Human Reproduction, Vol.29, No.2 pp. 351– 358, 2014 Advanced Access publication on November 27, 2013 doi:10.1093/humrep/det417

ORIGINAL ARTICLE Reproductive epidemiology

Moderate alcohol intake and menstrual cycle characteristics J. Lyngsø 1,*, G. Toft 1, B.B. Høyer1, K. Guldbrandsen 2, J. Olsen 2, and C.H. Ramlau-Hansen 2 1 Department of Occupational Medicine, Danish Ramazzini Centre, Aarhus University Hospital, Noerrebrogade 44, Build. 2C, Aarhus DK-8000, Denmark 2Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus 8000, Denmark

*Correspondence address. E-mail: [email protected]

study question: Does moderate alcohol intake affect menstrual cycle characteristics among women in the Danish population? summary answer: Levels of alcohol exposure as seen in this study do not substantially affect the menstrual cycle. what is known already: Animal studies indicate alcohol-induced disruptions of the reproductive system, but previous epidemiological studies addressing the possible association between alcohol intake and the menstrual cycle are sparse.

study design, size, duration: A cross-sectional study with retrospectively collected data including 82 146 pregnant Danish women in the Danish National Birth Cohort (DNBC) enrolled during the years 1996 –2002.

participants/materials, setting, methods: Information on weekly alcohol consumption and menstrual cycle characteristics before pregnancy was obtained through a computer-assisted telephone interview in pregnancy Week 12 –16. The associations between weekly alcohol consumption and menstrual cycle irregularity (≥7 days difference between cycles) and length (short cycle: ≤24 days, long cycle: ≥32 days) were analysed using logistic regression with weekly alcohol intake categorized into abstainers (0 drinks per week), low (0.5 – 2.0 drinks per week), moderate (2.5 –14.0 drinks per week) and high (14.0–86.5 drinks per week). Estimates are given as adjusted odds ratios with 95% confidence intervals. main results and the role of chance: The overall participation rate was 60% of the women invited. We found that a high weekly alcohol consumption was not associated with menstrual cycle disturbances. We observed higher odds of irregular and short cycles among abstainers when compared with women with a low weekly alcohol consumption, but found no trend of more cycle disturbances with higher alcohol consumption. limitations, reasons for caution: Possible limitations in our study include a risk of selection bias due to the moderate participation rate and the use of retrospective information on alcohol exposure and menstrual cycle characteristics before getting pregnant. The higher odds of irregular and short cycles among abstainers may reflect other health problems in these women rather than an actual effect of alcohol on the menstrual cycle. wider implications of the findings: The generalizability of the study results is restricted to women who manage to conceive and women who do not use oral contraceptives within 2 months before getting pregnant. This study suggests that the menstrual cycle is not substantially affected by higher alcohol consumption among the participating women. study funding/competing interest(s): Supported by a scholarship from Aarhus University Research Foundation. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. No conflict of interest declared. Key words: menstrual cycle / alcohol drinking / female reproduction

& The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]

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Submitted on July 19, 2013; resubmitted on September 26, 2013; accepted on October 22, 2013

352

Introduction and background

The objective of this study is to investigate the association between estimated alcohol intake and menstrual cycle length and irregularity among women participating in the DNBC, thereby representing the largest cohort to examine the association with defined menstrual disturbances and the potential of adjusting for possible confounders.

