Triphasic oral contraception: Metabolic effects in normal women and those with previous gestational diabetes

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teilung von Kardiotokogrammen. Geburtshilfe Frauenhcilkd 1981 ;41 :45. 4. Lotering FK, Wallenburg HC, Schouten H.J. lnterobserver and intraobserver variation in the assessment of antepartum cardiotocograms. AM .J OBSTET GY:\ECOL 1982; 144:70 I. 5. Flynn A, Kelly .J, Matthews K, et al. Predictive value of, and observer variability in, several ways of reporting antepartum cardiotocograms. Br .J Obstet Gynaecol 1982; 89:434. 6. Bobitt.JR. Abnormal anteparturn fetal heart rate tracings, failure to intervene, and fetal death: review of five cases reveals potential pitfalls of antepartum fetal monitoring. A~I .J 0BSTF.T GY:\ECOL 1979; 133:415.

7. Fleis .JL. Measuring nominal scale agreement among many observers. Psycho! Bull 1971 ;76:378. 8. Peck TM. Physician's subjectivity in evaluating oxytocin challenge tests. Obstet Gynecol 1980;56:13. 9. Cohen AB, Klapholz H, Thompson MS. Electronic fetal monitoring in clinical practice: a survey of obstetric opinion. Med Decis ~aking 1982;2:79. 10. Beaulieu ~D, Fabia.J, LeDuc B, et al. The reproducibility of intra part um cardiotocogram assessments. Can Med Assoc .J 1982;127:214. 11. Helfand M, Marton K, Uelancl K. Factors involved in the interpretation of fetal monitoring tracings. AM J OllSTET GY:\ECOL 1985;151:737.

Triphasic oral contraception: Metabolic effects in normal women and those with previous gestational diabetes Sven O. Skouby, M.D., Claus Kiihl, M.D., Lars M~dsted-Pedersen, M.D., Karsten Petersen, M.D., and Merete Sanvig Christensen, M.D.

Copenha[ien, Klampenhorg, and Hnlev, Denmark The effect of a low-dose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel) on glucose tolerance, plasma insulin and glucagon responses to glucose, fasting plasma cortisol, triglycerides, free fatty acids, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol was investigated in 16 women with previous gestational diabetes and in 19 normal women. Investigations were performed prior to the hormonal intake and after treatment for 2 and 6 months. Before treatment, the women with previous gestational diabetes had significantly elevated fasting glucose (p < 0.05) and impaired glucose tolerance (p < 0.05) when compared to those of the healthy control subjects. The glucose, insulin, and glucagon responses to oral glucose remained unchanged during the treatment period. Plasma cortisol increased in both groups (p < 0.05) whereas plasma triglycerides increased in the control subjects only (p < 0.05). Plasma free fatty acids, lipoproteins, and high-density lipoprotein cholesterol/total cholesterol ratio remained unchanged in both groups. The results suggest that a low-dose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel) is suitable as contraception even in women with a previous deterioration of glucose tolerance during pregnancy. (AM J 0BSTET GYNECOL 1985;153:495-500.)

Key words: Triphasic oral contraceptive, gestational diabetes, glucose tolerance, cortisol, lipid metabolism In 1963, Waine et al.' published the first report on alterations in carbohydrate metabolism following intake of oral contraceptives. Since then the risk of developing a deterioration of glucose tolerance during intake of the combined estrogen/progestogen compounds has been substantiated'· 1 and, together with the risk of consistent changes in plasma lipid levels, 1 this has caused great concern. As a consequence new low-

From the Diabetes Center, Departmmt of Obstetrir.1 and (;ynnolofD· Y, Ri14slwspitalet, Copenha14m; }foid@re Hospital, Klamj1enhor14; and the Department of Cliniral Chemistry, I I erlrv II os/1ital, H erle1•. RPCeived j(1r publication April 22, 1985; rn1i.1ed July 22, 1985; acreptedjul.v 26, 1985. Reprint reque.1L\: Sven Olaf Skoub\', M.D., Dwbetes Center, Department of Obstetrics and Gynernlogy Y 4042, Riph!/.\/1italet, DK-2 JOO Cof1e11/ia14en ¢, Denmark.

