Selected food intake and risk of multiple pregnancies

Fabio Parazzini1,2,4, Liliane Chatenoud1, Gaia Bettoni3, Luca Tozzi3, Simonetta Turco3, Matteo Surace1, Elisabetta Di Cintio1 and Guido Benzi1

1 Istituto di Ricerche Farmacologiche `Mario Negri', 2 Prima Clinica Ostetrico Ginecologica, Università di Milano, Milano and 3 Clinica Ostetrico Ginecologica, Università di Verona, Ospedale Policlinico, Verona, Italy


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In order to explore the association between multiple birth risk and diet, data were analysed from a case-control study on risk factors for multiple births conducted in Italy between 1988 and 1998. A total of 185 cases (median age 30 years) were interviewed: 36 women delivered monozygotic and 149 delivered spontaneous dizygotic multiple births. The control group comprised 498 women who gave birth at term (>37 weeks gestation) to healthy infants on randomly selected days at the same clinic. Women were specifically excluded if they reported a history of multiple pregnancy or they had received treatment for infertility for the index pregnancy. No marked differences emerged in daily intake between cases and controls and a total of 35 foods items, including the major sources of beta-carotene, retinol, ascorbic acid, vitamin D, E, methionine folate and calcium in the Italian diet. Likewise intake of selected micronutrients was largely similar in dizygotic cases, monozygotic cases and controls, with the only exception of a slightly lower intake of folates in dizygotic pregnancies in comparison with controls: this difference was statistically significant (P < 0.05), but limited in quantitative terms (mean daily intake of folate 192.4, 183.2 and 191.4 µg respectively in monozygotic, dizygotic cases and controls). In conclusion, the results of this study do not support the role of diet in the development of multiple births.

Key words: diet/epidemiology/foods/multiple births/risk factor


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Several observations have linked the intake of various nutrients/dietary factors to reproduction. There is now some evidence that low intake of salad or high intake of vitamin A increases the risk of malformations (Czeizel and Dudas, 1992Go; Czeizel et al., 1994aGo). Further, deficiencies of proteins or vitamin A have been associated in animals with the risk of miscarriage (O'Toole et al., 1974Go) and in humans of hydatidiform mole (Berkowitz et al., 1985Go; Parazzini et al., 1988Go).

With regard to multiple births, deprivation/low dietary intake during World War II has been suggested to explain the peak in twinning rates after the end of World War II observed in several countries (Parazzini et al., 1998Go; Bortolus et al., 1999Go). Otherwise, an association between vitamin supplementation and subsequent multiple birth has been reported in an Hungarian trial (Czeizel, 1993Go; Czeizel et al., 1994bGo). However this finding has not been confirmed in the Medical Research Council (MRC) study and in the prospective study of nutrition, smoking and pregnancy outcome conducted in the UK (MRC Vitamin Study Research Group, 1991Go; Mathews et al., 1999Go).

In order to explore the association between multiple birth risk and diet, data were analysed from a case control study on risk factors for multiple births conducted in Italy.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The general design of this study has been previously described (Parazzini et al., 1993Go, 1996Go). Briefly, between January 1988 and March 1998, a case-control study was conducted on risk factors for multiple pregnancies. Trained interviewers identified and questioned cases and controls using a standard questionnaire. Multiple births in patients who received treatments for infertility (assisted reproduction techniques or treatment for ovulation induction) were not included. An effort was made to define the zygosity. Between January 1988 and February 1989, the cases included in the study were women who delivered different sex multiple births at the Clinica Luigi Mangiagalli (the largest maternity hospital in Milan). In the periods 1989–1990 zygosity was defined on the basis of chromosome polymorphism in leukocytes (Paris Conference 1971, 1972Go), consequently all monozygotic twins included in the study were collected in that period. In other calendar periods, cases collected were women who delivered different sex multiple births only.

A total of 185 cases (median age 30 years) was interviewed: 36 women delivered monozygotic and 149 dizygotic multiple births. Of these, one delivered three babies. The control group comprised women who gave birth at term (>37 weeks gestation) to healthy infants on randomly selected days at the same clinic. Women were specifically excluded if they reported a history of multiple pregnancy or they had received treatment for infertility for the index pregnancy. A total of 498 control women (median age 30 years) were interviewed. Less than 2% of cases and controls refused to be interviewed. The present report is based on data collected until March 1998.

Information was collected on general sociodemographic characteristics, personal habits, gynaecological and obstetric history. Further, the weekly frequency of consumption of 35 food items before conception diagnosis was elicited, including the major sources of beta-carotene, retinol, ascorbic acid, vitamin D and E, methionine, folate and calcium. Information on portion size was also collected (small/average/large). The micronutrient intake of the food items considered was computed by multiplying the consumption frequency of each unit of food by the nutrient content of the standard average portions, using the Italian tables of food composition (Fidanza and Verdiglioni, 1988Go) integrated by other sources, when required (Souci et al., 1986Go; Paul and Southgate, 1988Go).

