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Abnormal hemoglobins and pregnancy
Abnormal hemoglobins PAUL Washington,
R.
McCURDY,
and pregnancy
M.D.
D. C.
of over 500 Negro mothers by electrophoresis. They found a lower incidence of the sickle cell trait in the Prenatal Clinic than is commonly reported but it was even lower among the nonpregnant control patients. Patients with sickle cell trait and with hemoglobin C trait had a greater frequency of abortions than did the control patients from the Prenatal Clinic who had normal hemoglobin. Nonetheless, the number of cases studied in each group was rather small and statistical significance may not be entirely credible. On the other hand, in a careful study which included electrophoretic analysis of hemoglobin and matched local controls, Whalley and co-workersi found that pyelonephritis was more frequent among pregnant patients with sickle cell trait than among those with normal hemoglobin. In other respects the two groups were similar. The present study was undertaken to determine if patients with abnormal hemoglobin traits or diseases had more frequent maternal or fetal complications.
T H E M A T E R N A L and fetal effects of abnormal hemoglobin syndromes have not been established. Prior to the use of hemoglobin electrophoresis, a number of reports attested to the dangers of the combination of pregnancy and sickle cell anemia, both to the mother and to the chi1d.l When hemoglobin electrophoresis was used for more precise diagnosis, it was then suggested that sickle cell-hemoglobin C (S-C) disease presented a greater hazard than did sickle cell anemia (S-S disease).z Others have confirmed these observations,3 but not all investigators agree.4‘” It has been postulated instead that the wide clinical variability of S-C disease is seen during pregnancy.” The effect of the interaction of abnormal hemoglobin traits and pregnancy is equally uncertain. Adams and associates’ found a higher incidence of toxemia and fetal loss (stillbirths, neonatal deaths, and abortions) among patients with sickle cell trait than is the national average. Their diagnosis was based upon sound clinical grounds but did include hemoglobin electrophoresis. not Abram? failed to confirm this predisposition to fetal death and maternal morbidity in a group of patients with the sickle cell trait. His diagnostic criteria included hemoglobin electrophoresis. The validity of comparison of local figures with national averages as was done in these two studies is open to question. Jenkins and Clark9 analyzed the hemoglobin
Materials
and
methods
During the period of study blood was examined from all patients who were admitted to the Prenatal Clinic at the District of Columbia General Hospital. A capillary hematocrit, a sickle cell preparation with sodium metabisulfite,l’ and a hemoglobin paper electrophoresis test at pH 8.V’ w-ere done at the first visit. When possible, patients in whom the hematocrit was less than 30 per cent were examined further and given treatment for anemia. After delivery, the charts of selected patients were reviewed for the outcome of present and past pregnancies. Fetal loss (stillbirths, abortions, and nronatal deaths) and major complications ane-
From the Georgetown University Medical Division, District of Columbia General Hospital, and the Department of Medicine, Georgetown University School of Medicine. Supported by Grants A-1171 and A-2823 from the National Institute of Arthritis and Metabolic Disease, National Institutes of Health, Bethesda, Maryland.
891
892
McCurdy
‘This trait
partially characterized hemoglobin L) but there was no further proof. Complications. The findings during pregnancy are depicted in Tables II, III, and IV and Fig. 1. In the groups with normal hemoglobin the proportion of patients who had toxemia of pregnancy, cesarean section, postpartum endometritis, and hemorrhage around delivery was not significantly different from that in the patients with abnormal hemoglobin traits. None of them differed from the others in the incidence 01 mode of fetal loss. Premature delivery was more common in patients with hemoglobin C trait than in individuals with normal hemoglobin. Pyelonephritis was more frequent in patients with sickle cell trait than in the other groups in this part of the study. One patient with sickle cell trait had a megaloblastic anemia of pregnancy. The incidence of anemia (hematocrit less than 30 per cent) was greater among the patients with sickle cell or hemoglobin C trait than among those with normal hemoglobins. All but 1 of these anemic patients, who could be reexamined and followed through a response to a therapeutic trial and who had normal hemoglobin or abnormal hemoglobin traits. were found to have iron deficiency. In the files of the Hematology Clinic there were 38 women patients with abnormal hemoglobin syndromes who had been pregnant at least once. Thus, the pregnancy records of 20 patients with sickle cell anemia, 14 with S-C disease, 3 with homozygoushemoglobin C disease, and 1 with C-thalassemia disease could be reviewed. The maternal complications of toxemia of pregnancy, cesarean section, postpartum endometritis, and antepartum hemorrhage were not significantly more frequent in these pa-
mia, hemorrhage, toxemia, cesarean section, and endometritis) were tabulated. These data were obtained for all patients found to have sickle cell trait, hemoglobin C trait, sickle cell anemia, S-C disease, or homozygous-hemoglobin C disease, for 492 randomly selected normal patients and for 104 randomly selected patients with normal hemoglobin and anemia (hematocrit less than 30 per cent). Additional women patients with abnormal hemoglobin syndromes were selected from the Hematology Clinic and their records examined for the outcome of any pregnancies. As a nonpregnant population control, similar blood studies were performed on Negro applicants for hospital employment. Statistical analyses were performed by means of the chi square test. Results