dose formulations with, first and foremost, reduced estrogen content but also containing new progestogens have been developed in the search for preparations with less potential risk. Triphasic preparations of ethinyl estradiol and levonorgestrel with a progestogen content less than that in any of the monophasic products have been introduced recently. As the estrogen/progestogen ratio of the combined oral contraceptives seems to be of major importance for the metabolic effects,'' " we were prompted to study the influence of a triphasic compound on glucose tolerance and plasma lipid/lipoprotein levels in women with a previously reduced glucose tolerance during pregnancy (gestational diabetes). For comparison a group of normal women was also investigated.

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Table I. Fasting values (mean ± SEM) of plasma glucose, insulin, glucagon, and cortisol in women with previous gestational diabetes (Prev. GDM) (n = I 6) and nondiabetic control subjects (n = I 9) using a lowdose triphasic oral contraceptive* Pretreatment Prev. GDM Glucose (mmol/L)t Insulin (pmol/L) Glucagon (pmol/L) Cortisol (nmol/L)

5.4 95 19 452

± ± ± ±

O. l:f: 8 2 52

I

2 mo

Controlf 4.9 95 21 459

± ± ± ±

Prev. GDM

0.1 11 2 33

5.3 110 17 558

± ± ± ±

0.2 12 2 3911

6 mo

I

Controls 5.1 111 20 643

± ± ± ±

Prev. GDM

0.1 9 2 2511

5.4 108 15 601

± ± ± ±

I

0.2:f: 9 I 46§

ControLf 5.0 112 20 649

± ± ± ±

0.1 9§ 3 27§

*Oral contraceptive containing ethinyl estradiol and levonorgestrel. tTo convert glucose concentration in millimoles per liter to milligrams per deciliter multiply by 18. :f:Women with previous gestational diabetes versus control subjects: p < 0.05. §Pretreatment versus 6 months: p <0.05. llPretreatment versus 2 months: p < 0.05.

Table II. Incremental glucose and insulin areas and decremental glucagon area (AUC) (mean ± SEM) calculated from oral glucose tolerance tests performed in women with previous gestational diabetes (Prev. GDM) (n = I 6) and in nondiabetic control subjects (n = 19) during intake of low-dose triphasic oral contraceptive* Pretreatment Prev. GDM / AUC glucose (mmol x min x L AUC insulin (nmol x min x L _,) AUC glucagon (pmol x min x L

1 ) 1 )

259 ± sot 36 ± 5 392 ± 93

2 mo

Controlf

Prev. GDM

131 ± 20 40 ± 7 562 ± 104

265 ± 46 39 ± 5 433 ± IOOt

I

6 mo Controlf

Prev. GDM

187 ± 29 36 ± 3 751 ± 133

299 ± 42t 38 ± 18 353 ± 84t

I

Controlf 163 ± 34 38 ± 17 849 ± 174

*Oral contraceptive containing ethinyl estradiol and levonorgestrel. tWomen with previous gestational diabetes versus control subjects: p < 0.05.

Material and methods Subjects. Sixteen women with previous gestational diabetes and 19 nondiabetic women were recruited into the study. Informed consent was obtained from all participants and the study was approved by the local ethics committee. All women were within 10% of their ideal body weight. The mean age of the women with previous gestational diabetes [28. 7 ± I. I (SEM) years, range I 7 to 30 years] was not significantly different from that of the controls [25.9 ± 0. I (SEM) years, range 23 to 35 years]. All participants were at least 6 months post partum, not breast-feeding, and without hormonal treatment for 3 months before entering the study. In the women with previous gestational diabetes the average period from the diagnostic oral glucose tolerance test was 9 months (range 6 to 18 months). Gestational diabetic patients had normal blood glucose concentrations in the fasting state but had diabetes diagnosed for the first time after a 50 gm oral glucose tolerance test in pregnancy. In the women with gestational diabetes, at least two glucose values of the oral glucose tolerance test exceeded the mean + 3 SD curve in a group of 46 normal nonpregnant control subjects evaluated by exactly the same procedure.' Our diag-

