Spontaneous abortion among insulin-dependent diabetic women

Spontaneous abortion among insulin-dependent diabetic women Menachem Miodovnik, M.D., Justin P. Lavin, M.D., Harvey C. Knowles, M.D., t Jane Holroyde, B.S., and Stanley J. Stys, M.D. Cincinnati, Ohio A prospective study was undertaken to evaluate the frequency of spontaneous abortion in clinically apparent pregnancies among insulin-dependent diabetic women evaluated prior to pregnancy. The study was done in 132 pregnancies occurring in 91 diabetic women. The spontaneous abortion rate was 30%; 70% of the pregnancies progressed beyond 20 weeks. The abortion rates for Classes S, C, D, and F through RT were 0%, 25%, 44%, and 22%, respectively. Initial serum levels of the ,a-subunit of human chorionic gonadotropin above 6000 mlU were usually associated with favorable outcome while levels below 6000 mlU were not predictive of outcome. Data from this study suggest that the risk of spontaneous abortion among insulin-dependent diabetic women may be substantially higher than for the general population. Higher abortion rates were generally associated with more advanced White classification of diabetes. Age at diagnosis was the only factor which showed a significant contribution to the risk of abortion. (AM J OasTET GVNECOL 1984;150:372-6.)

The frequency of spontaneous abortion among insulin-dependent diabetic women has been reported to be similar to that observed in the general population.v" Accurate information regarding spontaneous abortion rates is difficult to obtain as pointed out by several authors.v" Observation in prospective spontaneous abortion studies usually began at the time women first sought prenatal care. Such studies have many potential problems in accurately estimating rates of spontaneous abortion, for example, unreported or unproved early abortions, variable length of observation during a time when spontaneous abortions are frequent, and selfselection for early prenatal care by women who are symptomatic or at high risk of pregnancy loss. With these problems it is not surprising that reported spontaneous abortion rates have differed. Crude rates of 15% or less have been reported most commonly for studies of clinically apparent abortion.P" The use of radioimmunoassay for the detection of From the Division of Maternal-Fetal Medicine of the Department of Obstetrics and Gynecology and the Division of Metabolism of the Department of Internal Medicine, University of Cincinnati Medical Center. Supported in part byNational Institutes ofHealth Grant HD 11725, Diabetes in Pregnancy (Program Project Grant), United States Public Health Service Training in Perinatal Care and Research Grant MCH MCT 000174, and National Institutes of Health Clinical Research Center Grant RR 00068 (University of Cincinnati Medical Center). Receivedfor publication January 5, 1984; revised March 21,1984; acceptedMay 4,1984. Reprint requests: Menachem Miodovnik, M.D., Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, 231 Bethesda Ave. (ML 526), Cincinnati, OH 45267. tDeceased.

372

the {:l-subunit of human chorionic gonadotropin ({:lhCG) has provided a sensitive test for the diagnosis of early pregnancy. With this test it is now evident that abortion rates in the general population are higher than the frequencies quoted in the past.v !' The present study was undertaken to determine the rate of spontaneous abortion (fetal loss prior to 20 weeks' gestation) among insulin-dependent diabetic women who were evaluated prospectively prior to pregnancy. While determination of the serum {:l-hCG level was used routinely as a sensitive method for diagnosing early pregnancy, only pregnancies that were clinically apparent were included in the study. Material and methods

The study population consisted of 91 insulin-dependent diabetic women experiencing 132 pregnancies between June I, 1978, and January 31, 1983. These women were evaluated at the University of Cincinnati Medical Center in a special long-term study ofjuvenile diabetes, by one of the authors (H. C. K.), since the diagnosis of diabetes was made. All patients were seen regularly (twice yearly, at a minimum) and, as part of long-term overall management, had been instructed to report immediately any menstrual aberration or possibility of pregnancy. In many patients {:l-hCG levels were determined weekly after the cessation of contraception. Other women referred for care of pregnancy and diabetes were not included in the study since this might have introduced a selection bias. Pregnancy dating was based on menstrual dates and on physical and ultrasonic examination. The mean du-

