- Email: [email protected]
Fertility in Hemoglobin S-S and Hemoglobin S-C Disease*
Vol. 21, No.8, August 1970 Printed in U.S.A.
FERTILITY AND STERILITY
Copyright © 1970 by The Williams & Wilkins Co.
FERTILITY IN HEMOGLOBIN S-S AND HEMOGLOBIN S-C DISEASE* GAY D. DUNNE, B.A.,t
AND
ROSALINE R. JOSEPH, M.D.t
Department of Medicine, Temple University Health Sciences Center, Philadelphia, Pennsylvania
by an electrophoresis if positive results were obtained. The sickling test and electrophoresis were not standard procedures in the other reports cited. None of these studies was designed to yield conclusive data on fertility, because most were based on small numbers of patients selected because they were already pregnant. Because of the paucity of adequately controlled analysis of fertility in patients with sickle hemoglobinopathies, we undertook a retrospective study of our female patients with these conditions. A group of 46 Hgb S-S and S-C female patients was compared with a control group matched for selected characteristics influencing fertility. Patients with sickle cell trait (Hgb A-S) were excluded because of recently published evidence that fertility as measured by parity was not decreased in such women.14 Selection of the experimental group was accomplished by systematic review of Temple University Hospital's inpatient records for female patients with the diagnosis of Hgb S-S or Hgb S-C admitted to the hospital during the lO-year period, 1958-1968. The criteria for inclusion were (1) the patient must be of childbearing age (15-44 years), and (2) a confirmatory hemoglobin electrophoresis must be available. Twenty-five Hgb S-S and 21 Hgb S-C cases were accumulated in this manner. Information taken from each patient's records consisted of marital status, age, fertility history, and an estimate of socio* This study was supported by General Re- economic status. The fertility history insearch Support Grant 5 SOl FR05417-08. cluded number of pregnancies, number of t Junior medical student. live births, and any stillbirths or abortions t Associate professor of medicine. 630
The effect of sickle cell anemia or its variants on fertility has received scant attention in the medical literature. The course of pregnancy in women with sickle hemoglobinopathies has been frequently investigated with respect to complications, maternal and fetal mortality, and prematurity.5-8,l1 With few exceptions, however, these studies made but casual reference to fertility per se. When mentioned, the consensus was that fertility was decreased. 5, 10, 15 Curtis 5 reported that only 9 out of 15 of his hemoglobin S-S (Hgb S-S) patients had ever been pregnant, whereas 16 out of 18 of his hemoglobin S-C (Hgb S-C) patients had at least one pregnancy. Ricks 16 stated that the average number of pregnancies per sickle cell patient was 2.1-2.7, as opposed to a normal of 3.5. In a review of the literature up to 1956, 138 sickle cell patients had a total of 286 pregnancies, i.e., 2.07 pregnancies/patient. 8 Freeman and Ruth found a pregnancy rate of 2.28/Hgb S-S patient and 2.65/ Hgb S-C patient.9 Anderson et aI. found in a sample of 17 Hgb S-S, S-C, and S-thaI. pregnant women in Jamaica that the incidence of these hemoglobinopathies in their prenatal clinic population approximated the incidence in the general population. 1 These results, which contrast with those mentioned above, may have been due to the routine performance in this particular study of a sickling test on all pregnant females with a hemoglobin of less than 10.0 gm., followed
August 1970
631
HEMOGLOBIN S-S AND S-C DISEASE
reported. Socioeconomic status was classified as DPA, if the patient received aid from the Department of Public Assistance, or non-DPA. If such information was unavailable, but no member of the family was employed, the patient was placed in the DPA category. This experimental group was then subclassified into age groups of 5-year intervals, single or ever married groups, and DPA or non-DPA. This subclassification matrix was then used to match a control group on a one to one basis, allowing only the fertility history to vary. Forty-six Negro controls, admitted because of trauma, were selected from the inpatient records at Temple University Hospital over the same lO-year-period. These cases were then screened for a positive sickling test and were matched for the characteristics used to classify the experimental group members. RESULTS