nostic criteria correspond closely to those advocated by the National Diabetes Data Group." Treatment. The triphasic pills were administered cyclically in 3-week periods followed by one medicationfree week for 6 months. In each period, 30 µg of ethinyl estradiol plus 50 µg of levonorgestrel were taken during the first 6 days, 40 µg of ethinyl estiadiol plus 75 µg of levonorgestrel for the next 5 days. and 30 µg of ethinyl estradiol plus 125 µg of levonorgestrel during the last I 0 days. Investigative procedure. A 50 gm oral glucose tolerance test was performed in all women before treatment was started and after tablet intake for 2 and 6 months. Blood pressure and body weight were recorded at each testing. Before treatment, the oral glucose tolerance test was always performed in the secretory phase (days 2 I to 28) of the menstrual cycle and during treatment, in the last phase of the tablet intake (days I 5 to 2 I). All participants reported to the laboratory in the morning, after an overnight fast and abstinence from smoking and following at least 3 days of unrestricted diet(> I 50 gm of carbohydrate) and physical activity. A short plastic catheter was inserted into an antecubital vein and blood samples were drawn in

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chilled heparin-aprotinin tubes before the glucose challenge and 15, 30, 45, 60, 90, 120, 150, and 180 minutes after. Tubes were centrifuged at 4° C and plasma stored at - 20° C until assayed. Plasma glucose was determined by a dehydrogenase method. 9 Plasma insulin, glucagon, and total cortisol were measured by previously described radioimmunoassays" 10• 11 and a radiochemical assay was used for determination of free fatty acids. 12 Determination of total cholesterol and triglyceride levels was performed enzymatically by means of commercially available kits (CHOD-PAP and GPO-PAP, Boehringer-Mannheim A.G., Mannheim, West Germany). High-density lipoprotein cholesterol was determined after removal of low-density lipoprotein cholesterol and very-low-density lipoprotein cholesterol by precipitation with phosphorus-tungsten acid-magnesium chloride. The level of very-low-density lipoprotein cholesterol was calculated by the formula of Friedwald et al.'" and the lowdensity lipoprotein cholesterol level was obtained by subtraction of high-density lipoprotein cholesterol and very-low-density lipoprotein cholesterol from total cholesterol values. Calculations and statistics. A numerical expression for glucose tolerance was obtained by integration of each glucose concentration curve during 0 to 120 minutes with the fasting level used as a baseline, that is, the incremental area under the curve. The period 0 to 120 minutes was chosen to avoid the possible effect of the rebound hypoglycemia that was frequently found after this time. The incremental insulin areas and the decremental glucagon areas were calculated similarly. Results are presented as mean ± SEM. Comparison within one group of women was done by Student's t test for paired data. Comparisons between groups were estimated by Student's t test for unpaired data when variances of the groups were not significantly different judged by the variance ratio. When variances between groups were different, the Mann-Whitney U test was applied. Two-tailed p values <0.05 were considered significant. Results Body weight and blood pressure. No changes in body weight and blood pressure were found during the study. Plasma glucose, insulin, glucagon, and cortisol Fasting values (Table/). Before treatment fasting glucose values were significantly higher in the women with previous gestational diabetes than in the control subjects. This difference persisted after hormonal intake for 6 months. No changes in fasting glucose levels were observed within the groups during the study. During treatment a slight but significant increase in

Oral contraceptive use after gestational diabetes 497

Plasma glucose (mmol/I) 11

9 7

5 3 Plasma insulin (pmol/I) 800

A Controls, n = 19 • Prev.-GDM, n=16

600 400

200 0 Plasma glucagon (pmol/I)

