember that sickle cell crisis may change transfusions in treating anemia, but occur while the patient is under anesthesia. the hemoglobin levels considered as indica- The question of sterilization must arise in tions have varied as much as 4 grams/100 the discussion of sickle cell anemia. All the M1.25718 RiCkS23 performed exchange transfu- factors affecting a particular patient must be sions within 8 weeks of term on seven women evaluated: anemia, toxemia, number of crises, with proved sickle cell anemia. All had had parity, economic status, with the eminent con- a crisis at some time. The average pre-ex- sideration being the general well being of the change hematocrit was 20 per cent. The blood patient. removed was replaced by an identical volume of packed erythrocytes. The amount ranged Case reports from 2,400 to 3,000 cc. The blood used was less A review of the records at Detroit Osteopathic than 48 hours old and had been brought to Hospital for the past 20 years showed only room temperature before the transfusion. one case of sickle cell anemia associated with Hemoglobin electrophoresis performed 2 weeks pregnancy and one case of sickle cell trait later showed less than 5 per cent abnormal which was complicated at the time of preg- hemoglobin. The benefit is obviously tempor- nancy. ary, but exchange transfusion may carry the patient safely through the delivery period. Case 1—Sickle cell anemia and pregnancy With such a transfusion, the total blood vol- A 23-year-old Negro woman was admitted to ume remains constant. Browne 2 contended that the hospital on May 22, 1968, with the chief patients with anemia who receive transfusions complaint of abdominal pain, , and are very susceptible to reactions. He stated dyspnea. The patient was gravida II, para

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0-0-1-0, at approximately 4 months gestation. ute. The patient was given 2 units of packed The patient was known to have had sickle cells, treated symptomatically, and discharged cell anemia since 5 years of age. She had had 1 week later with a hemoglobin value of 9.6 more than 100 transfusions. A sympathectomy grams/100 ml. to the right leg had been performed because On August 17, 1968, the patient was admit- of intractable pain. In 1966 she had had serum ted with the same chief complaint. The hemo- hepatitis. globin value was 8.6 grams/100 ml. The pe- The physical examination showed the pa- ripheral smear showed toxic granulation and tient to be thin and asthenic. There were mul- Howell-Jolly bodies. The patient was given tiple areas of healed ulcers on the legs. A large three transfusions of packed cells and sent abdominal keloid was noted at the area of home 5 days later with a hemoglobin value of sympathectomy. Systolic gallop rhythm and 9.6 grams/100 ml. grade II-III/VI systolic murmur at the left On August 28, 1968, the patient was admit- sternal border and pulmonic area were present. ted with the chief complaint of intractable di- The uterus was at S+8.0 cm. arrhea present for the past 4 to 5 days. There The ECG (electrocardiographic) findings were no other complaints. The patient ap- were first degree right bundle branch block, peared dehydrated. The hemoglobin value was biventricular hypertrophy, and sinus tachy- 9.9 grams/100 ml. The reticulocyte count was cardia (120 beats per minute) . 14.2 per cent. Electrolytes were normal. Tele- The chest x-ray showed cardiac enlargement opelvimetry showed adequate measurements. with evidence of pulmonary congestion, prob- Cervix was 1-0-2-F-F-A by Stevens index. ably caused by high output failure. Fetal heart tones were 140 per minute. The The results of chemical examination were es- patient was treated with fluids and 2 units of sentially normal. The hematologic studies dis- packed cells, and discharged 2 weeks later. closed the following values: reticulocyte count, On October 6, 1968, the patient was admitted 65 per cent; hemoglobin, 8.8 grams/100 ml. The in active labor. The hemoglobin value was 6.8 peripheral smear showed marked anisocytosis, grams/100 ml. and the hematocrit, 20 per cent. poikilocytosis, hypochromasia, target cells, 15 Platelets were markedly decreased. The retic- nucleated erythrocytes per 100 leukocytes, and ulocyte count was 5.2 per cent. The blood pres- hyperlobulation of leukocytes. sure was 130/70 mm. Hg; the pulse rate, 118 The hemoglobin level fell steadily to 7.5 beats per minute; and the respiratory rate, 24 grams/100 ml. A total of 8 units of packed per minute. The patient gained 38 pounds dur- cells was transfused during the patients hos- ing pregnancy. No pretibial edema was pres- pital stay. She was placed on a regimen