Separate analyses of the single and married sickle and control patients were done with respect to fertility. Fertility was expressed in terms of live births because of the unreliability of the information on abortions and stillbirths gleaned from the records. Each marital group was compared with respect to the number of women with no live births and also for the mean number of live births. Similar analyses were performed on single Hgb S-S patients vs. Hgb S-C single patients, as well as for the married patients of both hemoglobin types. Significance of the difference between the groups was tested on the basis of the normal probability distribution for Tables 1 and 3 and the t distribution for Tables 2 and 4. Values appearing in the tables for the standard error of the difference between percentages or means were derived according to Schor's definition of the term, i.e., the square root of the sum of the squared errors for the individual groupsP
TABLE 1. Women with No Live Births by Marital Status Single
Married
Proportion %
Proportion %
Patients 13/21 62 Controls 9/21 43 Standard error of the dif- 15.10% ference between percentages
1/25 4 0/25 0 3.92%
TABLE 2. Live Births by Marital Status Single
Married
Patients Controls
Patients Controls
Number of women 21 21 Number of live births 10 16 Mean live births 0.48 0.76 Standard deviation 0.634 0.811 Standard error of the 0.225 difference between means
25
25 80 3.08 3.20 1.876 2.208 0.579
77
Table 1 lists the proportion and corresponding per cent of single and married women in patient and control groups who never had a live birth. The observed difference between percentages of single patients vs. controls was 19%, which was not found to be significant. The observed difference of 4% between married patients and controls was likewise not significant. It is of interest to note that the only married sickle cell patient who had no live births did have a pregnancy that terminated in a stillbirth. Thus she was not technically infertile. Table 2 summarizes the analyses of the mean number of live births in the two groups for single and married women separately. For the single women standard deviations were 0.634 and 0.811 for patients and controls respectively. The observed difference of 0.28 between mean live births of 0.48 and 0.76 did not prove to be significant. The standard deviation for the married patients was 2.208, for married controls 1.876. The observed difference of 0.12 live birth was not significant. Table 3 deals with the proportion and
632
DUNNE AND JOSEPH
TABLE 3. Patients with No Live Births by Hgb S-S or HgB S-C Single
Married
Proportion %
Proportion %
Hgb S-S 9/15 60 Hgb S-C 4/6 67 Standard error of the 23.0% difference between percentages
1/10 10 0/15 0 9.49%
TABLE 4. Live Births-Hb S-S vs. Hb S-C Single Hb S-S
Hb S-C
Number of women 15 Number of live births 8 Mean live births 0.53 0.33 Standard deviation 0.718 0.719 Standard error of the 0.267 difference between
Married Hb
s-s
Hb
10 17 1. 7 1.27
s-c
15 60 4.0 2.22 0.70
means
per cent of Hgb: S-S women having no live births compared with Hgb S-C women, expressed separately for the single and married groups. The observed difference between percentages for the single women was 7%, which was not significant. Similarly, the observed difference of 10% between married Hgb S-S and Hgb S-C women was not found to be significant. Table 4 represents results of the analyses performed to compare mean live births for the two hemoglobin types. For the single patients, standard deviations were 0.718 and 0.719 for Hgb S-S and S-C respectively. The observed difference between means of 0.20 live birth was not significant. Married Hgb S-S patients had a standard deviation of 1.27; that of married Hgb S-C patients was 2.22. In this case, the observed difference of 2.3 live births between the means was significant to a p of <0.01. DISCUSSION
An effective analysis of fertility is complicated by the mUltiplicity of factors influencing it. In this study race, sex, age, marital status, and socioeconomic status were held constant in the comparison of
Vol. 21