25 20

15

10 5 0

2

3

hours

Fig. 1. Plasma glucose, insulin, and glucagon values (mean ± SEM) during oral glucose tolerance tests performed in women with previous gestational diabetes (Prev.-GDM) (n = 16) and in nondiabetic control subjects (n = 19) before intake of a lowdose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel).

fasting insulin levels was observed in the control group. No changes occurred in the women with previous gestational diabetes. Fasting glucagon levels did not change in either group during the study. Fasting total cortisol levels increased significantly and similarly in both groups during treatment. Oral glucose tolerance test. Before treatment plasma glucose values (Fig. I) and the areas under the curves were higher in the women with previous gestational diabetes than in the control subjects (Table II). No changes in the plasma glucose values and the areas under the curves were observed within the groups during the study. Although the insulin response to the glucose load appeared to be slightly blunted in the women with previous gestational diabetes at the start of the study (Fig. l) the areas under the curves were not significantly different in the women with previous gestational dia-

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Table III. Fasting values (mean ± SEM) of plasma triglycerides, free fatty acids ( FFA) and the highdensity lipoprotein (HDL) cholesterol/total cholesterol ratio in women with previous gestational diabetes (Prev. GDM) (n = 16) and in nondiabetic control subjects (n = 19) using a low-dose triphasic oral contraceptive* Pretreatment Prev. GD,W Triglyclerides (mmol/L) FFA (mmol/L) HDL cholesterol/total cholesterol ratio

1.04 ± 0.1 767 ± 58 0.26 ± 0.01

I

Controls 0.91 ± 0.06 691 ± 63 0.29 ± 0.01

2 mo Prev. GDM j 1.01 ± 0.08 743 ± 41 0.28 ± 0.01

6 mo

ControL1 1.08 ± 0.09t 737 ± 67 0.29 ± 0.02

Prev. GDM j 1.10 ± 0.09 738 ± 58 0.28 ± 0.01

ControL1 1.06 ± o.os+ 699 ± 56 0.31 ± 0.02

*Oral contraceptive containing ethinyl estradiol and lernnorgestrel. tO versus 2 months: p < 0.05. +o versus 6 months: p < 0.05.

betes and the control subjects (Table II). In both the women with previous gestational diabetes and the control subjects one of nine insulin values increased significantly after hormonal intake for 2 months (the 45minute and 150-minute values, respectively). The 120minute plasma insulin value at the 6-month test was significantly higher than the pretreatment value in the women with previous gestational diabetes. However, no differences in the areas under the curves were observed in either group during the study (Table II). Before treatment plasma glucagon values and the areas under the curves were identical in the women with previous gestational diabetes and the control subjects (Fig. I and Table I). During treatment no changes in plasma glucagon were observed, although the suppression of glucagon was slightly more discernible in the women with previous gestational diabetes than in the control su~jects as judged by the changes in the areas under the curves (Table II). Plasma levels of free fatty acids, triglycerides, total cholesterol, and high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein cholesterol. Before and during treatment no differences in plasma free fatty acids were observed between the women with previous gestational diabetes and the control su~jects (Table III). During treatment, an increase in plasma triglycerides was found in the control subjects. Before treatment, total plasma cholesterol and high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein cholesterol concentrations were similar in both groups, and the concentrations remained unchanged during treatment. This was also reflected in a constant high-density lipoprotein cholesterol/total cholesterol ratio in both groups during the study (Table III).