Statistical analysis
The odds ratios (OR) and their 95% confidence intervals (CI) were calculated as estimates of relative risk of multiple birth for selected factors including education, family history of multiple birth and parity. To account simultaneously for the effects of age and those factors, unconditional multiple logistic regression with maximum likelihood fitting was used (Breslow and Day, 1980Go). Means and SD of food intake items were calculated using age, years of education, parity and family history as co-variates. When means of micronutrients were calculated, total energy intake was added to the other co-variates listed above.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The distribution of cases and controls according to selected characteristics is shown in Table IGo. Dizygotic cases were less frequently parous and less educated than controls. A family history of multiple birth was more frequently reported both from dizygotic and monozygotic cases.


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Table I. Distribution of cases and controls according to age and selected factors
 
Table IIGo shows the estimated mean daily intake of considered foods. Mean values of selected micronutrients such as beta-carotene, folate and calcium for cases and controls respectively are shown in Table IIIGo. No marked differences emerged in daily intake between cases and controls of considered foods. Likewise, intake of selected micronutrients was largely similar in dizygotic, monozygotic cases and controls with the only exception of a slightly lower intake of folates in dizygotic pregnancies in comparison with controls: the difference was statistically significant (P < 0.05), but limited in quantitative terms.


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Table II. Mean and SD of weekly intake of selected food items
 

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Table III. Mean and SD daily intake of selected micronutrients
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Limitations of this study should be considered. Dizygotic and monozygotic multiple pregnancies represent two different entities, thus any analysis of determinants of risk of multiple births should consider them separately. Unfortunately detailed information on zygosity was available only for cases interviewed during a limited period. Thus, although information was collected on about 185 multiple pregnancies, monozygotic pregnancies were only 36. Consequently, numbers were limited for formal statistical evaluation or inference on the differences between the two entities.

Information was collected while women were in hospital for delivery. The food frequency questionnaire was tested for reproducibility (D'Avanzo et al., 1997Go), but not validated. However, any potential problem of validation is unlikely to have produced any major misclassification between cases and controls. In addition, at the time of data collection, the possible relationship between diet and multiple birth was almost certainly unknown to interviewers and most of the women interviewed. Only a small portion of the questionnaire was related to dietary factors, so the interviewers' and patients' attention was probably not concentrated on those aspects.

Information was limited to only a few dietary items, in terms of usual number of portions per week. Still, the food groups investigated include the major sources of carotenoids and folates (vegetables and fruit), as well retinoids, vitamins and calcium (milk, cheese and eggs in Italy). Selection bias is also unlikely to have produced marked effects, especially since cases and controls were recruited in the same institutions and participation was practically complete. The choice of control women who delivered healthy infants at term may have introduced some potential bias. A low caloric intake may be associated with low birth weight infants. Since women who gave birth to low birth weight infants were not included in the control group, but were included among cases, an association between diet and multiple births may arise. However, the inclusion and exclusion of cases who delivered low birth weight infants did not markedly change the result of this analysis (data not shown). Further, allowance was made for potential confounders, including indicators of socio-economic status, and other major known or likely determinants of the risk of multiple births. Bearing in mind these limitations, the results of this study do not show any association between selected dietary factors considered including milk, cheese and potatoes and risk of multiple birth.

Published findings on the relationship between diet/vitamin intake and multiple births are scanty and controversial. Nylander (Nylander, 1979Go) noted that in Nigeria the dizygotic twinning rate was four times higher in lower social class than in upper social class women. He suggested that such a high incidence might be due to the presence in the diet of oestrogen-like substances. Also, food storage conditions were suggested to have some influence on hormonal concentrations. For example zearalenone, a mycotoxin, may have an oestrogenic potency.

Some findings from a Hungarian randomized controlled trial have suggested that periconceptional multivitamin supplementation may increase the rate of multiple births (Czeizel, 1993Go; Czeizel et al., 1994bGo). Similar findings, although not completely consistent, also emerged from a re-analysis of data sets of three American studies on risk factors for congenital malformations (Werler et al., 1997Go). Other randomized studies, however, did not confirm these findings (MRC Vitamin Study Research Group, 1991Go; Mathews et al., 1999Go). No association was found between selected food intake (including major sources of vitamins in Italian diet) and risk of multiple births in the current study. In particular, estimated intakes of vitamins were not associated with the risk of dizygotic and monozygotic pregnancies. Although amounts of vitamins may be more elevated after supplementation than those due to diet intake, the results of this study do not support the existence of a major role of diet in the development of multiple births.


    Notes
 
4 To whom correspondence should be addressed at: Istituto di Ricerche Farmacologiche `Mario Negri', Via Eritrea 62, 20157 Milano, Italy. E-mail: parazzini{at}irfmn.mnegri.it Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 14, 2000; accepted on November 3, 2000.