sicklers vs. normals, but such factors as fertility of sexual partners, oral contraceptive history, or emotional disturbances which might adversely affect fertility were not evaluated. The definition of fertility is another perplexing problem. The demographic equation for the general fertility rate for a given year is number of live births/WOO females of childbearing age. 3 Obstetrics, however, views fertility as the ability to conceive. 19 Because some patients may have been reticent to disclose their abortions, or the examining physician's questioning technic may have lacked thoroughness, live births were used as a fertility index in this study. Segregation of single and married women was maintained throughout all of the analyses. It was felt that separate evaluation was necessary because the single women might tend to conceal not only their abortions, but more important for our data, their live births. This would be particularly true for children born to an adolescent mother, for these offspring are often raised by the grandmother. The ratio of Hgb S-S cases to Hgb S-C cases found in this study (25: 21) varies from frequencies found in other studies. Wintrobe cites the incidence of Hgb S-S disease among the Negro population as 0.3-1.3%, but merely states that the occurrence of Hgb S-C is much smaller.20 If we accept that as a general guideline, Curtis' sample of 15 Hgb S-S: 18 S-C females was grossly out of proportion. 5 McCurdy found an incidence of 0.09% for both Hgb S-S and Hgb S-C in a population of pregnant women taken from a prenatal clinic. 13 It is difficult to compare results obtained in this study with other reported figures, because most other studies are in terms of number of pregnancies per mother, while our data included women never experiencing pregnancy. If the 20 reported abortions and stillbirths for all of our Hgb S-S and S-C women were added to the 87 live births, our mean number of 2.3 pregnancies is
August 1970
633
HEMOGLOBIN S-S AND S-C DISEASE
quite close to Eisenstein's reported figure of 2.07 for a group of 138 sickle cell patients. 8 His sample undoubtedly included Hgb S-C and S-thal. as well as Hgb S-S, because diagnosis was not based on electrophoresis. This figure also falls within the range of 2.1-2.7 derived by Ricks. 16 It has been postulated that, although fertility may be generally decreased in the Hgb S-S population, the number of pregnancies per female who has conceived is normal,5 This cannot be verified for lack of an accepted standard figure for the Negro female. Curtis believed his figure of 2.3 pregnancies/Hgb S-S patient who had conceived to be relatively norma1. 5 On the other hand, 3.5 was considered a normal value in Ricks' study.16 According to our data, it is clear that, taken as a combined group, the fertility of our Hgb S-S and S-C women is comparable to that of normal, healthy Negro females. However, the decreased number of live births in married Hgb S-S as compared to married Hgb S-C patients does cast doubt on whether the two hemoglobin types have equal fertility. The similarity of the results for the single Hgb S-S vs. Hgb S-C patients provides evidence against this statement. An investigation based on a larger sample size would help to clarify this point. The etiology of the infertility supposedly associated with sickle cell anemia has typically been attributed to the presence of anemia or chronic illness. 2, 5, 15, 18 Sodeman stated that anemia per se is a familiar cause of sterility and abortion, ensuing from depressed spermatogenesis and oogenesis. The limited exposure of chronically ill patients to the possibility of pregnancy has also been cited as a cause of infertility.8,15 These factors did not appear to influence the fertility of our patients, although no attempt was made to evaluate ovarian function or sexual exposure. Finally, reduced longevity has been offered as an explanation for reduced fer-
