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Biomedical subjects

K J Rothman

Publications and source records attributed to K J Rothman.

At least 19 recordsLinked to original sources

Maternal heat exposure and neural tube defects.

OBJECTIVE: To determine if exposure to hot tub, sauna, fever, or electric blanket during early pregnancy was associated with an increased risk for neural tube defects (NTDs). DESIGN: Prospective follow-up study. SETTING: Mostly private obstetric practices, primarily in New England. PARTICIPANTS: A cohort of 23,491 women having serum alpha-fetoprotein screening or an amniocentesis were identified. Complete exposure and outcome information was available for 97% of these women. OUTCOME MEASURES: Relative risks (RRs) were used to compare incidence of NTD in those exposed to heat with those who were not exposed to any heat. Crude RRs were calculated directly from the data. Unconfounded RRs were calculated using logistic regression. RESULTS: Women reporting any heat exposure (sauna, hot tub, fever, or electric blanket) in early pregnancy had a crude risk of their fetuses developing NTD of 1.6 (95% CI [confidence interval], 0.9 to 2.9). Women reporting exposure to sauna, hot tub, or fever in early pregnancy had a crude risk of their fetuses developing NTD 2.2 times that of women without heat exposure (95% CI, 1.2 to 4.1). For hot tub use, the crude RR was 2.9 (95% CI, 1.4 to 6.3); for sauna, 2.6 (95% CI, 0.7 to 10.1); for fever, 1.9 (95% CI, 0.8 to 4.1); and for electric blanket, 1.2 (95% CI, 0.5 to 2.6). Multivariate adjusted RRs for individual heat sources, after controlling for maternal age, folic acid supplements, family history of NTD, and exposure to other heat sources, were for hot tub use, 2.8 (95% CI, 1.2 to 6.5); sauna, 1.8 (95% CI, 0.4 to 7.9); fever, 1.8 (95% CI, 0.8 to 4.1); and electric blanket, 1.2 (95% CI, 0.5 to 2.6). When only hot tub, sauna, and fever were considered and the women's exposure to each tallied, compared with no heat exposure, the RR for NTDs increased from 1.9 (95% CI, 0.9 to 3.7) after one type of heat exposure to 6.2 (95% CI, 2.2 to 17.2) after two types of heat exposure. CONCLUSIONS: Exposure to heat in the form of hot tub, sauna, or fever in the first trimester of pregnancy was associated with an increased risk for NTDs. Hot tub exposure appeared to have the strongest effect of any single heat exposure. Exposure to electric blanket was not materially associated with increased risk for NTDs.

Cohort Studies

Maternal zinc and fetal neural tube defects.

Among the factors implicated in the heterogeneous etiology of neural tube defects (NTDs) is the trace element zinc (Zn). In a case-control study, we collected midtrimester maternal toenail samples for multiple trace element analyses, including Zn, which were assayed by neutron activation analysis. We studied 17 women with NTD offspring and 1,787 controls. The crude OR for NTD comparing Zn values greater than normal range to normal Zn values was 3.2 (95% CI 1.1,9.7). These results were not materially affected when adjustment was made for folic acid supplementation. An overall increased risk for NTD associated with increasing toenail Zn was also evident. A matched subset of 17 cases and 73 controls yielded a crude OR of 3.1 (95% CI 0.9,10.3) when cases with elevated Zn (greater than or equal to 120 ppm) were compared to those with normal Zn. Matched analyses controlling for folic acid supplements, family history of NTD, assay batch, age of mother and year of delivery yielded an OR of 5.0 (95% CI 1.1,21.6). This study reveals an association between increased toenail Zn in the second trimester of pregnancy and the risk of having a child with an NTD. Whether Zn sequestration has resulted in relative Zn deficiency at the site of neural tube closure remains uncertain.

Case-Control Studies

Rats.

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Animals

The ethics of research sponsorship.

Growing concern regarding ethics in science has prompted calls for reform. These proposals include the mandatory identification of funding source and prohibition of any financial connection between an investigator and a company whose product is being studied. Such reforms imply that scientific work supported by industry should not be considered reliable, that any potential for fraud or subconscious alteration of the work should be considered damning in itself. This thinking will promote an ad hominem evaluation of science, rather than an evaluation based on merits. The reality is that no scientist is impartial. To focus on the circumstances of the work rather than the work itself has the ironic effect of detracting from overall objectivity. Scientific objectivity does not arise through cultivation in the minds of individual scientists, none of whom can lay claim to this pinnacle of rationality, but by the process of open, rational criticism itself. Those who encourage that work be judged in respect to the funding source are slighting honest industry scientists and stifling rational discourse.