Incidence, Hemoglobin electrophoresis was performed on blood from 3,333 patients from the Prenatal Clinic and from 209 women applicants for employment. The results are found in Table I. Sickle cell trait was found in 6.4 per cent of the pregnant patients and 6.7 per cent of the control patients. The incidence of hemoglobin C: trait was 1.3 per cent and 3.3 per cent. respectively. Three patients with sickle cell anemia (0.09 per cent), 3 with S-C disease (0.09 per cent), and 2 with homozygoushemoglobin C disease (0.06 per cent) attended the Prenatal Clinic during the period of study. These disorders were not found among the nonpregnant control patients. OnIy the difference in incidence of hemoglobin C trait is significant (p = 0.05). In addition, 14 prenatal patients (0.4 per cent) had the electrophoretic pattern of sickle cell trait but negative sickle cell preparations. Table I. Abnormal
hemoglobin 1
Prenatal clinic Normal women$ Normal men$
AA 3,062 188 108
traits /
in pregnant
AS*
(
AC
206 14 5
*Hemoglobins named in order of decreasing concentration, Y‘AD” signifies electrophoretic pattern of sickle cell trait, ZNegroes reporting for pre-employment physical examinations
43
7 5
women
as compared
1 “AD”+
1
SS
/
to controls CC
1 Total
14
3
SC
3
2
3,333
0 0
0 1
0 0
0 0
e.g., AS is sickle cell trait, etc. but a negative sickle cell preparation. at District of Columbia General
/
Hospital.
209 119
Volume Number
90 7, part
Abnormal
1
tients than they were in those with normal hemoglobin. Patients with sickle cell anemia or with S-C disease had pulmonary complications and pyelonephritis more frequently than any other patients. Premature delivery was more common in patients with sickle cell anemia. Postpartum hemorrhage was more frequent in patients with S-C disease. Patients with sickle cell anemia lost 34.6 per cent of their babies; those with S-C disease lost 15.3 per cent. Both figures are greater than the fetal loss for all other groups, but only for patients with sickle cell anemia is the difference clearly statistically significant. Among the 878 patients whose charts were esamined 4 maternal deaths were recorded. After giving birth to a premature infant, 1 patient with sickle cell trait died of bilateral pneumonitis and congestive heart failure. One patient with sickle cell anemia died suddenly in what appeared to be a sickle cell crisis. Two patients with neither anemia nor an abnormal hemoglobin also died. One of these had aspiration and atelectasis after a hysterectomy for a ruptured uterus and the other had massive pulmonary collapse after a cesarean section. A number of patients with sickle cell anemia had miscellaneous complications. One had previously developed an anti-U antibody as a result of blood transfusion.“’ The 2 surviving infants from the 6 pregnancies had positive direct Coombs’ tests, but neither became jaundiced or anemic and neither required exchange transfusion. A second patient had a vitreous hemorrhage and a retinal tear’” on the first postpartum day and a third had a severe postpartum psychosis and a cerebral vascular accident, hut recovered. Still another developed initial symptoms of aseptic necrosis of both femoral heads during pregnancy. Four of the patients with sickle cell anemia had a profound drop of hematocrit near term. Two of these appeared to have superimposed megaloblastic anemia of pregnancy. Few of the patients with S-C disease OI llomozygous-hemoglobin C disease had other complications. Two with S-C and 1 with C-C had megaloblastic anemia of preg-
hemoglobins
and
Table II. Incidence less than
of anemia 30 per cent) during Not anemic /No. 1
893
(hematorrit pregnant!’
Anemic ____-. 1 9%
Total lN0. j
11.7 18.9 21 .o 7.2
J,Otz :I06 -1.:; 1 -i
*Hemoglobins named in order of decwaaing s.s.. AS is sickle cell trait, etc.
con~g.nrra-
AA AS* AC “AD” tion.
/ -.--
pregnancy
?,705 167 34 13
No. 357 39 9 1
nancy. A patient with S-C disease had erythrocytic hypoplasia from temporary chloramphenicol therapy for pyelonephritis. Nearly all of these patients had a greater degree of anemia than is normal chlring pregnancy, but not out of proportion ttr the hematocrit when not pregnant. Comment Truly representative figures for thr incidence of abnormal hemoglobin traits and diseases in the Negro population arc not available because all such data are subject to a bias introduced by the source of blood samples. In this context, the incidence of sickle cell trait is the same in the study group from the Prenatal Clinic as in the control employees, but the frequency of hemoglobin C trait is significantly higher in the study series. No explanation for the latter seems apparent. Although “hemoglobin I)‘. trait was not further characterized, its incitirnce (0.4 per cent’) approximates that reported in another large series of Negro patients.“” The data presented above show an increased frequency of anemia among patients with these abnormal hemoglobin traits. Iron deficiency was the usual cause, but thr*re seems to be no reason for this to occur rnor(‘ often in such patients. Similarlv there is no apparent cause for the observed inclcasecl frequency of premature labor in parirnts with the hemoglobin C trait. Pyelombphritis is more common in pre,qnant patients with sickle cell trait than in the other groups. Renal complications including pyelonel~hritis are also probably more frequent in nonpregnant patients with sickle cell trait. Dctspite
is presumptively
595 206 43 14 20 14 3 1
AA AS AC “AD” ss SC CC C-thalassemia
*Significant.