tility in patients with sickle cell hemoglobinopathies. 5, 7, 8, 15 Most statements on longevity in this group are based on statistics concluding that few such patients live to the third decade and none survives past the age of 40. 6• 12,20 There is increasing evidence that the age distribution of Hgb S-S is changing,4 to which we can contribute the results of our review of records. In Eisenstein's population of 138 women, only 12 out of 138 mothers or 9% were over the age of 30. 8 In comparison, 16 out of 46 or 35% of our sample of Hgb S-S plus Hgb S-C patients were older than 30 years. We feel that diminished life span is no longer acceptable as an explanation for diminished fertility. The results of this analysis indicate that our sample of females with sickle hemoglobinopathies has normal fertility according to our fertility index of live births. A study based on a larger sample, composed of patients and controls from several institutions, in which fertility is measured in a single standard is certainly warranted before any general conclusions regarding fertility in sickle cell states can be made. SUMMARY
Using live births as a measure, the fertility of 46 female patients diagnosed as Hgb S-S or Hgb S-C was investigated and compared with 46 controls matched for selected characteristics influencing fertility. Analyses of patients vs. controls were performed separately for single and married women. No significant difference in number of women having no live births or in mean live births was observed for either marital group. A comparison of single Hgb S-S patients with single Hgb S-C patients revealed no significant difference in mean live births or in number of women with no live births; likewise, the number of married women with no live births was very similar for the two hemoglobin types. However, the observed difference between mean live
DUNNE AND JOSEPH
634
births for married Hgb S-S and Hgb S-C women was significant to p < 0.01. It was concluded that fertility in our population of women with sickle hemoglobinopathies was normal, but further studies were suggested to substantiate this statement. Acknowledgments. The authors wish to thank Shirley S. Braverman, Ph.D., of the Department of Biostatistics at the Temple University School of Medicine for her advice concerning the statistical analyses of our data and W. S. M. Arrata, M.D., and Leslie Iffy, M.D., of the Department of Obstetrics and Gynecology at Temple University Hospital for their helpful evaluations of this study. REFERENCES 1. ANDERSON, M., WENT, L. N., MAcIvER, J. C., AND DIXON, H. G. Sickle cell disease in pregnancy. Lancet 2:516,1960. 2. APTHORP, G. H., MEASDAY, B., AND LEHMANN, H. Pregnancy in sickle cell anemia. Lancet 1 :1344, 1963. 3. BOGUE, D. J. Principles oj Demography. Wiley, New York, 1969. 4. CHARACHE, S., AND RICHARDSON, 'S. N. Prolonged survival of a patient with sickle cell anemia. Arch Intern Med (Chicago) 113:844, 1964. 5. CURTIS, E. M. Pregnancy in sickle cell anemia, sickle cell-hemoglobin C disease, and variants thereof. Amer J Obstet Gynec 77: 1312, 1959. 6. DUCKETT, H. C., AND DAVIS, C. D. Sickle
Vol. 21
cell anemia complicated by pregnancy. Amer J Obstet Gynec 66 :409, 1963. 7. EASTMAN, AND HELLMAN, L. M. Obstetrics (ed. 13). Appleton-Century-Crofts, New York, 1966. 8. EISENSTEIN, M. 1., POSNER, A. C., AND FRIEDMAN, S. Sickle cell anemia in pregnancy. Amer J Obstet Gynec 72 :622, 1956. 9. FREEMAN, M. G., AND RUTH, G. J. SS disease, SC disease, and CC disease-obstetric considerations and treatment. Clin Obstet Gynec 12 :134, March, 1969. 10. KOBAK, A. J., STEIN, P. J., AND DARO, A. F. Sickle cell anemia in pregnancy. Amer J Obstet Gynec 41 :811, 1941. 11. LAROS, R. K. Sickle cell-hemoglobin C disease and pregnancy. Penn Med 70:73,1967. 12. LINMAN, J. W. Principles oj Hematology. Macmillan, New York, 1966. 13. MCCURDY, P. R. Abnormal hemoglobins and pregnancy. Amer J Obstet Gynec 90:891, 1964. 14. PEARSON, H. A., AND VAUGHAN, E. O. Lack of influence of sickle cell trait on fertility and successful pregnancy. Amer J Obstet Gynec 105 :203, 1969. 15. PUCKETT, T. G. Sickle cell hemoglobinopathies associated with pregnancy. J Okla Med Ass 59:15,1966. 16. RICKS, P. Sickle cell anemia in pregnancy. Obstet Gynec 17 :583, 1961. 17. SCHOR, S. S. Fundamentals oj Biostatistics. Putnam, New York, 1968. 18. SODEMAN, W. A. Anemia in pregnancy. Amer J Med Sci 200:117,1940. 19. WILLSON, J. R., BEECHAM, C. T., AND CARRINGTON, E. R. Obstetrics and Gynecology (ed. 3). Mosby, St. Louis, 1966. 20. WINTROBE, M. M. Clinical Hematology (ed. 6). Lea & Febiger, Philadelphia, 1967.