Spontaneous abortion among diabetic women 373

Volume 150 Number 4

ration of pre gn ancy at d iagnosis was 7.7 ± 0.3 weeks. T he pregnancies were characterized as to whether th ey ended prio r to or contin ue d beyond 20 wee ks of gestation . Whe n avai lable, abortion and surgical specimens were se n t for path olo gic and genetic studies. All of th e abortio ns were sym pto matic as evidenced by blee ding and cramping. I n all cases curettage was pe rformed, and abortio n was proved by h isto path o logic examination of all specimens. I n three other patients eval uated by H . C. K., curettage was not performed, a nd the diagnosis of pregnancy was made as a res ult of high levels of se ru m ,B-hCG. These patients were follo wed u p u ntil se ru m ,B-hCG levels were unde tec table . These three abo rtio n s were called chemical abo rtio n s and were th ere fo r e not include d in the study sinc e the only evidence of pregna ncy was the elevated se rum ,B-hCG level in t he presence of mi ld spotting and me nstrual irregularity. Management of diabetes in most patients pr io r to pregnancy included once-daily injections of intermediate-acting insu lin and diet and exercise regu lation. Dia betes manage ment d uring pregnancy was simi lar to that used a t major diabetes centers. Once pregnancy was diagnosed, sp lit-dosage regi mens, inclu d in g both short- and intermediate-acting insulins along with d ietary and other ma nipulat ions, were instituted to im prove the control of d iabetes. Serum ,B-h CG levels were measured by a doubleantibody method . The reagents for the assay were provided by the Na tional Institute of Arthritis, Metabolism, and Digestive Diseases and the antibody u sed was highl y spec ific fo r the ,B-subunit. T he coe fficients of variation of the two inte rn al references representing the lower an d higher par ts of the standard curve were 7. 19% a nd 13.28% , respectivel y, between assays. The coefficients of var iation within assays were 8.67% an d 10.27%, respectively. Data analysis was performed on all 32 pregna ncies and on the first study pregnancy for each of the 9 1 women. T he Statistical Analysis System of SAS In stitute Inc. was used for data management. The spontaneous abortion rat es were compared with the use of X2 analysis and Fish er's exact test. ,B-hCG levels were studied with analysis of covariance. Lo gistic binary re gression was use d to assess the independent assoc iation of multiple risk factors wit h spontaneous abortion, controlling for the other factors. Va lues of p < 0.05 were considered significant. Results

Ninety-three (70%) of t he pregnancies contin ued be yond 20 weeks' ge sta tion, while 39 (30%) of the pre gna ncies term in ated in spontaneous abortion . The mean age of the study populatio n was 24.4 ± 0.4 years. The

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0

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6 3 5

7

8

9 10 11 12 13 14 15 16 17 19 Weeks Gestation

Fig. 1. Distribution of spontaneous abortions by weeks' gestation .

Table I. Pregnancy ou tcome versus prior abortion Pr egnanci es >20 weeks' gestation n

First pregnancy No prior loss One prior loss More than 1 loss Total

31 27 27 8 93

I

Spontaneous abortion

%

n

74 73 66 67

10 14 4

70

39

II

I

%

Total

26 27 34 33 30

42 37 41 12 132

mea n ages were 24.6 ± 0. 5 years for the patients whose pregnancies co ntin ue d beyond 20 weeks' ges tatio n a nd 23 .9 ± 0.6 years of age for the patients wit h spo nta neous abortion. Thirty-four (87 %) of the abortions occurred in the first trimester and five ( 13%) occurred in the second trimester. T he earliest abortion occurred in the fifth week of pregnancy and the la test at the nineteenth week of pregnancy. T he distribution is show n in Fig. I . T he study pregnancies were classified by the n umbe r of prior spontaneous abortio ns. The results are shown in Table I. There were no statistical differences in outcome when the pregnancies were grouped in this manner. T he ra tes of spontaneous abortion for Classes B, C, D and F through RT were 0% (0 of 8), 25% (16 of 63), 44 % ( 19 of 43), and 22% (4 of 18), respectively. The rate of spon ta neo us abortion for Class D wome n was significantly higher than the rate for Class C subjects. No other d ifferences were sig nificant presumably be-

