Bruce V. Stadel

Lactic Acidosis in Patients with Diabetes Treated with Metformin

To the Editor: From May 1995, when metformin was introduced in the United States, through June 30, 1996, the Food and Drug Administration (FDA) received reports of lactic acidosis in 66 patients tr...

Tubal Infertility and the Intrauterine Device

To study the association between intrauterine devices (IUDs) and pelvic inflammatory disease, we compared contraceptive histories in 4185 while women--283 nulliparous women with primary tubal infertility, 69 women with secondary tubal infertility, and 3833 women admitted for delivery at seven collaborating hospitals from 1981 to 1983. The relative risk of tubal infertility associated with IUD use was calculated by means of multivariate logistic regression to control for confounding factors, including region, year of menarche, religion, education, smoking, and reported number of sexual partners. The adjusted risk of primary tubal infertility associated with any IUD use before a first live birth was 2.0 (95 per cent confidence limits, 1.5 to 2.6) relative to nonuse. Users of the Dalkon Shield had an adjusted risk of 3.3 (1.7 to 6.1), users of the Lippes Loop or Saf-T-Coil had a risk of 2.9 (1.7 to 5.2), and users of copper IUDs had a risk of 1.6 (1.1 to 2.4). Women who reported having only one sexual partner had no increased risk of primary tubal infertility associated with IUD use. The adjusted risk of secondary tubal infertility associated with use of a copper IUD after a first live birth was not statistically significant (1.5; 95 per cent confidence limits, 0.8 to 3.0), whereas the risk from similar use of noncopper devices was significant (2.8; 1.3 to 5.9). We conclude that tubal infertility is associated with IUD use, but less so with copper IUDs.

Primary Tubal Infertility in Relation to the Use of an Intrauterine Device

Women who use an intrauterine device (IUD) are at increased risk of acute pelvic inflammatory disease, but the relation of the IUD to subsequent infertility is not established. We interviewed 159 nulligravid women with tubal infertility to determine their prior use of an IUD. Their responses were compared with those of a matched group who conceived their first child at the time the infertile women started trying to become pregnant. The risk of primary tubal infertility in women who had ever used an IUD was 2.6 times that in women who had never used one (95 per cent confidence interval, 1.3 to 5.2). The observed difference between cases and controls was not uniform for different types of IUD. The relative risk associated with use of a Dalkon Shield was 6.8 (1.8 to 25.2), and that associated with use of either a Lippes Loop or Saf-T Coil IUD was 3.2 (0.9 to 12.0). The smallest elevation in risk was found among users of copper-containing IUDs (relative risk, 1.9 [0.9 to 4.0] for all women who had ever used a copper-containing IUD). The relative risk for women who used only a copper-containing IUD was 1.3 (0.6 to 3.0). We conclude that use of the Dalkon Shield (and possibly of plastic IUDs other than those that contain copper) can lead to infertility in nulligravid women.

Appendectomy and the risk of tubal infertility.

We studied the importance of a history of appendectomy for appendicitis in 279 women with laparoscopically or surgically diagnosed tubal infertility and a control group of 957 fertile women. After controlling for the effects of age, use of an intrauterine device for contraception, a history of pelvic inflammatory disease, and other potential confounding variables, we found that no excess risk of tubal infertility was associated with a simple appendectomy without rupture. However, when the operation was reportedly for a ruptured appendix, the relative risk of tubal infertility was 4.8 (95 percent confidence interval, 1.5 to 14.9) for women who had never been pregnant and 3.2 (95 percent confidence interval, 1.1 to 9.6) for women with one or more previous pregnancies. We conclude that the early diagnosis and treatment of suspected appendicitis in girls and women of reproductive age may reduce the incidence of tubal infertility resulting from the sequelae of a ruptured appendix.

Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone

We report 13 cases of benign intracranial hypertension (IH) in children with growth hormone (GH) deficiency treated with GH in the United States. The group consisted of eight boys and five girls, 3 to 16 years of age (median, 9 years). The interval from starting GH therapy to diagnosis of IH was 2 weeks or less in six patients, between 2 and 12 weeks in four, 8 months in one, 5 years in one, and unknown in one. Seven patients were not known to have previously described IH risk factors; the other six had at least one factor each. All patients but one had headache, nausea, vomiting, and visual changes. All had papilledema, and cerebrospinal fluid pressures were elevated (> 250 mm H2O) in all nine patients tested. The GH dosage range was 0.17 to 0.35 mg per kilogram body weight per week (median, 0.30 mg/kg per week) for the 11 patients with dosage data. After discontinuation of GH and treatment with lumbar punctures and/or medications, signs and symptoms resolved in eight children; in two of these children signs and symptoms reappeared when GH therapy was restarted. In four patients signs and symptoms resolved while GH therapy was continued; one child was treated with a ventriculoperitoneal shunt because of an arachnoid cyst, after which GH was restarted without subsequent IH. In the 12 patients with idiopathic GH deficiency the course of IH was benign, with complete resolution of all signs and symptoms. Because doses and scheduling of GH administration have changed since the introduction of recombinant GH, higher doses and increased frequency of administration may be contributing to the development of IH in some patients. We suggest beginning therapy at the lowest recommended dose, with gradual titration to higher doses, and the performance of routine funduscopic examinations during initiation of GH therapy and whenever signs or symptoms of IH develop.