FERTILITY AND STERILITY
Copyright © 1970 by The Williams & Wilkins Co.
FERTILITY IN HEMOGLOBIN S-S AND HEMOGLOBIN S-C DISEASE* GAY D. DUNNE, B.A.,t
AND
ROSALINE R. JOSEPH, M.D.t
Department of Medicine, Temple University Health Sciences Center, Philadelphia, Pennsylvania
by an electrophoresis if positive results were obtained. The sickling test and electrophoresis were not standard procedures in the other reports cited. None of these studies was designed to yield conclusive data on fertility, because most were based on small numbers of patients selected because they were already pregnant. Because of the paucity of adequately controlled analysis of fertility in patients with sickle hemoglobinopathies, we undertook a retrospective study of our female patients with these conditions. A group of 46 Hgb S-S and S-C female patients was compared with a control group matched for selected characteristics influencing fertility. Patients with sickle cell trait (Hgb A-S) were excluded because of recently published evidence that fertility as measured by parity was not decreased in such women.14 Selection of the experimental group was accomplished by systematic review of Temple University Hospital's inpatient records for female patients with the diagnosis of Hgb S-S or Hgb S-C admitted to the hospital during the lO-year period, 1958-1968. The criteria for inclusion were (1) the patient must be of childbearing age (15-44 years), and (2) a confirmatory hemoglobin electrophoresis must be available. Twenty-five Hgb S-S and 21 Hgb S-C cases were accumulated in this manner. Information taken from each patient's records consisted of marital status, age, fertility history, and an estimate of socio* This study was supported by General Re- economic status. The fertility history insearch Support Grant 5 SOl FR05417-08. cluded number of pregnancies, number of t Junior medical student. live births, and any stillbirths or abortions t Associate professor of medicine. 630
The effect of sickle cell anemia or its variants on fertility has received scant attention in the medical literature. The course of pregnancy in women with sickle hemoglobinopathies has been frequently investigated with respect to complications, maternal and fetal mortality, and prematurity.5-8,l1 With few exceptions, however, these studies made but casual reference to fertility per se. When mentioned, the consensus was that fertility was decreased. 5, 10, 15 Curtis 5 reported that only 9 out of 15 of his hemoglobin S-S (Hgb S-S) patients had ever been pregnant, whereas 16 out of 18 of his hemoglobin S-C (Hgb S-C) patients had at least one pregnancy. Ricks 16 stated that the average number of pregnancies per sickle cell patient was 2.1-2.7, as opposed to a normal of 3.5. In a review of the literature up to 1956, 138 sickle cell patients had a total of 286 pregnancies, i.e., 2.07 pregnancies/patient. 8 Freeman and Ruth found a pregnancy rate of 2.28/Hgb S-S patient and 2.65/ Hgb S-C patient.9 Anderson et aI. found in a sample of 17 Hgb S-S, S-C, and S-thaI. pregnant women in Jamaica that the incidence of these hemoglobinopathies in their prenatal clinic population approximated the incidence in the general population. 1 These results, which contrast with those mentioned above, may have been due to the routine performance in this particular study of a sickling test on all pregnant females with a hemoglobin of less than 10.0 gm., followed
August 1970
631
HEMOGLOBIN S-S AND S-C DISEASE
reported. Socioeconomic status was classified as DPA, if the patient received aid from the Department of Public Assistance, or non-DPA. If such information was unavailable, but no member of the family was employed, the patient was placed in the DPA category. This experimental group was then subclassified into age groups of 5-year intervals, single or ever married groups, and DPA or non-DPA. This subclassification matrix was then used to match a control group on a one to one basis, allowing only the fertility history to vary. Forty-six Negro controls, admitted because of trauma, were selected from the inpatient records at Temple University Hospital over the same lO-year-period. These cases were then screened for a positive sickling test and were matched for the characteristics used to classify the experimental group members. RESULTS