No.
IV. Percentage
Category
Table
$Range.
&3
3 1
named
age at time
tHemoglobins
*Mean
cc C-thalassemia
order
of
decreasing
10.2 9.7 12.3 19.0 34.6* 15.5 5.3 0.0
Fetal loss (%I
(l-9) 19 2
2,369 847 214 37 (;;I
Total pregnancies
2.4 3.0 5.6* 2.7 10.2* 1.7
Premature infants (%I
and
anemia).
e.g.,
AS
14.8 17.9 7.0 14.3 5.0 00 0.0 0.0
3.0 6.3* 0.0 0.0 10.0* 21.4* 33.3 0.0
3.9 5.8 9.3 0.0 5.0 14.3 00 0.0
~__
0 0
2
23 12 4 0 1
Cesarean section
reviewed
8.9 12.6 16.3 7.2 20.0 14.3 0.0 0.0
etc.
were
Cesarean section
Itrait,
0 0
2
53 26 7 1 4
postpartum fever
charts
Postpartum fever
cell
0
1
3
18 13 0 0 2
Pyelonephritis
whose
is sickle
Pyelonephritis
0 0
0
1
88 37 i
Toxemia
patients
complications
cell
0 0
1
57 25 12 1 5
Total premature infants
for
Toxemia
fetal
S (sickle
concentration,
(O-3) A
241 82 26 7 (“-i,
Total fetal loss
complications
hemoglobin
fetal
of maternal
homozygous
in
of study.
(l$;~W§ (17-53) 36.6 35.0
14
SC
Mean age*
and
24.5 25.0 26.6 21.1 25.0
No.
Maternal
595 206 43 14 19
Category
III.
AA ASt AC “AD” SSS
-
Table
2.4 1.9 2.3 0.0 1 o.o* 7.1 0.0 0.0
Anteparturn hemorrhage
Patients
0 0
1
0 2
1
14 4
Antepartum hemorrhage
4.5 2.4 2.3 7.2 5.0 21.4* 0.0 0.0
Postpartum hemorrhage
(7%)
0 0
3
27 5 1 1 1
Postpartum hemorrhage
Patients
(No.)
0.5 1.9 0.0 0.0 25.0* 7.1 0.0 0.0
Pneumonia
0 0
1
3 4 0 0 5
Pneumonia
5.7 8.7 18.6* 7.2 20.0* 14.3 0.0 0.0
Prematurity
1
34 18 8 1 4
Prematurity
0 0
0
1
2 1 0 0
Maternal death
0.0 0.0 0.0 0.0 20.0 14.3 0.0 ~- 0.0
Increased anemia
Painful crisis
0 0
0
0 0 0 0 2
crisis
ful
Pain-
0.0 0.0 0.0 0.0 10.6 0.0 0.0 0.0 . ~. ~...--~_
1 0
1
0 0 0 0 4
Excessively increased anemia
Abnormal
ELI Normal m AS I AC t!JI “A D” e ss USC
POST - PARTUM FEVER POST - PARTUM HEMORRHAGE
‘*
Hemoglobin
PNEUMONIA
TOXEMIA
PYELONEPHRI
TIS l
PREMATURE INFANTS
FETAL
.
LOSS
.
0
IO
20
30
40
PERCENT
Fig.
1. Frequency of complications during pregnancy in patients with normal hemoglobin, abnormal hemoglobin traits, and abnormal hemoglobin diseases. (The asterisk denotes significant difference.)