Materials and Methods Study population The study is based upon data from the DNBC in which a total of 92 743 pregnant women were enrolled. The women participated in the early pregnancy interview (n ¼ 90 139) and provided information about lifestyle during the years 1996– 2002 after the first antenatal care visit at their general practitioner. If a woman had a miscarriage before responding to the interview, she was offered a slightly modified version of this interview (spontaneous abortion interview, n ¼ 2604) shortly after the miscarriage. About 50% of the general practitioners in Denmark participated in the recruitment process, and 60% of the invited women accepted the invitation, resulting in a participation rate of 30% of all the pregnant women in the country during that time period. At the antenatal care visit, the woman received oral and written information about the DNBC and was included as a participant in the cohort if she mailed back a signed informed consent following the antenatal care visit. Inclusion criteria for the cohort, besides being pregnant, were; living in Denmark; intention to carry the pregnancy to term and speaking Danish well enough to participate in four telephone interviews during pregnancy and early motherhood (Juhl et al., 2001). The women provided information on exposures by means of a computer-assisted telephone interview scheduled in pregnancy Week 12 or as soon as possible thereafter (range 7 – 40 weeks). Detailed information on this cohort is described elsewhere (Olsen et al., 2001) and an English version of the interviews and further information about data collection are available at www.dnbc.dk. The study protocols were approved by the Danish Data Protection Board (2013-41-1495) and the DNBC Steering Committee (2013-02) before initiation of the study.

Excluded women From the 92 743 women interviewed, 764 were excluded from the analysis due to reports of reproductive diseases, including endometriosis, bleeding disorders, unspecified diseases in the ovaries, cancer in the ovaries, unspecified diseases in the uterus, fibroids or malformation of the uterus. Also, 613 were excluded because they used oral contraceptives when getting pregnant or used them 2 months before getting pregnant (n ¼ 9216). Another four women were excluded due to likely reporting error (average cycle length ,16 days). Thus, the final study population comprised 82 146 Danish women of reproductive age (79 811 women from the early pregnancy interview and 2335 from the spontaneous abortion interview).

Exposure to alcohol All women were asked about the average weekly consumption of bottles of beer, glasses of wine and glasses of spirits, respectively, before getting pregnant. The answers were recorded in units of alcohol (drinks) as none, ,1 bottle/glass per week or the number of bottles/glasses per week. No validation study has been performed regarding the questions used to assess alcohol intake or the fact that alcohol content of beer can vary greatly. However, the definition of a drink followed the definition of the Danish National Board of Health with one drink containing 12 g of alcohol which is equivalent to one normal bottle of beer and an average for a serving of wine or spirits in Denmark (Juhl et al., 2001). If less than one unit per week

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Alcohol intake may affect the female reproductive function in numerous ways. Studies in rats and monkeys have demonstrated alcohol-induced disruptions of the reproductive system with both decreased and increased levels of estradiol, decreased levels of progesterone, reduced ovarian weight, amenorrhea and prolonged interval between menstruations (Van Thiel et al., 1978; Mello et al., 1983; Gavaler and Van Thiel, 1987; Dees et al., 2000; Emanuele et al., 2001). Epidemiologic studies have shown longer waiting time to pregnancy and increased risk of infertility in women with a high intake of alcohol (Olsen et al., 1997; Eggert et al., 2004; Mutsaerts et al., 2012). Also, low levels of alcohol have been suggested to have a negative impact on female fecundity (Grodstein et al., 1994; Hakim et al., 1998; Jensen et al., 1998). However, others do not find any association between moderate alcohol intake and waiting time to pregnancy (Olsen et al., 1983; Joesoef et al., 1993; Curtis et al., 1997). A study within the Danish National Birth Cohort (DNBC) found that moderate drinkers had slightly shorter waiting times than abstainers (Juhl et al., 2001) and that the association was most pronounced among women drinking wine (Juhl et al., 2003). Menstrual cycle disturbances have been associated with several risk factors, including younger and older ages (Collett et al., 1954; Harlow et al., 2000), low and high BMI (Jensen et al., 1999), smoking (Rowland et al., 2002), extreme exercise (Chen and Brzyski, 1999), work stress (Hatch et al., 1999) and chemical compounds such as polychlorinated biphenyls (Buck Louis et al., 2011). A few studies have examined the possible association between alcohol intake and menstrual cycle regularity, but these studies are small and much of the research involves studies of animals or a high level of alcohol intake which often correlate with other risk factors (Hugues et al., 1980; Mendelson and Mello, 1988; Becker et al., 1989). In female rats, acute and high alcohol exposure is found to disrupt the female hypothalamic –pituitary –gonadal axis (LaPaglia et al., 1997) and alter the secretion of gonadotrophins during the estrous cycle (Alfonso et al., 1993). In humans, several studies have reported an association between alcohol intake and elevated estrogen levels in premenopausal women (Reichman et al., 1993; Eriksson et al., 1996; Muti et al., 1998; Sarkola et al., 1999) and a study on 31 alcoholic females found that chronic alcoholism was associated with a defect in the cyclic control of sex hormones at the hypothalamo– pituitary level (Hugues et al., 1980). Also, alcoholic women are shown to have higher frequencies of menstrual length variability when compared with nonalcoholics (Becker et al., 1989). A study on 917 American women found that irregular or interrupted periods were only increased in women who reported high levels of alcohol intake (six or more drinks at least 5 days a week; Wilsnack et al., 1984). Several possible mechanisms of action have been suggested: the alcohol-induced rise in estradiol is likely to be a consequence of alcohol metabolism (Mendelson et al., 1987), while others have suggested that alcohol induces an increased aromatization of testosterone to estradiol (Gavaler et al., 1993). However, the mechanism of action by alcohol on the female reproductive hormones most likely involves several pathways (Gill, 2000). In contrast, a study including 2912 women from the US navy showed no association between alcohol intake and menstrual symptoms such as ‘excessive frequency’ or ‘irregular periods’ (Kritz-Silverstein et al., 1999), and an association between alcohol intake and female fecundity is still not established.