Separate analyses of the single and married sickle and control patients were done with respect to fertility. Fertility was expressed in terms of live births because of the unreliability of the information on abortions and stillbirths gleaned from the records. Each marital group was compared with respect to the number of women with no live births and also for the mean number of live births. Similar analyses were performed on single Hgb S-S patients vs. Hgb S-C single patients, as well as for the married patients of both hemoglobin types. Significance of the difference between the groups was tested on the basis of the normal probability distribution for Tables 1 and 3 and the t distribution for Tables 2 and 4. Values appearing in the tables for the standard error of the difference between percentages or means were derived according to Schor's definition of the term, i.e., the square root of the sum of the squared errors for the individual groupsP
TABLE 1. Women with No Live Births by Marital Status Single
Married
Proportion %
Proportion %
Patients 13/21 62 Controls 9/21 43 Standard error of the dif- 15.10% ference between percentages
1/25 4 0/25 0 3.92%
TABLE 2. Live Births by Marital Status Single
Married
Patients Controls
Patients Controls
Number of women 21 21 Number of live births 10 16 Mean live births 0.48 0.76 Standard deviation 0.634 0.811 Standard error of the 0.225 difference between means
25
25 80 3.08 3.20 1.876 2.208 0.579
77
Table 1 lists the proportion and corresponding per cent of single and married women in patient and control groups who never had a live birth. The observed difference between percentages of single patients vs. controls was 19%, which was not found to be significant. The observed difference of 4% between married patients and controls was likewise not significant. It is of interest to note that the only married sickle cell patient who had no live births did have a pregnancy that terminated in a stillbirth. Thus she was not technically infertile. Table 2 summarizes the analyses of the mean number of live births in the two groups for single and married women separately. For the single women standard deviations were 0.634 and 0.811 for patients and controls respectively. The observed difference of 0.28 between mean live births of 0.48 and 0.76 did not prove to be significant. The standard deviation for the married patients was 2.208, for married controls 1.876. The observed difference of 0.12 live birth was not significant. Table 3 deals with the proportion and
632
DUNNE AND JOSEPH
TABLE 3. Patients with No Live Births by Hgb S-S or HgB S-C Single
Married
Proportion %
Proportion %
Hgb S-S 9/15 60 Hgb S-C 4/6 67 Standard error of the 23.0% difference between percentages
1/10 10 0/15 0 9.49%
TABLE 4. Live Births-Hb S-S vs. Hb S-C Single Hb S-S
Hb S-C
Number of women 15 Number of live births 8 Mean live births 0.53 0.33 Standard deviation 0.718 0.719 Standard error of the 0.267 difference between
Married Hb
s-s
Hb
10 17 1. 7 1.27
s-c
15 60 4.0 2.22 0.70
means
per cent of Hgb: S-S women having no live births compared with Hgb S-C women, expressed separately for the single and married groups. The observed difference between percentages for the single women was 7%, which was not significant. Similarly, the observed difference of 10% between married Hgb S-S and Hgb S-C women was not found to be significant. Table 4 represents results of the analyses performed to compare mean live births for the two hemoglobin types. For the single patients, standard deviations were 0.718 and 0.719 for Hgb S-S and S-C respectively. The observed difference between means of 0.20 live birth was not significant. Married Hgb S-S patients had a standard deviation of 1.27; that of married Hgb S-C patients was 2.22. In this case, the observed difference of 2.3 live births between the means was significant to a p of <0.01. DISCUSSION
An effective analysis of fertility is complicated by the mUltiplicity of factors influencing it. In this study race, sex, age, marital status, and socioeconomic status were held constant in the comparison of
Vol. 21