this increase of pyelonephritis among patients with the sickle cell trait there was no increase of toxemia of pregnancy. These complications have no statistically demonstrable effect on the outcome of the pregnancy, but a high incidence of induced abortions in the socioeconomic group studied could mask a small but significant increase in the frequency of fetal loss among any of these patients. These data are in agreement with those reported by Whalley and associates.” On the other hand, the presence of an abnormal hemoglobin syndrome in a gravid woman adversely affects fetal survival, maternal morbidity, and probably maternal death. Curti? suggested that patients with S-C disease were more seriously affected than those with sickle cell anemia, which is just the reverse of the situation outside of pregnancy. Although the results of hemoglobin electrophoresis were not included, earlier reports1 of serious complications during pregnancy in patients with sickle cell
hemoglobins
and
pregnancy
895
disease were consistent with this, as they often described splenomegaly and minimal symptomatology when not pregnant. These are both more characteristic of sickk* cell variants than of true sickle cell anemia. More recently, case reports which ha\,e included the results of hemoglobin eicctrophoresis” have also stressed the dangers of pregnancy in the patient with S-C disease. Anderson and co-workers5 have challenged this view, suggesting that the manifestations of S-C disease are as diverse during pregnancy as at other times. Some may be completely asymptomatic. Patients with more severe disease are more likely to have symptoms which would lead both to a hematological diagnosis and to greater difficulties during pregnancy. The data presented above clearly dtmonstrate a greater than usual incidence of rnaternal and fetal complications in patients with sickle cell anemia, particularly of pyelonephritis, premature delivery, fetal loss, pulmonary infarcts or pneumonia, and possibly antepartum hemorrhage. Patients with S-C disease had a greater frequency of pyelonephritis, postpartum hemorrhage, and perhaps pneumonitis. All of these disorders may be attributed to blockage of small blood vessels with sickled cells resulting in infarcts of the lung, kidney, or placenta. During the course of this study 2 patients each with sickle cell anemia and wilh s-f2 disease and 1 each with homozygoushemoglobin C disease and with sickle cell trait were found to have megaloblastic anemia of pregnancy. Since no special effort to unmask mild cases of this disorder was made: the incidence may be somewhat underestitnated. The folic acid requirement is greater for patients who have hemolysis and for those who are pregnant. Consequently, the Crequent occurrence of megaloblastic anemia caused by insufficient supply of folio: acid might be expected in patients with bot.11 h+ molytic disease and pregnancy. The number of patients with homozygoushemoglobin C disease or C-thalassemia disease in this series is quite small. Except for the megalohlastic anemia of precnanc)’
896
McCurdy
found in one of the former, no fetal or maternal complications could he attributed to these combinations. Can any practical recommendations be derived from this study? For patients with abnormal hemoglobin traits, good standard prenatal care should suffice with proper evaluation and therapy should complications arise. In particular, patients with sickle cell trait should be watched for the development of pyelonephritis, preferably with periodic urine cultures. On the other hand, patients with sickle cell anemia or S-C disease require more careful observation. The urine should also be cultured at intervals. The hematocrit or hemoglobin concentration should be determined frequently. Folic acid should be supplemented in amounts of 1 to 5 mg. daily, preferably apart from other medication. Most of these patients have little need for additional iron. Increasing anemia is an indication for further hematologic study including bone marrow examination. Blood transfusion may be necessary to treat hemorrhage or symptoms of anemia. The hazards of blood transfusion contraindicate its routine administration to these patients, but those who have painful crisis or evidence for local infarction either with the current pregnancy or in the past may benefit from “prophylactic” administration of 300 cc. of normal red cells every 2 to 4 months during
pregnancy.‘” Even with these precautions there is a greater than normal likelihood 01 a maternal complication or a fetal death in mothers with sickle cell anemia or sickle cell-hemoglobin C disease. Summary
and
conclusions
Hemoglobin from 3,333 prenatal patients was analyzed by electrophoresis for abnormal hemoglobins and the records sampled and examined for the outcome of pregnancy. An additional group of women patients from the Hematology Clinic who had been known to have abnormal hemoglobin syndromes was investigated for the pregnancy history. The charts were reviewed for 596 patients with normal hemoglobin, 206 with sickle cell trait, 43 with hemoglobin C trait, 11 with “hemoglobin D” trait, 20 with sickle celI anemia, 14 with S-C disease, 3 with homozygous-hemoglobin C disease, and 1 with C-thalassemia disease. Evidence is presented from the two groups of patients that only sickle cell anemia and S-C disease present a distinctly increased ha-ard to mother or fetus. In general, S-C disease is the more benign of the two. Recommendations for the management of pregnancy in patients with abnormal hemoglobins are presented. I gratefully acknowledge the srcrrtarial assistance of Grneva D. Curry in the preparation of this material.
REFERENCES
1. Eisenstein, M. I., Posner, A. C., and Friedman, S.: AM. J. OEST. & GYNEC. 72: 622, 1956. 2.
Curtis, 1312.
E. M.: AM.
J. OBST.
& GYNEC.
77:
1959.
Henderson, A. B., Prince, A. E., and Greene, J. B.: New England J. Med. 264: 1276, 1961. 4. Molina, V., .Jr., and Marks, S.: Bull. Tulane 3.
M. Fat.
17: 19, 1957.
Anderson, M., Went, L. N., MacIver, J. E., and Dixon, H. G.: Lancet 2: 516, 1960. 6. River, G. L., Robbins, A. B., and’ Schwartz, S. 0.: Blood 18: 385. 1961. F. E., and Diggs, 7. Adams, J. Q., Whitacre, 5.
L.
W.:
Obst.
&
Gynec.
2: 335,
1953.
a. 9.
Abrams, J.: Obst. & Gynec. 14: 123, 1959. Jenkins, M. E., and Clark, J. F. J.: AM, J.