Lyngsø et al.

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Alcohol intake and the menstrual cycle

was reported, this was coded as half a drink per week. In the analysis, each type of beverage was added together to give a total alcohol consumption variable, reported as drinks per week.

Menstrual cycle characteristics The participants were asked about their menstrual cycle characteristics in the period when trying to become pregnant. They were asked whether their menstruations were regular, in the sense that they were able to predict the time of the next menstruation within 1 week. Further, women reporting regular cycles were asked about the number of days from the first day of one menstruation to the first day in the next. For this study, women who reported a difference of 7 days or more in cycle lengths between months were defined as having irregular cycles (Kolstad et al., 1999; Small et al., 2006). Short cycles were defined as 24 days or less, whereas long cycles were 32 days or more. These definitions are based on the distribution of cycle length and fertility in relation to cycle length in prospective studies (Kolstad et al., 1999; Small et al., 2006). All three types of menstrual disorders are treated as separate outcomes.

Information about covariates was also obtained from the early pregnancy interviews. A priori, we determined which covariates to include in the analysis based on a review of the literature. We included data on age at pregnancy, age at menarche, tobacco smoking, pre-pregnancy BMI, chronic diseases and the women’s occupational status. Age of menarche was generated by combining data on age of menarche and school grades for those who reported a grade rather than age of menarche and categorized as follows: ≤12 years (≤6th grade), 13 – 14 years (7th– 8th grade) and ≥15 years (≥9th grade). As smoking was only reported during pregnancy, we used this as a proxy of the women’s smoking habits before pregnancy, recognizing that some pregnancy non-smokers may have been smokers before pregnancy. Prepregnancy BMI based on self-reported weight and height was classified according to the WHO classification (,18.5 kg/m2, 18.5 – 24 kg/m2, 25 – 29 kg/m2 and .30 kg/m2; World Health Organization, 2000). The variable chronic diseases were generated from the interviews and included women reporting metabolic diseases, eating disorders or psychiatric disorders. The social variable was based on data on her and her partner’s occupational status with six categories (higher grade professionals, lower grade professionals, skilled workers, unskilled workers, students and unemployed) and clarified according to the highest status in the household.