sicklers vs. normals, but such factors as fertility of sexual partners, oral contraceptive history, or emotional disturbances which might adversely affect fertility were not evaluated. The definition of fertility is another perplexing problem. The demographic equation for the general fertility rate for a given year is number of live births/WOO females of childbearing age. 3 Obstetrics, however, views fertility as the ability to conceive. 19 Because some patients may have been reticent to disclose their abortions, or the examining physician's questioning technic may have lacked thoroughness, live births were used as a fertility index in this study. Segregation of single and married women was maintained throughout all of the analyses. It was felt that separate evaluation was necessary because the single women might tend to conceal not only their abortions, but more important for our data, their live births. This would be particularly true for children born to an adolescent mother, for these offspring are often raised by the grandmother. The ratio of Hgb S-S cases to Hgb S-C cases found in this study (25: 21) varies from frequencies found in other studies. Wintrobe cites the incidence of Hgb S-S disease among the Negro population as 0.3-1.3%, but merely states that the occurrence of Hgb S-C is much smaller.20 If we accept that as a general guideline, Curtis' sample of 15 Hgb S-S: 18 S-C females was grossly out of proportion. 5 McCurdy found an incidence of 0.09% for both Hgb S-S and Hgb S-C in a population of pregnant women taken from a prenatal clinic. 13 It is difficult to compare results obtained in this study with other reported figures, because most other studies are in terms of number of pregnancies per mother, while our data included women never experiencing pregnancy. If the 20 reported abortions and stillbirths for all of our Hgb S-S and S-C women were added to the 87 live births, our mean number of 2.3 pregnancies is
August 1970
633
HEMOGLOBIN S-S AND S-C DISEASE
quite close to Eisenstein's reported figure of 2.07 for a group of 138 sickle cell patients. 8 His sample undoubtedly included Hgb S-C and S-thal. as well as Hgb S-S, because diagnosis was not based on electrophoresis. This figure also falls within the range of 2.1-2.7 derived by Ricks. 16 It has been postulated that, although fertility may be generally decreased in the Hgb S-S population, the number of pregnancies per female who has conceived is normal,5 This cannot be verified for lack of an accepted standard figure for the Negro female. Curtis believed his figure of 2.3 pregnancies/Hgb S-S patient who had conceived to be relatively norma1. 5 On the other hand, 3.5 was considered a normal value in Ricks' study.16 According to our data, it is clear that, taken as a combined group, the fertility of our Hgb S-S and S-C women is comparable to that of normal, healthy Negro females. However, the decreased number of live births in married Hgb S-S as compared to married Hgb S-C patients does cast doubt on whether the two hemoglobin types have equal fertility. The similarity of the results for the single Hgb S-S vs. Hgb S-C patients provides evidence against this statement. An investigation based on a larger sample size would help to clarify this point. The etiology of the infertility supposedly associated with sickle cell anemia has typically been attributed to the presence of anemia or chronic illness. 2, 5, 15, 18 Sodeman stated that anemia per se is a familiar cause of sterility and abortion, ensuing from depressed spermatogenesis and oogenesis. The limited exposure of chronically ill patients to the possibility of pregnancy has also been cited as a cause of infertility.8,15 These factors did not appear to influence the fertility of our patients, although no attempt was made to evaluate ovarian function or sexual exposure. Finally, reduced longevity has been offered as an explanation for reduced fer-