374 Miodovnick et al. Am

Table II. Outcome of 132 pregnancies among

Table III. Pregnancy outcome by study year

the 91 women in the study

Pregnancies >20 weeks' gestation

No. of spontaneous abortions No. of study pregnancies

I

2 3 4 Total No. of women

0

53 9 0 0 62

I

1

8 8 2 2 20

I

2

4 4 8

I

3

October 15, 1984 J Obstet Gynecol

Total No. of women

61 21 7 2 91

cause of the small numbers of pregnancies in the other classes. When the initial study pregnancies for the 91 women were analyzed separately, the spontaneous abortion rate was found to be 27% (25 of 91). This spontaneous abortion rate and the differences among White classifications were essentially identical to those found when all 132 pregnancies were analyzed. The rates of spontaneous abortion for Classes B, C, D, and F through RT were 0% (0 of 6), 27% (9 of 43), 45% (14 of 31), and 18% (2 of 11), respectively. Forty-nine women reported 84 pregnancies prior to their enrollment in the present study. The spontaneous abortion rate among these 84 prior pregnancies was 31 %, which is equivalent to the rate for the study pregnancies. For 42 women in the study, the index pregnancy was their first; 26% (11 of 42) of these pregnancies aborted spontaneously prior to 20 weeks' gestation. The spontaneous abortion rates for primigravid women by White Classes B, C, D, and F through RT were 0% (0 of 0), 15% (3 of 20),47% (7 of 15), and 14% (1 of 7), respectively. When the outcome is evaluated by individual patient rather than by pregnancy, 78 women experienced 93 pregnancies of >20 weeks' gestation. Two pregnancies (2%) ended with stillbirth; one infant had multiple anomalies. Two other pregnancies (2%) ended with neonatal death, and both infants had multiple anomalies. Eighty-nine (96%) had successful outcomes. Twenty-nine women experienced 39 abortions, including 16 women who experienced both a pregnancy of >20 weeks' gestation and an abortion. Four women experienced one pregnancy >20 weeks' gestation and two spontaneous abortions (Table Il). For women experiencing two or more abortions, a chromosomal study was performed on products of conception at least once. All specimens showed a normal chromosomal complement. With the use of a logistic regression analysis the following possible predictors for abortion were considered in several combinations: number of previous abortions, age at diagnosis, current age, duration of

Study year

1978 1979 1980 1981 1982 1983 Total

n

8 20 26 21 16 2 93

I

%

73 71 70 68 70 100 70

Spontaneous abortion n

3 8

II

10 7 0 40

I

%

27 29 30 32 30 30

Total

II

28 37 31 23 2 132

diabetes, maternal weight, gravidity, parity, and presence of benign or proliferative retinopathy. Age at diagnosis of diabetes was the only factor which showed a significant contribution to the risk of abortion. When the spontaneous abortion rate was evaluated by study year (Table Ill), no significant difference was noted in the abortion rate throughout the study period. In 112 pregnancies for which serum ,a-hCG levels were available, analysis of covariance was used to compare differences between pregnancies continuing beyond 20 weeks and those terminating in spontaneous abortion. Adjustment for the week of gestation was made since serum ,a-hCG varies over time from conception. There was a statistically significant difference between the mean adjusted ,a-hCG level for the two groups. The adjusted mean for pregnancies which were carried >20 weeks was 2995 ± 313 mIU and that for the spontaneous abortion group was 1045 ± 372 mIU. Post hoc analysis was performed on the ,a-hCG levels to evaluate the proportion of pregnancies with initial values greater or less than 6000 mIU. Only 11% (2 of 19) pregnancies with an initial ,a-hCG level >6000 mIU had spontaneous abortions compared to 33% (31 of 93) of pregnancies with ,a-hCG levels <6000 mIU; however, this difference is not statistically significant. Comment

Pedersen" concluded that the spontaneous abortion rate among insulin-dependent diabetic women was approximately 10%, a rate similar to the recognized frequency of spontaneous abortion in the general population at that time. Gellis and Hsia" summarized the Joslin Clinic experience from 1948 to 1956, and reviewed seven other published reports. A total of 1707 pregnancies were analyzed; 209 (12.2%) ended in spontaneous abortion. The frequencies of spontaneous abortion in eight series were from 3.8% to 28.0% with an overall mean of 13.9% and a median of 12.1%.3 Kitzmiller et al." found that at the Joslin Clinic during 1975 through 1976, 21 of 168 pregnancies (12.5%) ended in spontaneous abortion. None of the previously mentioned studies of pregnant diabetic women has re-

Spontaneous abortion among diabetic women 375

Volume 150 Number 4

Table IV. Clinical spontaneous abortion rate in four study populations

No. of women in study No. of pregnancies Clinical apparent abortion Chemical abortion Successful outcome

Whittaker et al," (volunteer women)

Miller et at." (volunteer women)

Chartier et al." (infertile women)