Statistical analysis Missing information In total, exposure-data were missing for 0.5%, data on irregular cycle were missing for 0.5% while data on cycle length were missing for 17.4% of the included women (Table I). As complete-case analysis may lead to biased estimates (Rubin and Little, 1987; Sterne et al., 2009), we used multiple imputations to complete the dataset. We generated 50 complete datasets with imputed data. The following variables were included as predictors in the main imputation model: beer, wine, spirits, irregular cycle, mean cycle length, minimum cycle length, maximum cycle length, age at pregnancy, age at menarche, smoking, prepregnancy BMI, chronic diseases, occupational status, parity, time to pregnancy, coffee, binge drinking and preference of red or white wine. We performed a sensitivity analysis, using different imputation models including both a smaller and larger number of predictors and creating two additional datasets (m ¼ 20 and 80). In addition, we compared results

Data analysis The associations between alcohol intake and menstrual cycle characteristics were modelled by using multiple logistic regression analysis. Total alcohol consumption was categorized into four groups; abstainers (0 drinks per week), low (0.5– 2.0 drinks per week), moderate (2.5 –14.0 drinks per week) and high (14.0–86.5 drinks per week) consumption. As indicated by others (Juhl et al., 2001; Schmidt and Pinborg, 2012), the group of abstainers may include women with medical reasons not to drink and, thus, we chose the group with a low alcohol intake as reference in our analyses a priori. Odds ratios (ORs) for short and long cycles were estimated by using logistic regression in separate models with normal cycles as reference (length 25 –31 days). As only women reporting regular cycles were asked to report their cycle length, data on cycle length are not missing at random. Therefore, the analyses concerning cycle length (short and long cycles) are restricted to women with regular cycle. All outcome variable estimates are presented as crude and adjusted ORs with 95% confidence intervals (CIs), where a high OR indicates higher odds of cycle disturbances due to higher alcohol exposure. To take into account that some women appeared twice in the study because they had more than one pregnancy during study recruitment, robust standard errors were used. In addition, logistic regression analysis with alcohol exposure as a continuous variable was performed to test for trend, thereby giving the odds of cycle disturbances for each unit increase in alcohol exposure (Kirkwood and Sterne, 2003). To allow for a flexible association between alcohol intake and menstrual cycle characteristics alcohol data were also modelled using restricted cubic splines with seven knots in the presentation of irregular cycle, using an alcohol intake of two drinks per week as reference (Durrleman and Simon, 1989; Greenland, 1995). In the splines, we modelled the estimated adjusted OR with 95% CI of irregular cycle as a function of the weekly alcohol consumption (drinks per week). In a sub-analysis, we made a multiple linear regression analysis between continuous alcohol exposure and continuous mean cycle length for women with regular cycles. Further, we stratified data according to type of alcohol (beer, wine or spirits) to asses if the association differed for women preferring different kinds of alcohol, as women with the same drinking habits are believed to represent a more homogenous group.

Results Characteristics of the 82 146 women included in the study are presented in Table I. About 16% reported having irregular cycle. Only 68 962 reported regular cycle and thus reported their cycle length. A total of 4.4% had short cycles while 5.0% had long cycles. Compared with women with low alcohol consumption, abstainers were in general younger, multiparous, smokers, less often of normal weight, had more chronic diseases and lower occupational status. Women who had a high alcohol intake were older, more often nulliparous, smokers, had more often normal weight, chronic diseases and higher occupational status in comparison with women with low alcohol consumption. The

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Covariates

using the strategy of complete-case analysis (i.e. when only subjects with full information on the variables needed in any given analysis were included) with multiple imputation-based analysis. All imputations were implemented with the ice add-on command and the built-in mi estimate command of STATA 11 (Stata Corporation, College Station, TX, USA).

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Lyngsø et al.