10.
Whalley, P. J., Pritchard, J. A., and Richards, J. R., Jr.: J. A. M. A. 186: 1132, 1963.
OBST.
&
GYNEC.
84:
57,
11. Jandl, J. H., Erslev, A. J., and Greenberg, M. S.: Anemia and Polycythemia, in Page, L. B., and Culver, P. J., editors: Syllabus of Laboratory Examinations in Clinical Dia,gnosis, Harvard University Press, Cambridge, 1960, p. 132. 12. Singer, K : Am. J. Med. 18: 633, 1955. 13. Sanger. R., Race, R. R., Greenwalt, T. J., and Sasaki. T.: VOX Sanguinis 5: 73, 1955. 14. Goodman, G., von Sallmann, L., and Holland, M. G.: A. M. A. Arch. bphth. 58: 655. 15 16.
1957.
Cheinoff, A. I.: Blood 11: 907, 1956. Anderson, R., Cassell, M., Mullinax, G. L., and Chaplin, H.. Jr.: Arch. Int. Med. 111: 268,
1963.
1962. 19th and Washington
Massachusetts 3, D. C.
Avenue,
S.E
R.
McCURDY,
and pregnancy
M.D.
D. C.
of over 500 Negro mothers by electrophoresis. They found a lower incidence of the sickle cell trait in the Prenatal Clinic than is commonly reported but it was even lower among the nonpregnant control patients. Patients with sickle cell trait and with hemoglobin C trait had a greater frequency of abortions than did the control patients from the Prenatal Clinic who had normal hemoglobin. Nonetheless, the number of cases studied in each group was rather small and statistical significance may not be entirely credible. On the other hand, in a careful study which included electrophoretic analysis of hemoglobin and matched local controls, Whalley and co-workersi found that pyelonephritis was more frequent among pregnant patients with sickle cell trait than among those with normal hemoglobin. In other respects the two groups were similar. The present study was undertaken to determine if patients with abnormal hemoglobin traits or diseases had more frequent maternal or fetal complications.
T H E M A T E R N A L and fetal effects of abnormal hemoglobin syndromes have not been established. Prior to the use of hemoglobin electrophoresis, a number of reports attested to the dangers of the combination of pregnancy and sickle cell anemia, both to the mother and to the chi1d.l When hemoglobin electrophoresis was used for more precise diagnosis, it was then suggested that sickle cell-hemoglobin C (S-C) disease presented a greater hazard than did sickle cell anemia (S-S disease).z Others have confirmed these observations,3 but not all investigators agree.4‘” It has been postulated instead that the wide clinical variability of S-C disease is seen during pregnancy.” The effect of the interaction of abnormal hemoglobin traits and pregnancy is equally uncertain. Adams and associates’ found a higher incidence of toxemia and fetal loss (stillbirths, neonatal deaths, and abortions) among patients with sickle cell trait than is the national average. Their diagnosis was based upon sound clinical grounds but did include hemoglobin electrophoresis. not Abram? failed to confirm this predisposition to fetal death and maternal morbidity in a group of patients with the sickle cell trait. His diagnostic criteria included hemoglobin electrophoresis. The validity of comparison of local figures with national averages as was done in these two studies is open to question. Jenkins and Clark9 analyzed the hemoglobin
Materials
and
methods
During the period of study blood was examined from all patients who were admitted to the Prenatal Clinic at the District of Columbia General Hospital. A capillary hematocrit, a sickle cell preparation with sodium metabisulfite,l’ and a hemoglobin paper electrophoresis test at pH 8.V’ w-ere done at the first visit. When possible, patients in whom the hematocrit was less than 30 per cent were examined further and given treatment for anemia. After delivery, the charts of selected patients were reviewed for the outcome of present and past pregnancies. Fetal loss (stillbirths, abortions, and nronatal deaths) and major complications ane-
From the Georgetown University Medical Division, District of Columbia General Hospital, and the Department of Medicine, Georgetown University School of Medicine. Supported by Grants A-1171 and A-2823 from the National Institute of Arthritis and Metabolic Disease, National Institutes of Health, Bethesda, Maryland.