91 92 II (13%) 7 74

197 152 14 (14%) 50 87

147 90 14 (20%) 19 57

vealed a frequency of spontaneous abortion as high as that detected in the present investigation. The true rate of spontaneous abortion in the normal pregnant population is still uncertain. Two large studies have reported a spontaneous abortion rate of approximately 10%.'2- 13 These studies may underestimate the true abortion rate because of the failure to recognize early abortions. Indeed, others have reported higher frequencies of spontaneous abortion.v " Whittaker et al." evaluated 91 normal volunteer women with serum measurements of hCG levels on day 25 of each cycle after cessation of contraception. Seven were believed to have chemical abortions, and 11 (13%) had clinical abortions. Miller et al." studied 197 normal women who wished to conceive; the diagnosis of pregnancy was based on the detection of l3-hCG in urine samples obtained at monthly intervals. Fifty subjects had chemical abortions (the sole evidence of pregnancy was an increased concentration of urinary l3-hCG) and 14 (14%) had clinical abortions. Chartier et al." reported on the risk of abortion in 147 women attending an infertility clinic. The plasma l3-hCG level was measured during the late luteal phase. There were 19 chemical and 14 (20%) clinical abortions. When the 30% rate of clinical abortions in the present insulindependent diabetic group is compared to the results in nondiabetic women (Table IV), the results suggest that insulin-dependent diabetic women may be at a higher risk. Still such a conclusion must be taken with caution since the numbers of subjects are small in all studies. One of the strengths of the present study is that the women are all active patients of one physician and were encouraged to contact him if they were interested in becoming pregnant or as soon as they suspected that they might be pregnant. This early contact probably resulted in less underestimation of clinically apparent spontaneous abortions than in most other studies. All losses were clinically confirmed, eliminating the patient's subjective judgment regarding possible early pregnancy loss. Furthermore, the spontaneous abortion rate in the present study was consistent over time, the yearly abortion rate varying from 27% to 32%. In the present study, the analysis of spontaneous abortion rate in regard to White classification showed a

Cincinnati (insulin-dependent diabetic women)

91 132 39 (30%)

Excluded from study

93

progressive increase III abortion rate from Class B through Class D; however, the abortion rate for Classes F and R was lower than that for Class D. This lower rate among Classes F and R was not significantly different; this reflects the small numbers but may also be a result of preselection, since many Class F and R patients may avoid pregnancy because of their substantial risk factors. This study included only a small number of Class B patients (8 of 132 pregnancies), none of whom experienced an abortion. Warburton and Fraser!" have reported that a patient with a previous spontaneous abortion has a greater probability of abortion in subsequent pregnancy. In the present study women who had one previous spontaneous abortion did not have a higher abortion rate (34%) in the index pregnancy than did diabetic women who had no previous spontaneous abortion (27%). However, the risk of abortion calculated by Warburton and Fraser for women with a previous abortion is substantially lower than the 30% abortion rate seen uniformly across this study's population. Nygren et al." have suggested that hCG levels can be used to predict the probability of spontaneous abortion among women with vaginal bleeding. The results of the present study indicate that initial l3-hCG levels have poor prognostic significance with regard to the probability of spontaneous abortion. Individual serum 13hCG levels >6000 mID were associated with favorable outcome while serum l3-hCG levels <6000 mID were not predictive of outcome. Since serum l3-hCG increases with time in the early weeks of gestation, an initial serum l3-hCG level of <6000 mID may reflect either very early gestation or an unhealthy pregnancy. Since some pregnancies will abort prior to the time when the l3-hCG level would normally exceed 6000 mID, values of >6000 mID indicate a more advanced gestation with a lesser probability of spontaneous abortion. In summary, a spontaneous abortion rate of 30% for 132 pregnancies occurring in 91 insulin-dependent diabetic women was documented. These women were all seen regularly by one physician prior to the onset of pregnancy. The data strongly suggest that the abortion rate among insulin-dependent diabetic women may be

Miodovnick et al.

substantially h igh er than that co mmon ly re ported fo r the general populat ion. The risk of spo ntaneo us abortion may be h igher for those with diagnosis of d iab et es at an earl ier ag e; thi s is co nsis te n t with the fin di n gs tha t Class D pat ients had a sign ifican tly hi gh er rate th an those with Class C. REFERENCES I. White P. Pre gn an cy co mp licating diabetes. In: J oslin EP, Roo t HF, Whi te P, Mar ble A, ed s. Treatmen t of diabetes mellitus, 9th ed . Ph ilad elphia : Lea & Febiger, 1952 :676. 2. Ped er sen J. The pregnant dia be tic and her newborn. 2nd ed . Baltimore: Williams & Wilkins, 1977 :198 . 3. Gellis SS, Hsia DY-Y. The infa n t of the diabetic mother. J Dis Ch ild 1959;97: 1. 4. Kitzmiller JL, Cloherty Jr, You nger MD, Tabatabaii A, Rothchild SB, Sosenko I , Ep stein MF, Singh S, Neff RK. Diabetic pregnancy and perin atal mo rb id ity. AM J OBSTET GYNECOL 1978 ;131 :560. 5. Taylor WF. On th e met hod ology of me asuring the probability of feta l death in a prospective stud y. Hum Bioi 1964;36:86. 6. Ja nse n RPS. Spo ntaneous abortion incidence in th e treat ment o f in fertility. AMJ O BSTET GYNECO L 1982; 143 : 45I. 7. Abramson FD. Spontaneous feta l de ath in man . Soc BioI 1973;20:375 .