of ent. A transfusion of 4 units of packed cells progestational agents. Narcotics were adminis- was given. After a normal labor, the patient tered for symptomatic treatment of pain. The was given an epidural anesthetic and no prob- patient was discharged 2 Y2 weeks later with lems developed. A viable infant, weighing 6 hemoglobin value of 10.6 grams/100 ml. and pounds 2 ounces, was delivered with rotation reticulocyte count of 17.8 per cent. from left occipitoposterior to left occipito-an- The patient was re-admitted on July 31, terior with Laufe-Kielland forceps. At 1 min- 1968, with the chief complaint of leg and ab- ute the Apgar score was 5. A moderate amount dominal pain. The hemoglobin value was 8.0 of uterine bleeding was present. Fourteen grams/100 ml. The reticulocyte count was 28.1 hours after delivery, the patient had a grand per cent. Fetal heart tones were 148 per min- mal type of seizure. Within the next 6 hours,

1274/104 three more seizures occurred. The blood pres- Case 2—Sickle cell trait and pregnancy sure was 190/100 mm. Hg. The hemoglobin A Negro woman, age 27, gravida II, para 0-1- was 9.6 grams/100 ml. There were cocci in the 0-0, was admitted in labor at 42 weeks gesta- urine, but no albumin. No focal neurologic tion. The admitting hemoglobin value was 11.4 signs were present. The hemoglobin level de- grams/100 ml. Fetal heart tones were 140 per creased daily and on October 14, 1968, it was minute. Labor progressed slowly. Fetal heart 7.1 grams/100 ml. A transfusion of 2 units of tones disappeared and slight vaginal bleeding packed cells raised the hemoglobin to 9.9 was present. Cesarean section was performed grams/100 ml. The patient complained of and a stillborn infant was delivered. A diag- cephalalgia and leg pain. Left ankle pain de- nosis of abruptio placentae was made. Postop- veloped and then thrombophlebitis of the left eratively, the patient developed ileus. The leg. An ulcer formed on the left arm at the hemoglobin value decreased to 7.9 grams/100 area of an injection. The EEG findings were ml. A sickle cell prep was positive (40 per normal. The patient was treated symptomat- cent sickled cells). The hemoglobin electropho- ically and for eclampsia. When this paper was resis showed the patient to have sickle cell written, the patient was still hospitalized. trait, a fact which had not been known previ- ously. On the second postoperative day, the Discussion. Prenatal care of the patient with patient developed dyspnea, chest pain, and sickle cell anemia should be very aggressive. tachycardia (120 beats per minute), and there One may question the use of multiple trans- was a grade II/VI systolic murmur at the left fusions during the early months of gestation sternal border. No cyanosis was present. Lung when the hemoglobin value was not drastically scan showed decreased vascularization of the low even though the patient was having a entire left lung field, especially the left lower crisis. It must be remembered that crises are lobe, suggesting the possibility of an infiltra- not related to anemia. I do believe that the tive process through pulmonary embolization. possibility of hemorrhagic problems at deliv- The remainder of the postoperative period was ery warrants the use of transfusions at that uneventful. time. Administration of an epidural anesthetic is to be questioned, since hypotension, cerebral Discussion. This case shows that the pregnant anoxia, and then cerebral thrombosis could patient with sickle cell trait may have prob- have resulted. Pudendal block or local infiltra- lems of pregnancy greater than those of nor- tion would probably have been more prudent. mal pregnant patients, as well as problems of The cause of the convulsions is hard to ascer- sickle cell disease greater than those of non- tain: Did they result from eclampsia or from pregnant patients with sickle cell trait. sickle cell anemia with cerebral thrombosis? The only clue to the answer is the blood pres- Summary sure elevation, a development which is seen This paper discusses the pathophysiology of more frequently with toxemia than with sickle the various manifestations of sickle cell dis- cell anemia. I was also concerned with the pos- ease and the effect of these hemoglobinopath- sibility that the symptomatic treatment of pain ies on reproduction. with narcotics might lead to addiction in this Fertility appears to be reduced in sickle cell patient. Definite steps should be taken to pre- anemia, but not in the other sickle cell diseases. vent another pregnancy. The prognosis for In sickle cell anemia and sickle cell C disease, this patient is poor. profound morbidity and mortality are present.