Comment In earlier studies on oral contraceptives containing 50 µg of estrogen and having a high progestogen content an overall risk of 44% for developing an oral glu-

cose tolerance test showing diabetes has been registered in women with previous gestational diabetes. 11 · 1" Prescription of the traditional oral contraceptive compounds has therefore to a large extent been avoided in these women. In the present study no changes in oral glucose tolerance test results were found in either women with previous gestational diabetes or in the control subjects during a 6-month period when a low-dose triphasic compound was taken. None of the women with previous gestational diabetes developed a worsening of the oral glucose tolerance test results during the treatment despite higher than normal glucose levels before entering the study. The significance of the slight increase in a few of the plasma insulin concentrations observed during the oral glucose tolerance tests in both groups is opposed by the unchanged areas under the curves. The differences observed in the decremental glucagon areas under the curves between the women with previous gestational diabetes and the control subjects may possibly reflect differences in pancreatic a-cell response to oral glucose, but the interpretation is blurred because of the marked scattering of the individual plasma values. We have previously reported a study where a lowdose monophasic combination of 30 µg of ethinyl estradiol and 150 µg of levonorgestrel was administered to women with previous gestational diabetes. We found a more marked increase in the insulin response to oral glucose in these women than in the women with previous gestational diabetes in the present study.'' As the progestogen component in combination compounds seems to be mainly responsible for the influence on glucose homeostasis,'" this increase might have been due to the higher progestogen dosage in the monophasic compound. Only a few other studies have dealt with the influence on glucose metabolism of low-dose oral contraceptives in women with a previous abnormality of glucose tolerance. Spellacy et al.'" studied 24 women who took a monophasic contraceptive contain-

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ing 30 µg of ethinyl estradiol and 400 µg of norethindrone for 6 months. Two of 19 women with a normal control oral glucose tolerance test exhibited a slight deterioration in test results; five women with previous borderline abnormal control glucose tests all demonstrated improvement during 6 months of treatment. Pyorala et al."" investigated the effect of treatment with progestogen only (50 µg of norethindrone and 30 µg of lynestrenol) in women with previous gestational diabetes. Intake of norethindrone-containing compounds was followed by a slight deterioration of glucose tolerance whereas no changes were observed following ingestion of the lynestrenol compounds. The mechanism behind the inHuence on glucose metabolism of contraceptive steroid compounds is not yet known in detail, but there is evidence that progestogens alone or combined with estrogens induce a decrease in tissue sensitivity to insulin.'"· "'" "" Moreover, the increased plasma cortisol levels found in women treated with oral contraceptives may impair glucose tolerance as the result of an increase in hepatic glucose production and an inhibition of glucose uptake in peripheral cells."" Since Wynn et al."' demonstrated elevated triglyceride levels during oral contraceptive treatment, various changes in the levels of lipids and lipoproteins have been reported.' Besides an increased plasma triglyceride concentration, oral contraceptive use is also associated with an increase in low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and total cholesterol, whereas the high-density lipoprotein cholesterol concentration might be decreased. These changes are positively associated with the quantity of the estrogen component although the progestogens may also modify these values depending on their biochemical constitution.'' "Raised total cholesterol, triglyceride, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol levels are positively associated with the risk of developing atherosclerotic circulatory diseases, whereas an inverse relationship with the high-density lipoprotein cholesterol concentrations exists."' The reports on the influence of the triphasic ethinyl estradiol/levonorgestrel compound on lipid/lipoprotein levels in nondiabetic women have been promising as the high-density lipoprotein cholesterol/total cholesterol ratio is unaffected by the treatment,'; but the increase in plasma triglyceride found in the present study among the control subjects is consistent with results that indicate that triphasic compounds raise plasma triglycerides to a greater extent than the low-dose monophasic ethinyl estradiol/levonorgestrel combinations." It is remarkable, however, that in our study the triglycerides remained unchanged in the women with previous gestational diabetes during the period of hormonal treat-