O ctober 15, 1984 A m J Ob stet Gyne col

8. Whi tta ker PG, T aylor A, Lind T . Unsus pected pregnan cy loss in healthy wo men. Lan cet 1983; I : 1126. 9. Miller J F, William son E, Glue J, Go rdo n YB, Grudz inskas J G, Sykes A. Fetal loss afte r implantat ion : a prospe ctive stu d y. Lancet 1980 ;2:554. 10. Chartier M, Roger M, Barr at J, Michelo n B. Measureme nt of plasma human chorionic gon do tropin (hC G) and ,I3-hCG act ivities in the late lu teal pha se: evid ence of the occurrence of spo nta neous mens trual abortions in in fe rtile women. Fertil Ster iI1 979 ;3 1:134. I I. Poland BJ, Miller JR, J on es DC, T r imble BK. Reproductive cou nseli ng in pat ient s who have ha d a spo n ta neo us abo rt io n . AMJ OBSTET GYNECOL 1977 ; 127:6 85 . 12. T ietze C. Introductio n to the statistics of abortion . In : En gle E, ed. Pregnancy wastage. Spri ng field : Charles C Tho mas , 1953: 135. 13. Un ited Nations, Departm ent of Social Affairs: Fetal, infant and childhood mortality. I. The statistics. New York: United Nations, 1954. 14. Warburton D, Fraser FC. O n th e probability that a wom an who has a spontan eo us abo rt ion will abort in subseq ue n t pregnancies. Br J Obstet Gyna ecol 1961 ;68:78 4. 15. Nygre n KG, Johansson EDB, Wid e L. Evalua tion of the prognosis of threaten ed abortion fro m the peripheral plasm a levels of pro gesterone, estradiol, and human chorionic go na dotro pin. AM J OBSTET GYNECOL 1973; 116:91 6.

Immunoreactive gonadotropin-releasing hormone level in maternal circulation throughout pregnancy T, M. Siler-Khodr, Ph.D., G. S. Khodr, M.D., and G. Valenzuela, M.D. S an Anton io, Texas Immunoreactive gonadotropin-releasing hormone was quantitated in maternal blood. Circulating levels of gonadotropin-releasing hormone were found to be significantly higher during pregnancy than in nonpregnant cycling women . The highest concentrat ions of gonadotropin-releasing hormone immunoreactivity were observed in the first half of pregnancy with values at 20 to 42 weeks being significantly lower. A correlation with placental human chorionic gonadot ropin-releasing hormone concentrat ions and maternal circulat ing gonadotropin-releasing hormone levels was noted. Four pregnancies that resulted in premature labor and/or delivery had very low circulating maternal gonadotropin-releasing hormone concentrations, possibly reflecting placental dysfunction in these cases . (A M

J

OSSTET GYNECOL 1984;150:376-9.)

We have dem onstrated th e pre sence and synthesis of an imm u noreactive and bioreactive chorio n ic gon ad oFrom the Department ofObstetrics and Gynecology, The University of T exas H ealth Science Center at San Antonio. R eceived f or publication Novem ber 10, 1983; rev ised February 27, 1984; accepted May 23 , 1984. R eprint requests: T. M. Siler-Kh odr, Ph.D ., Department ofObstetrics and Gynecology, The Univer sity of Texas H ealth Science Center at San An tonio, 7703 Floyd Curl Drive, San Antonio, TX 78284. 376

tropin-releasin g hormon e in the human term placenta.': 2 This hu man chorionic gonadotropin-re leasing hormo ne has been localized predominantly in th e cyto tro p hoblast," and we have show n th at it is synthesized and secreted by human placen tal tissue in vitro." 4 We have also reported th at the placental content and co nce ntra tion vary with gestational age, 1 attaining maximal co ncen tr ation in early gestation and declining in mid- and late gestation. Since it is secre te d into culture