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The risk to the fetus is definitely increased, 12. Paterson, J. C. S., and Sprague, C. C.: Observation on the genesis of crises in sickle cell anemia. Ann Intern Med 50:1502-7, but close supervision of the patient and insti- Jun 59 13. Shaw, N. E.: Observations on the intramedullary blood-flow tution of prophylactic measures decrease pre- and marrow-pressure in bone. Clin Sci 24:311-8. Jun 63 maturity and the perinatal death rate. Folic 14. Adams, J. Q.: Sudden death in pregnancy due to the sickle acid should be administered to help prevent cell trait. Southern Med J 60:898-901, Jul 57 15. Nadel, J. A., and Spivack, A. P.: Surgical management of sic- severe anemia. The incidence of bone pain kle cell anemia: The use of packed red blood cell transfusions. Ann Intern Med 48:399-406, Feb 58 crisis is increased in pregnancy, especially in 16. Anderson, G. W., and Busby, T.: Sickle cell anemia and preg- the last trimester. The greatest danger associ- nancy. Amer J Obstet Gynec 58:75-89, Jul 49 17. Fujikura, T., and Froehlich, L.: Diagnosis of sickling by pla- ated with such crises is marrow embolization. cental examination. Geographic differences in incidence. Amer J Ob- General complaints should be treated sympto- stet Gynec 100:1122-9, 16 Apr 68 18. Anderson. M., et al.: Sickle-cell disease in pregnancy. Lancet matically. Whatever ones philosophy of pa- 2:516-21, 3 Sep 60 tient care, he must understand the pathophysi- 19. Curzen, P.: Sickle-cell disease with "leather pouch" uterus. Brit Med J 1:1360, 28 May 64 ology of the disease process. Only with this 20. Curtis, E. M.: Pregnancy in sickle cell anemia, sickle cell- knowledge can he hope to deliver a viable fetus hemoglobin C disease, and variants thereof. Amer J Obstet Gynec 77:1312-23, Jun 59 and maintain the health of the mother. 21. McCurdy, P. R.: Abnormal hemoglobins and pregnancy. Amer J Obstet Gynec 90:891-6, 1 Dec 64 22. Laros, R. K.: Sickle cell disease and pregnancy. Documenta- tion is offered for the deleterious effect of pregnancy on the course of sickle cell disease. Penn Med 70:73-7, May 67 1. Ricks, P., Jr.: Sickle cell anemia and pregnancy. Obstet Gynec 23. Ricks, P., Jr.: Further experience with exchange transfusion (NY) 17:513-6, Apr 61 in sickle cell anemia and pregnancy. Amer J Obstet Gynec 100:1087- 2. Browne, R. A.: Anaesthesia in patients with sickle-cell anaemia. 91, 15 Apr 68 Brit J Anaesth 37:181-8. Mar 65 Diggs, L. W., Ahmann, C. F., and Bibb, J.: The incidence and sig- 3. Koneman, E. W., Miale, J. B., and Mason, A.: Current bio- nificance of the sickle cell trait. Ann Intern Med 7:769-78, Dec 33 chemical and genetic concepts in the diagnosis of sickle cell-thalas- Eisenstein, M. I., Posner, A. C., and Friedman, S.: Sickle-cell semia. A study of eight families. Amer J Clin Path 90:1-20, Jul 63 anemia in pregnancy. Review of literature with additional case his- 4. Itano, H. A.: Human hemoglobin. Science 117:89-94, 30 Jan 63 tories. Amer J Obstet Gynec 72:622-34. Sep 66 5. Adams, J. Q.. Whitacre, F. E., and Diggs, L. W.: Pregnancy Movitt, E. R., Mangum, J. F.. and Porter, W. R.: Sickle cell- and sickle cell disease. Obstet Gynec 2:335-52, Oct 53 hemoglobin C disease. Quantitative determination of iron kinetics and hemoglobin synthesis. Blood 21:635-45, May 63 6. Oliner, H. L., and Heller, P.: Megaloblastic erythropoiesis and acquired hemolysis in sickle-cell anemia. New Eng J Med 261:19-22, Rywlin, A. M., Block, A. L., and Werner, C. S.: Hemoglobin C and 2 Jul 59 S disease in pregnancy. Report of a case with bone marrow and fat emboli. Amer J Obstet Gynec 86:1065-9, 15 Aug 63 7. Hendrickse, J. P., and Watson-Williams, E. J.: The influence of hemoglobinopathies on reproduction. Amer J Obstet Gynec 94:739- Whalley, P. J., Martin, F. G., and Pritchard, J. A.: Sickle cell 48, 1 Mar 66 trait and urinary tract infection during pregnancy. JAMA 189:903- 6, 21 Sep 64 8. Harrow, B. R., Sloane, J. A., and Liebman, N. C.: Roentgeno- logic demonstration of renal papillary necrosis in sickle-cell trait. New Eng J Med 268:969-76. 2 May 63 9. Cochran, R. T., Jr.: Hyposthenuria in sickle cell states. Arch Intern Med (Chicago) 112:222-5, Aug 63 This paper, which received a 1969 Philips-Roxane Award, was writ- ten during Dr. Baums residency in the Department of Obstetrics 10. Fullerton, W. T., and Watson-Williams, E. J.: Haemoglobin and Gynecology, Detroit Osteopathic Hospital, Detroit, Michigan, of SC disease and megaloblastic anaemia of pregnancy. J Obstet Gy- which Dr. Harvey C. Orth is chairman. naec Brit Comm 69:729-35, Oct 62 11. Diggs, L. W.: Sickle cell crises. Amer J Clin Path 44:1-19, Jul Dr. Baum, Detroit Osteopathic Hospital, 12623 Third Avenue, De- 65 troit, Michigan 48203.

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