tility in patients with sickle cell hemoglobinopathies. 5, 7, 8, 15 Most statements on longevity in this group are based on statistics concluding that few such patients live to the third decade and none survives past the age of 40. 6• 12,20 There is increasing evidence that the age distribution of Hgb S-S is changing,4 to which we can contribute the results of our review of records. In Eisenstein's population of 138 women, only 12 out of 138 mothers or 9% were over the age of 30. 8 In comparison, 16 out of 46 or 35% of our sample of Hgb S-S plus Hgb S-C patients were older than 30 years. We feel that diminished life span is no longer acceptable as an explanation for diminished fertility. The results of this analysis indicate that our sample of females with sickle hemoglobinopathies has normal fertility according to our fertility index of live births. A study based on a larger sample, composed of patients and controls from several institutions, in which fertility is measured in a single standard is certainly warranted before any general conclusions regarding fertility in sickle cell states can be made. SUMMARY
Using live births as a measure, the fertility of 46 female patients diagnosed as Hgb S-S or Hgb S-C was investigated and compared with 46 controls matched for selected characteristics influencing fertility. Analyses of patients vs. controls were performed separately for single and married women. No significant difference in number of women having no live births or in mean live births was observed for either marital group. A comparison of single Hgb S-S patients with single Hgb S-C patients revealed no significant difference in mean live births or in number of women with no live births; likewise, the number of married women with no live births was very similar for the two hemoglobin types. However, the observed difference between mean live
DUNNE AND JOSEPH
634
births for married Hgb S-S and Hgb S-C women was significant to p < 0.01. It was concluded that fertility in our population of women with sickle hemoglobinopathies was normal, but further studies were suggested to substantiate this statement. Acknowledgments. The authors wish to thank Shirley S. Braverman, Ph.D., of the Department of Biostatistics at the Temple University School of Medicine for her advice concerning the statistical analyses of our data and W. S. M. Arrata, M.D., and Leslie Iffy, M.D., of the Department of Obstetrics and Gynecology at Temple University Hospital for their helpful evaluations of this study. REFERENCES 1. ANDERSON, M., WENT, L. N., MAcIvER, J. C., AND DIXON, H. G. Sickle cell disease in pregnancy. Lancet 2:516,1960. 2. APTHORP, G. H., MEASDAY, B., AND LEHMANN, H. Pregnancy in sickle cell anemia. Lancet 1 :1344, 1963. 3. BOGUE, D. J. Principles oj Demography. Wiley, New York, 1969. 4. CHARACHE, S., AND RICHARDSON, 'S. N. Prolonged survival of a patient with sickle cell anemia. Arch Intern Med (Chicago) 113:844, 1964. 5. CURTIS, E. M. Pregnancy in sickle cell anemia, sickle cell-hemoglobin C disease, and variants thereof. Amer J Obstet Gynec 77: 1312, 1959. 6. DUCKETT, H. C., AND DAVIS, C. D. Sickle
Vol. 21
cell anemia complicated by pregnancy. Amer J Obstet Gynec 66 :409, 1963. 7. EASTMAN, AND HELLMAN, L. M. Obstetrics (ed. 13). Appleton-Century-Crofts, New York, 1966. 8. EISENSTEIN, M. 1., POSNER, A. C., AND FRIEDMAN, S. Sickle cell anemia in pregnancy. Amer J Obstet Gynec 72 :622, 1956. 9. FREEMAN, M. G., AND RUTH, G. J. SS disease, SC disease, and CC disease-obstetric considerations and treatment. Clin Obstet Gynec 12 :134, March, 1969. 10. KOBAK, A. J., STEIN, P. J., AND DARO, A. F. Sickle cell anemia in pregnancy. Amer J Obstet Gynec 41 :811, 1941. 11. LAROS, R. K. Sickle cell-hemoglobin C disease and pregnancy. Penn Med 70:73,1967. 12. LINMAN, J. W. Principles oj Hematology. Macmillan, New York, 1966. 13. MCCURDY, P. R. Abnormal hemoglobins and pregnancy. Amer J Obstet Gynec 90:891, 1964. 14. PEARSON, H. A., AND VAUGHAN, E. O. Lack of influence of sickle cell trait on fertility and successful pregnancy. Amer J Obstet Gynec 105 :203, 1969. 15. PUCKETT, T. G. Sickle cell hemoglobinopathies associated with pregnancy. J Okla Med Ass 59:15,1966. 16. RICKS, P. Sickle cell anemia in pregnancy. Obstet Gynec 17 :583, 1961. 17. SCHOR, S. S. Fundamentals oj Biostatistics. Putnam, New York, 1968. 18. SODEMAN, W. A. Anemia in pregnancy. Amer J Med Sci 200:117,1940. 19. WILLSON, J. R., BEECHAM, C. T., AND CARRINGTON, E. R. Obstetrics and Gynecology (ed. 3). Mosby, St. Louis, 1966. 20. WINTROBE, M. M. Clinical Hematology (ed. 6). Lea & Febiger, Philadelphia, 1967.