Oral contraceptive use after gestational diabetes 499

ment and that free fatty acids also remained stable. The plasma lipids were thus unaffected by the hormonal intake, despite the elevated glucose levels. Furthermore, the unchanged high-density lipoprotein, lowdensity lipoprotein, and very-low-density lipoprotein cholesterol levels together with a constant high-density lipoprotein cholesterol/total cholesterol ratio in both groups appear favorable from a clinical point of view."'' The laboratory findings in the present study are thus consistent with population studies indicating a link between the epidemiologic characteristics of the oral contraceptives and their dosage and biochemistry. ei; Although long-term metabolic side effects should also be excluded, the relatively progestogen-deficient triphasic preparations seem suitable as safe contraception even in women with a previous deterioration of glucose tolerance during pregnancy. The skilled technical assistance of Lene Poulsen, Connie Kuhl, Marie-Louise Borgen, and Birgitte Ki~rskov Foss is gratefully acknowledged. The contraceptive compound Triquilar was kindly supplied by Schering, Copenhagen, Denmark.

REFERENCES I. Waine H, Frieden EH, Caplan HI, et al. Metabolic effects of Enovid in rheumatoid patients. Arthritis Rheum 1963;6:796. 2. Kalkhoff RK. Effects of oral contraceptive agents on carbohydrate metabolism . .J Steroid Biochem 1975;6:949. 3. Furman BL Impairment of glucose tolerance produced by diuretics and other drugs. Pharmacol Ther 1981; 12: 61'.t 4. Wallace RB, Hoover .J, Barret-Connor E, et al. Altered plasma lipid and lipoprotein levels associated with oral contraceptive and oestrogen use. Lancet 1979;2: 111. 5. Briggs ~IH, Briggs M. Randomized prospective studies on metabolic effects of oral contraceptives. Acta Obstet Gynecol Scand 1982; I 05(suppl):25. 6. Larsson-Cohn lJ, Fahreus L, Wallen tin L, Zador G. Effects of the estrogenicity of levonorgestrel/ethinylestradiol combinations on the lipoprotein status. Acta Obstet Gvnecol Scand 1982; 105(suppl):40. 7. Kiihl C, Holst .JJ. Plasma glucagon and the insulin: glucagon ratio in gestational diabetics. Diabetes 1976;25: 16. 8. '.\lational Diabetes Data Group. Classification and diagnosis and other categories of glucose intolerance. Diabetes 1979;28: I 039. 9. Dolhofer R, Weiss L, Wieland OH. Experience with the glucose-dehydrogenase-UV method for the determination of blood glucose. J Clin Chem Clin Biochem 1976; 14:415. 10. Kuhl C. Glucose metabolism during and after pregnancy in normal and gestational diabetic women. I. influence of normal pregnancy on serum glucose and insulin concentration during basal fasting conditions and after a challenge with glucose. Acta Endocrinol l 975;79:709. 11. Dash RJ, England BJ, Midgley AR Jr, '.\liswender GD. A specific non-chromatographic radioimmunoassay for human plasma cortisol. Steroids 1975;26:64 7. 12. Ho RJ, Meng HC. A simple and ultrasensitive method for determination of free fatty acid by radiochemical assay. Anal Biochem 1969;3 I :426. 13. Friedwald WT, Levy RI, Fredrickson DS. Estimation of plasma low density lipoprotein cholesterol concentration

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15.

16. 17. 18. 19.

20.

without use of the preparative ultracentrifuge. Cl in Chem 1972; 18:499. Beck P, Wells SA. Comparison of the mechanisms underlying carbohydrate intolerance in subclinical diabetic women during pregnancy and during post-partum oral contraceptive steroid treatment. J Clin Endocrinol Metab 1969;29:807. Szabo AJ, Cole HS, Grimaldi RD. Glucose tolerance in gestational diabetic women during and after treatment with a combination-type oral contraceptive. N EnglJ Med I 970;282:646. Beck P. Comparison of the metabolic effects of chlormadione acetate and conventional contraceptive steroids in man. J Clin Endocrinol Metab 1970;30:785. Skouby SO, M!illsted-Pedersen L, Kuhl C. Low dosage oral contraception in women with previous gestational diabetes. Obstet Gynecol I 982;59:325. Spellacy WNS. Carbohydrate metabolism during treatment with estrogen, progestogen, and low-dose oral contraceptives. AMJ 0BSTET Gv~ECOL 1982;142:732. Spellacy WN, Buhi WC, Birk SA. Carbohydrate metabolism prospectively studied in women using a low-estrogen oral contraceptive for six months. Contraception 1979;20:137. Pyorala T, Vahapassi .J, Huhtala M. The effect of lynes-

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24. 25.