Fibrocystic breast disease in oral-contraceptive users. A histopathological evaluation of epithelial atypia.

Epidemiological studies show a lower frequency of fibrocystic breast disease among long-term users of oral contraceptives than among women who have never used them. Fibrocystic disease may be a precursor of breast cancer; yet the incidence of breast cancer does not appear to differ between pill-takers and nontakers. To resolve this conflict, we examined the problem from a histologic standpoint in 205 premenopausal women, and found that this decreased frequency applied only to fibrocystic disease in which epithelial atypia was minimal or absent. In women with marked atypia there was no significant difference in frequency among long-term users as compared to women who have never used oral contraceptives. These findings suggest that a spectrum of cystic disease exists and that the long-term use of oral contraceptives protects against the forms of fibrocystic disease that are not firmly associated with an increased risk of breast cancer, but not against the premalignant forms.

Breast cancer risk in relation to type of estrogen contained in oral contraceptives.

We report analyses designed to address the recent hypothesis that women who use combination-type OCs containing ethinylestradiol (EE) are at increased risk of breast cancer before age 45, if use of such OCs occurs prior to first term pregnancy (FTP). Our findings, based on data from 1679 cases and 1689 controls, 20-44 years of age, from the population-based Cancer and Steroid Hormone Study, are against the hypothesis. The relative risk of breast cancer by duration of exclusive use prior to FTP of OCs containing EE is estimated to be 1.0 (1-12 months EE use), 1.2 (13-48 months EE use), and 0.9 (49+ months EE use). There was no evidence of a latent effect. Among parous women with 49+ months exclusive use prior to FTP of EE-containing OCs, the relative risk of breast cancer was estimated as 0.9 (0-4 years after FTP) and 0.6 (5-9 years after FTP). Among nulliparous women with 49+ months exclusive use of EE-containing OCs, the relative risk of breast cancer was estimated as 1.0 (0-4 years since first use), 0.7 (5-9 years since first use), and 1.1 (10-14 years since first use). With regard to exclusive use of OCs containing mestranol, parous women who used such preparations long-term before their FTP showed no alteration of breast cancer risk, even 15 years or more after pregnancy. Nulliparous women with exclusive use of ME-containing OCs did show elevations in breast cancer risk, but the magnitude of risk in relation to duration of use and latent interval shows no pattern that suggests a cause-effect relationship.

Fibroadenoma in oral contraceptive users. A histopathologic evaluation of epithelial atypia

We have reviewed histologically a series of 120 fibroadenomas which formed part of the case material from a previous case‐control epidemiological investigation of the relationship between oral contraceptive use and breast disease. We evaluated the epithelial component of the fibroadenoma for degree of cytologic atypia. This study indicates that the reduced risk for fibroadenoma among long‐term users of oral contraceptives does not vary according to the degree of epithelial atypia present. This is in contrast to our previously reported findings for fibrocystic disease, in which the decreased frequency of occurrence of the disease in long‐term users of oral contraceptives was found only for cases with no or minimal epithelial atypia.

Oral Contraceptive Use in Women With a Family History of Breast Cancer

&NA; To evaluate the effect of oral contraceptive use on the risk of breast cancer from 20‐54 years of age in women with a family history of the disease, we analyzed data from the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. For 2 years, beginning December 1980, the study enrolled from eight geographical areas in the United States 4730 women with breast cancer and 4646 controls who were breast cancer‐free. For women with a first‐degree family history of breast cancer, 554 cases and 280 controls, there was no evidence that use of oral contraceptives, even long‐term, contributed to their risk of the disease. Neither total duration of use nor duration of use before first term pregnancy bore any relationship with breast cancer risk. Analyses designed to reveal a potential latent effect also showed no evidence of an adverse effect. For women with a second‐degree family history of breast cancer, 777 cases and 595 controls, some isolated elevations in risk were observed for selected subgroups of oral contraceptive users. Detailed analyses of oral contraceptive formulation, the characteristics of the women involved, and the patterns of risk observed by latent period and duration of use suggest that these results, most within the limits of chance variation, are not likely to be a consequence of oral contraception. (Obstet Gynecol 73:977, 1989)

Consistency and plausibility in epidemiologic analysis: Application to breast cancer in relation to use of oral contraceptives

Consistency and plausibility are fundamental criteria for judging cause and effect from observational studies. They are applied here to the interpretation of data from a population-based case-control study of oral contraceptives and breast cancer. A preliminary analysis of oral contraceptive use in young nulliparous women, who had no family history of either breast cancer or benign breast disease, showed a statistically significant dose-response, with long-term users (49 months or more) having an apparent 4-fold elevation in risk of early breast cancer. Further analyses, however, revealed striking inconsistencies which were biologically implausible. These effectively undermine cause and effect as an explanation for the initial finding.