891
892
McCurdy
‘This trait
partially characterized hemoglobin L) but there was no further proof. Complications. The findings during pregnancy are depicted in Tables II, III, and IV and Fig. 1. In the groups with normal hemoglobin the proportion of patients who had toxemia of pregnancy, cesarean section, postpartum endometritis, and hemorrhage around delivery was not significantly different from that in the patients with abnormal hemoglobin traits. None of them differed from the others in the incidence 01 mode of fetal loss. Premature delivery was more common in patients with hemoglobin C trait than in individuals with normal hemoglobin. Pyelonephritis was more frequent in patients with sickle cell trait than in the other groups in this part of the study. One patient with sickle cell trait had a megaloblastic anemia of pregnancy. The incidence of anemia (hematocrit less than 30 per cent) was greater among the patients with sickle cell or hemoglobin C trait than among those with normal hemoglobins. All but 1 of these anemic patients, who could be reexamined and followed through a response to a therapeutic trial and who had normal hemoglobin or abnormal hemoglobin traits. were found to have iron deficiency. In the files of the Hematology Clinic there were 38 women patients with abnormal hemoglobin syndromes who had been pregnant at least once. Thus, the pregnancy records of 20 patients with sickle cell anemia, 14 with S-C disease, 3 with homozygoushemoglobin C disease, and 1 with C-thalassemia disease could be reviewed. The maternal complications of toxemia of pregnancy, cesarean section, postpartum endometritis, and antepartum hemorrhage were not significantly more frequent in these pa-
mia, hemorrhage, toxemia, cesarean section, and endometritis) were tabulated. These data were obtained for all patients found to have sickle cell trait, hemoglobin C trait, sickle cell anemia, S-C disease, or homozygous-hemoglobin C disease, for 492 randomly selected normal patients and for 104 randomly selected patients with normal hemoglobin and anemia (hematocrit less than 30 per cent). Additional women patients with abnormal hemoglobin syndromes were selected from the Hematology Clinic and their records examined for the outcome of any pregnancies. As a nonpregnant population control, similar blood studies were performed on Negro applicants for hospital employment. Statistical analyses were performed by means of the chi square test. Results
Incidence, Hemoglobin electrophoresis was performed on blood from 3,333 patients from the Prenatal Clinic and from 209 women applicants for employment. The results are found in Table I. Sickle cell trait was found in 6.4 per cent of the pregnant patients and 6.7 per cent of the control patients. The incidence of hemoglobin C: trait was 1.3 per cent and 3.3 per cent. respectively. Three patients with sickle cell anemia (0.09 per cent), 3 with S-C disease (0.09 per cent), and 2 with homozygoushemoglobin C disease (0.06 per cent) attended the Prenatal Clinic during the period of study. These disorders were not found among the nonpregnant control patients. OnIy the difference in incidence of hemoglobin C trait is significant (p = 0.05). In addition, 14 prenatal patients (0.4 per cent) had the electrophoretic pattern of sickle cell trait but negative sickle cell preparations. Table I. Abnormal
hemoglobin 1
Prenatal clinic Normal women$ Normal men$
AA 3,062 188 108
traits /
in pregnant
AS*
(
AC
206 14 5
*Hemoglobins named in order of decreasing concentration, Y‘AD” signifies electrophoretic pattern of sickle cell trait, ZNegroes reporting for pre-employment physical examinations
43
7 5
women
as compared
1 “AD”+
1
SS
/
to controls CC
1 Total
14
3
SC
3
2
3,333
0 0
0 1
0 0
0 0
e.g., AS is sickle cell trait, etc. but a negative sickle cell preparation. at District of Columbia General
/
Hospital.
209 119
Volume Number
90 7, part
Abnormal
1
tients than they were in those with normal hemoglobin. Patients with sickle cell anemia or with S-C disease had pulmonary complications and pyelonephritis more frequently than any other patients. Premature delivery was more common in patients with sickle cell anemia. Postpartum hemorrhage was more frequent in patients with S-C disease. Patients with sickle cell anemia lost 34.6 per cent of their babies; those with S-C disease lost 15.3 per cent. Both figures are greater than the fetal loss for all other groups, but only for patients with sickle cell anemia is the difference clearly statistically significant. Among the 878 patients whose charts were esamined 4 maternal deaths were recorded. After giving birth to a premature infant, 1 patient with sickle cell trait died of bilateral pneumonitis and congestive heart failure. One patient with sickle cell anemia died suddenly in what appeared to be a sickle cell crisis. Two patients with neither anemia nor an abnormal hemoglobin also died. One of these had aspiration and atelectasis after a hysterectomy for a ruptured uterus and the other had massive pulmonary collapse after a cesarean section. A number of patients with sickle cell anemia had miscellaneous complications. One had previously developed an anti-U antibody as a result of blood transfusion.“’ The 2 surviving infants from the 6 pregnancies had positive direct Coombs’ tests, but neither became jaundiced or anemic and neither required exchange transfusion. A second patient had a vitreous hemorrhage and a retinal tear’” on the first postpartum day and a third had a severe postpartum psychosis and a cerebral vascular accident, hut recovered. Still another developed initial symptoms of aseptic necrosis of both femoral heads during pregnancy. Four of the patients with sickle cell anemia had a profound drop of hematocrit near term. Two of these appeared to have superimposed megaloblastic anemia of pregnancy. Few of the patients with S-C disease OI llomozygous-hemoglobin C disease had other complications. Two with S-C and 1 with C-C had megaloblastic anemia of preg-
hemoglobins
and
Table II. Incidence less than
of anemia 30 per cent) during Not anemic /No. 1
893
(hematorrit pregnant!’