Conflict of Interest

Mortality from cancer of the colon or rectum among workers exposed to ethyl acrylate and methyl methacrylate.

Mortality from colon and rectum cancer has been reviewed in three cohorts working in 1933-1982 in two plants manufacturing and polymerizing acrylate monomers. The two cohorts with later dates of hire showed no excess mortality. In the earliest cohort, excess colon cancer seemed restricted to men employed extensively in the early 1940s in jobs entailing the highest exposures to vapor-phase ethyl acrylate (EA) and methyl methacrylate (MMA) monomer and volatile by-products of the EA/MMA polymerization process. The excess mortality appeared only some two decades after the equivalent of three years' employment in jobs with the most intense exposures. A smaller elevation in colon cancer mortality also appeared in a low-exposure group in the early cohort. Rectal cancer mortality was elevated in the same categories that showed excess rates of colon cancer death. Because of the lower rates, the rectal cancer results are more imprecise.

Acrylates

Tampon absorbency, composition and oxygen content and risk of toxic shock syndrome.

Tampon use has been identified as a major risk factor for toxic shock syndrome, although the etiologic role of tampons is not clearly understood. Two epidemiologic studies conducted to date have reported an association between tampon absorbency and risk of toxic shock syndrome. This finding is not corroborated by laboratory studies, however, which have suggested that absorbency may be a marker for other characteristics that create an environment conductive to the elaboration of toxic shock syndrome toxin 1. We used data from the previously reported Tri-state study to estimate simultaneously the effects of tampon oxygen content, absorbency and chemical composition. Although the data are sparse, oxygen content was more strongly associated with risk of toxic shock syndrome than either absorbency or chemical composition. The results suggest that it may be possible to develop a highly absorbent tampon that is not associated with a high risk of toxic shock syndrome.

Acrylates

Bromocriptine and puerperal seizures.

Case reports have prompted concern that the use of bromocriptine mesylate to prevent lactation in the puerperium increases the risk of postpartum seizure. We conducted a record-based case-control study of postpartum seizures in three data bases to evaluate this relation. We identified 43 women who had a postpartum seizure, and we matched 319 controls individually by hospital of delivery, quinquenium of age, and time of delivery. Overall, women taking bromocriptine had a 22% lower risk for seizures, that is, the relative risk estimate was 0.78, with a 90% confidence interval of 0.29 to 1.87. A reduction in seizure risk is consistent with reports of antiseizure activity for bromocriptine in various species, including humans. We found a small positive association between bromocriptine use and seizures occurring more than 72 hours after delivery, with a relative risk estimate of 1.6 after controlling for seizure history. This association was offset by a strong negative association between bromocriptine use and early-occurring seizures. The pattern of an initial reduced risk followed by an increase to normal or above-normal levels of risk could result from an antiseizure activity of bromocriptine, with a rebound in risk when bromocriptine is withdrawn.

Adolescent

Mortality of cellulose fiber production workers.

Mortality was studied among 1271 employees of a cellulose fiber production plant in Rock Hill, South Carolina, in the United States. Each subject was employed for at least three months between 1 January 1954 and 1 January 1977 in jobs that entailed exposure to the highest concentrations of methylene chloride. In the cohort 122 deaths were identified through 1 September 1986, and mortality rates for the cohort were compared with mortality rates for York County, South Carolina. Deficit mortality was observed for cancers of the respiratory system, breast, and pancreas and from ischemic heart disease. Excess mortality was observed for cancers of the buccal cavity and pharynx and the liver and biliary tract, and for melanoma as well. The largest relative excess was for liver and biliary tract cancers. There were only four deaths in this category; however, three of the four deaths were cancer of the biliary tract (3 observed, 0.15 expected, standardized mortality ratio 20).

Biliary Tract Neoplasms

No adjustments are needed for multiple comparisons.

Adjustments for making multiple comparisons in large bodies of data are recommended to avoid rejecting the null hypothesis too readily. Unfortunately, reducing the type I error for null associations increases the type II error for those associations that are not null. The theoretical basis for advocating a routine adjustment for multiple comparisons is the "universal null hypothesis" that "chance" serves as the first-order explanation for observed phenomena. This hypothesis undermines the basic premises of empirical research, which holds that nature follows regular laws that may be studied through observations. A policy of not making adjustments for multiple comparisons is preferable because it will lead to fewer errors of interpretation when the data under evaluation are not random numbers but actual observations on nature. Furthermore, scientists should not be so reluctant to explore leads that may turn out to be wrong that they penalize themselves by missing possibly important findings.