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trenol and norethindrone on the carbohydrate and lipid metabolism in subjects with gestational diabetes. Ann Chir Gynaecol 1979;68:69. De Pirro R, Forte F, Bertoli A, Greco AV, Lauro R. Changes in insulin receptors during oral contraception. J Clin Endocrinol Metab 1981;52:29. Scrivastava MC, Oakley NW, Tomkins CV, Sonksen PH, Wynn V. Insulin metabolism, insulin sensitivity and hormonal responses to insulin infusion in patients taking oral contraceptive steroids. Eur J Clin Invest 1975;5:425. Munck A. Glucocorticoid inhibition of glucose uptake by peripheral tissues: old and new evidence, molecular mechanisms, and physiological significance. Perspect Biol Med 197l;14:265. Wynn V, Doar .J, Mills GL. Some effects of oral contraceptives on serum lipid and lipoprotein levels. Lancet 1966;2:720. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: High density lipoprotein as a protective factor against coronary heart disease: The Framingham study. Am J Med I 977;62:707. Bottinger LE, Boman G, Eklund G, Westerholm B. Oral contraceptives and thromboembolic disease: Effects of lowering oestrogen content. Lancet 1977; I: l 097.

a-Thalassemia hydrops fetalis: Clinical and ultrasonographic considerations Glenford Guy, M.D., Deborahj. Coady, M.D., Valerie Jansen, M.S.,jon Snyder, M.D., and Stanley Zinberg, M.D. New York, New York Five pregnant Southeast Asian women presenting during a 14-month period with mlcrocytic anemia, preeclampsia, and size-date discrepancies were all ultimately diagnosed as carrying fetuses with homozygous o.-thalassemia hydrops fetalis. The perinatal complications of this hemoglobin disorder are unique to persons of this ethnic background and include uniform fatality for the affected infant, maternal preeclamptic morbidity, and retained placenta. In this report the obstetric ultrasound findings are presented and the clinical manifestations are discussed, with recommendations made to reduce this emerging public health problem in the United States. (AM J OssrET GvNECOL 1985;153:500-4.)

Key words: o:-Thalassemia, hydrops fetalis, Bart's hemoglobin disease, obstetric ultrasound, preeclampsia The genetically determined disorder of hemoglobin production o:-thalassemia, in the homozygous state of Bart's hemoglobin hydrops fetalis, results in uniform fatality for the affected fetus. 1.2 In addition, the mothers of these fetuses are at high risk for severe morbidity. From the Departments of Obstetrics and Gynecology, New York Infirmary-Beekman Downtown Hospital and New York UniversityBellevue Medical Center. Received for publication June 7, 1985; accepted August 15, 1985. Reprint requesl\.' Deborah]. Coady, M.D .. Department of Obstetrics and Gynecology, New York Infirmary-Beekman Downtown Hospital, 170 William St., New York, NY 10038.

500

The problems resulting from this disorder are relatively unique to Southeast Asians. 2 · 3 In the United States, screening of Southeast Asians has revealed incidence rates of up to 11 % for o:-thalassemia trait and up to 39% for inherited hemoglobin disorders in general."· 1 Hydrops fetalis from immunologic and nonimmunologic causes often represents end-stage disease in the fetus.' Nonimmunologic causes of hydrops fetalis have become more conspicuous in the face of good screening and prophylaxis for rhesus-immunization disease. Homozygous o:-thalassemia in the fetus presents as a non-