Anemic ____-. 1 9%
Total lN0. j
11.7 18.9 21 .o 7.2
J,Otz :I06 -1.:; 1 -i
*Hemoglobins named in order of decwaaing s.s.. AS is sickle cell trait, etc.
con~g.nrra-
AA AS* AC “AD” tion.
/ -.--
pregnancy
?,705 167 34 13
No. 357 39 9 1
nancy. A patient with S-C disease had erythrocytic hypoplasia from temporary chloramphenicol therapy for pyelonephritis. Nearly all of these patients had a greater degree of anemia than is normal chlring pregnancy, but not out of proportion ttr the hematocrit when not pregnant. Comment Truly representative figures for thr incidence of abnormal hemoglobin traits and diseases in the Negro population arc not available because all such data are subject to a bias introduced by the source of blood samples. In this context, the incidence of sickle cell trait is the same in the study group from the Prenatal Clinic as in the control employees, but the frequency of hemoglobin C trait is significantly higher in the study series. No explanation for the latter seems apparent. Although “hemoglobin I)‘. trait was not further characterized, its incitirnce (0.4 per cent’) approximates that reported in another large series of Negro patients.“” The data presented above show an increased frequency of anemia among patients with these abnormal hemoglobin traits. Iron deficiency was the usual cause, but thr*re seems to be no reason for this to occur rnor(‘ often in such patients. Similarlv there is no apparent cause for the observed inclcasecl frequency of premature labor in parirnts with the hemoglobin C trait. Pyelombphritis is more common in pre,qnant patients with sickle cell trait than in the other groups. Renal complications including pyelonel~hritis are also probably more frequent in nonpregnant patients with sickle cell trait. Dctspite
is presumptively
595 206 43 14 20 14 3 1
AA AS AC “AD” ss SC CC C-thalassemia
*Significant.
No.
IV. Percentage
Category
Table
$Range.
&3
3 1
named
age at time
tHemoglobins
*Mean
cc C-thalassemia
order
of
decreasing
10.2 9.7 12.3 19.0 34.6* 15.5 5.3 0.0
Fetal loss (%I
(l-9) 19 2
2,369 847 214 37 (;;I
Total pregnancies
2.4 3.0 5.6* 2.7 10.2* 1.7
Premature infants (%I
and
anemia).
e.g.,
AS
14.8 17.9 7.0 14.3 5.0 00 0.0 0.0
3.0 6.3* 0.0 0.0 10.0* 21.4* 33.3 0.0
3.9 5.8 9.3 0.0 5.0 14.3 00 0.0
~__
0 0
2
23 12 4 0 1
Cesarean section
reviewed
8.9 12.6 16.3 7.2 20.0 14.3 0.0 0.0
etc.
were
Cesarean section
Itrait,
0 0
2
53 26 7 1 4
postpartum fever
charts
Postpartum fever
cell
0
1
3
18 13 0 0 2
Pyelonephritis
whose
is sickle
Pyelonephritis
0 0
0
1
88 37 i
Toxemia
patients
complications
cell
0 0
1
57 25 12 1 5
Total premature infants
for
Toxemia
fetal
S (sickle
concentration,
(O-3) A
241 82 26 7 (“-i,
Total fetal loss
complications
hemoglobin
fetal
of maternal
homozygous
in
of study.
(l$;~W§ (17-53) 36.6 35.0
14
SC
Mean age*
and
24.5 25.0 26.6 21.1 25.0
No.
Maternal
595 206 43 14 19
Category
III.
AA ASt AC “AD” SSS
-
Table
2.4 1.9 2.3 0.0 1 o.o* 7.1 0.0 0.0
Anteparturn hemorrhage
Patients
0 0
1
0 2
1
14 4
Antepartum hemorrhage
4.5 2.4 2.3 7.2 5.0 21.4* 0.0 0.0
Postpartum hemorrhage
(7%)
0 0
3
27 5 1 1 1
Postpartum hemorrhage
Patients
(No.)
0.5 1.9 0.0 0.0 25.0* 7.1 0.0 0.0
Pneumonia
0 0
1
3 4 0 0 5
Pneumonia
5.7 8.7 18.6* 7.2 20.0* 14.3 0.0 0.0
Prematurity
1
34 18 8 1 4
Prematurity
0 0
0
1
2 1 0 0
Maternal death
0.0 0.0 0.0 0.0 20.0 14.3 0.0 ~- 0.0
Increased anemia
Painful crisis
0 0
0
0 0 0 0 2
crisis
ful
Pain-
0.0 0.0 0.0 0.0 10.6 0.0 0.0 0.0 . ~. ~...--~_
1 0
1
0 0 0 0 4
Excessively increased anemia
Abnormal
ELI Normal m AS I AC t!JI “A D” e ss USC
POST - PARTUM FEVER POST - PARTUM HEMORRHAGE
‘*
Hemoglobin
PNEUMONIA
TOXEMIA
PYELONEPHRI
TIS l
PREMATURE INFANTS
FETAL
.
LOSS
.
0
IO
20
30
40
PERCENT
Fig.