Bias

Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects.

We examined the relation of multivitamin intake in general, and folic acid in particular, to the risk of neural tube defects in a cohort of 23,491 women undergoing maternal serum alpha-fetoprotein screening or amniocentesis around 16 weeks of gestation. Complete questionnaires and subsequent pregnancy outcome information was obtained in 22,776 pregnancies, 49 of which ended in a neural tube defect. The prevalence of neural tube defect was 3.5 per 1000 among women who never used multivitamins before or after conception or who used multivitamins before conception only. The prevalence of neural tube defects for women who used folic acid-containing multivitamins during the first 6 weeks of pregnancy was substantially lower--0.9 per 1000 (prevalence ratio, 0.27; 95% confidence interval, 0.12 to 0.59 compared with never users). For women who used multivitamins without folic acid during the first 6 weeks of pregnancy and women who used multivitamins containing folic acid beginning after 7 or more weeks of pregnancy, the prevalences were similar to that of the nonusers and the prevalence ratios were close to 1.0.

Adult

Predictive values, relative risks, and overall benefits of high and low maternal serum alpha-fetoprotein screening in singleton pregnancies: new epidemiologic data.

In a prospective study of maternal serum alpha-fetoprotein screening for both high and low values, we assessed the overall predictive value, sensitivity, specificity and relative risks for congenital defects and complications of pregnancy. Among 13,486 women with singleton pregnancies interviewed at the time of screening (15 to 20 weeks of gestation), 3.9% had high and 3.4% had low values. A high maternal serum alpha-fetoprotein value was associated with the following adverse outcomes: neural tube defects (relative risk = 224), other major congenital defects (relative risk = 4.7), fetal deaths (relative risk = 8.1), neonatal death (relative risk = 4.7), low birth weight (relative risk = 4.0), newborn complications (relative risk = 3.6), oligohydramnios (relative risk = 3.4), abruptio placentae (relative risk = 3.0) and preeclamptic toxemia (relative risk = 2.3). A low maternal serum alpha-fetoprotein value was associated with chromosomal defects (relative risk = 11.6) for fetal death (relative risk = 3.3). Either high or low maternal serum alpha-fetoprotein values were associated with 34.2% of all major congenital defects, 19.1% of all stillbirths and fetal-neonatal deaths, 11.0% of major pregnancy complications, and 15.9% of serious newborn complications. Maternal serum alpha-fetoprotein screening provides an important adjunctive tool for the identification of high-risk pregnancy and adverse neonatal outcome.

Adolescent

Bias arising in case-control studies from selection of controls from overlapping groups.

Three examples are used to demonstrate that the selection of controls from categories that overlap can lead to bias. Case-control studies that use friend controls and the practice of age-matching controls to cases within a specified number of years (caliper matching) are examples of the selection bias described in the paper. The bias resulting from the use of friend controls can be large and, since the use of friend controls is common, this source of bias is of considerable practical consequence. The use of friend controls or the selection of controls according to other variables with categories that overlap should be avoided.

Age Factors

Carcinogenicity of dark liquor.

To investigate whether the non-alcohol content of distilled alcoholic beverages affects the carcinogenicity of the beverage, we conducted an epidemiologic study of laryngeal and hypopharyngeal cancer. We interviewed 384 cases (or spouses, for deceased cases), and compared their responses with those of 876 controls. We classed distilled liquors as dark or light, a rough division according to content of potentially carcinogenic compounds in the beverages. The relative effect on hypopharyngeal cancer risk was much stronger for those who reported high consumption of dark liquor (relative risk = 4.4, 90% confidence interval = 2.9, 6.8) than for those reporting comparable consumption of light liquor (relative risk = 1.3, 90% CI = 0.8, 2.1). For laryngeal cancer, consumption of dark liquor had a smaller effect, and there was little distinction between the effects of dark and light liquor. The data appear consistent with the theory that the non-alcoholic content of distilled alcoholic beverages is a determinant of cancer risk, and that alcoholic beverages act topically rather than systemically in their carcinogenic action.

Alcoholic Beverages