1. Frequency of complications during pregnancy in patients with normal hemoglobin, abnormal hemoglobin traits, and abnormal hemoglobin diseases. (The asterisk denotes significant difference.)
this increase of pyelonephritis among patients with the sickle cell trait there was no increase of toxemia of pregnancy. These complications have no statistically demonstrable effect on the outcome of the pregnancy, but a high incidence of induced abortions in the socioeconomic group studied could mask a small but significant increase in the frequency of fetal loss among any of these patients. These data are in agreement with those reported by Whalley and associates.” On the other hand, the presence of an abnormal hemoglobin syndrome in a gravid woman adversely affects fetal survival, maternal morbidity, and probably maternal death. Curti? suggested that patients with S-C disease were more seriously affected than those with sickle cell anemia, which is just the reverse of the situation outside of pregnancy. Although the results of hemoglobin electrophoresis were not included, earlier reports1 of serious complications during pregnancy in patients with sickle cell
hemoglobins
and
pregnancy
895
disease were consistent with this, as they often described splenomegaly and minimal symptomatology when not pregnant. These are both more characteristic of sickk* cell variants than of true sickle cell anemia. More recently, case reports which ha\,e included the results of hemoglobin eicctrophoresis” have also stressed the dangers of pregnancy in the patient with S-C disease. Anderson and co-workers5 have challenged this view, suggesting that the manifestations of S-C disease are as diverse during pregnancy as at other times. Some may be completely asymptomatic. Patients with more severe disease are more likely to have symptoms which would lead both to a hematological diagnosis and to greater difficulties during pregnancy. The data presented above clearly dtmonstrate a greater than usual incidence of rnaternal and fetal complications in patients with sickle cell anemia, particularly of pyelonephritis, premature delivery, fetal loss, pulmonary infarcts or pneumonia, and possibly antepartum hemorrhage. Patients with S-C disease had a greater frequency of pyelonephritis, postpartum hemorrhage, and perhaps pneumonitis. All of these disorders may be attributed to blockage of small blood vessels with sickled cells resulting in infarcts of the lung, kidney, or placenta. During the course of this study 2 patients each with sickle cell anemia and wilh s-f2 disease and 1 each with homozygoushemoglobin C disease and with sickle cell trait were found to have megaloblastic anemia of pregnancy. Since no special effort to unmask mild cases of this disorder was made: the incidence may be somewhat underestitnated. The folic acid requirement is greater for patients who have hemolysis and for those who are pregnant. Consequently, the Crequent occurrence of megaloblastic anemia caused by insufficient supply of folio: acid might be expected in patients with bot.11 h+ molytic disease and pregnancy. The number of patients with homozygoushemoglobin C disease or C-thalassemia disease in this series is quite small. Except for the megalohlastic anemia of precnanc)’
896
McCurdy
found in one of the former, no fetal or maternal complications could he attributed to these combinations. Can any practical recommendations be derived from this study? For patients with abnormal hemoglobin traits, good standard prenatal care should suffice with proper evaluation and therapy should complications arise. In particular, patients with sickle cell trait should be watched for the development of pyelonephritis, preferably with periodic urine cultures. On the other hand, patients with sickle cell anemia or S-C disease require more careful observation. The urine should also be cultured at intervals. The hematocrit or hemoglobin concentration should be determined frequently. Folic acid should be supplemented in amounts of 1 to 5 mg. daily, preferably apart from other medication. Most of these patients have little need for additional iron. Increasing anemia is an indication for further hematologic study including bone marrow examination. Blood transfusion may be necessary to treat hemorrhage or symptoms of anemia. The hazards of blood transfusion contraindicate its routine administration to these patients, but those who have painful crisis or evidence for local infarction either with the current pregnancy or in the past may benefit from “prophylactic” administration of 300 cc. of normal red cells every 2 to 4 months during
pregnancy.‘” Even with these precautions there is a greater than normal likelihood 01 a maternal complication or a fetal death in mothers with sickle cell anemia or sickle cell-hemoglobin C disease. Summary
and
conclusions
Hemoglobin from 3,333 prenatal patients was analyzed by electrophoresis for abnormal hemoglobins and the records sampled and examined for the outcome of pregnancy. An additional group of women patients from the Hematology Clinic who had been known to have abnormal hemoglobin syndromes was investigated for the pregnancy history. The charts were reviewed for 596 patients with normal hemoglobin, 206 with sickle cell trait, 43 with hemoglobin C trait, 11 with “hemoglobin D” trait, 20 with sickle celI anemia, 14 with S-C disease, 3 with homozygous-hemoglobin C disease, and 1 with C-thalassemia disease. Evidence is presented from the two groups of patients that only sickle cell anemia and S-C disease present a distinctly increased ha-ard to mother or fetus. In general, S-C disease is the more benign of the two. Recommendations for the management of pregnancy in patients with abnormal hemoglobins are presented. I gratefully acknowledge the srcrrtarial assistance of Grneva D. Curry in the preparation of this material.
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