Table I Characteristics of the 82 146 women according to weekly alcohol consumption before pregnancy. Weekly alcohol consumption before pregnancy (drinks per week)

.............................................................................................................................................. Abstainers (0)

Low (0.5 –2.0)

Moderate (2.5– 14.0)

High (>14.0)

Missinge

Total

............................................................................................................................................................................................. Total, n (%)

10 863 (13.2)

33 694 (41.0)

36 106 (44.0)

1098 (1.3)

385 (0.5)

82 146 (100.0)

Irregular cycle (≥7 daysa) Yes, n (%)

1957 (18.0)

5273 (15.6)

5285 (14.6)

181 (16.5)

66 (17.1)

12 762 (15.5)

No, n (%)

8854 (81.5)

28 253 (83.9)

30 630 (84.8)

913 (83.2)

312 (81.0)

68 962 (84.0)

191 (0.5)

4 (0.4)

7 (1.8)

28.2 (2.4)

27.9 (2.4)

796 (72.5)

266 (69.1)

Missing, n (%)

52 (0.5) b

Cycle length (days) , mean (SD) Normal cycle (25– 31), n (%)

168 (0.5)

28.1 (2.5)

28.2 (2.4)

28.3 (2.3)

7613 (70.1)

24 531 (72.8)

26 836 (74.3)

422 (0.5) 28.2 (2.4) 60 042 (73.1)

594 (5.5)

1558 (4.6)

1448 (4.0)

47 (4.3)

23 (6.0)

3670 (4.4)

487 (4.5)

1724 (5.1)

1893 (5.2)

50 (4.6)

7 (1.8)

4161 (5.0)

2169 (20.0)

5881 (17.5)

5929 (16.4)

205 (18.7)

89 (23.1)

14 273 (17.4)

28.9 (4.5)

29.5 (4.1)

30.5 (4.3)

30.4 (5.6)

28.5 (4.9)

29.9 (4.3)

4 (0.0)

4 (0.0)

5 (0.0)

1 (0.1)

1 (0.3)

15 (0.0)

Missing, n (%) Age (years), mean (SD) Missing, n (%) Parity 0, n (%)

3770 (34.7)

13 933 (41.4)

17 751 (49.2)

754 (68.7)

225 (58.4)

36 433 (44.4)

≥1, n (%)

6975 (64.2)

19 405 (57.6)

17 812 (49.3)

322 (29.3)

155 (40.3)

44 669 (54.4)

543 (1.5)

22 (2.0)

5 (1.3)

1044 (1.2) 20 478 (24.9)

Missing, n (%)

118 (1.1)

356 (1.0)

Age of menarche (years) ≤12, n (%)

3067 (28.2)

8467 (25.1)

8555 (23.7)

291 (26.5)

98 (25.5)

13–14, n (%)

5927 (54.6)

19 409 (57.6)

21 013 (58.2)

611 (55.6)

215 (55.8)

47 175 (57.4)

≥15, n (%)

1744 (16.1)

5450 (16.2)

6220 (17.2)

186 (16.9)

54 (14.0)

13 654 (16.6)

125 (1.2)

368 (1.1)

318 (0.9)

10 (0.9)

18 (4.7)

Missing, n (%)

839 (1.0)

c

Smoking

Yes, n (%)

3550 (32.7)

7935 (23.6)

8973 (24.9)

569 (51.8)

163 (42.3)

21 190 (25.8)

No, n (%)

7307 (67.3)

25 751 (76.4)

27 122 (75.1)

528 (48.1)

218 (56.6)

60 926 (74.2)

1 (0.1)

4 (1.0)

Missing, n (%)

6 (0.1)

8 (0.0)

11 (0.0)

30 (0.0)

Pre-pregnancy BMI (kg/m2) ,18.5, n (%)

655 (6.0)

1517 (4.5)

1461 (4.0)

57 (5.2)

17 (4.4)

3707 (4.5)

18.5–24, n (%)

6090 (56.1)

21 289 (63.2)

26 058 (72.2)

817 (74.4)

251 (65.2)

54 505 (66.4)

25–29, n (%)

2388 (22.0)

7001 (20.8)

6156 (17.0)

155 (14.1)

69 (17.9)

15 769 (19.2)

≥30, n (%)

1515 (13.9)

3326 (9.9)

1908 (5.3)

48 (4.4)

25 (6.5)

6822 (8.3)

215 (2.0)

561 (1.7)

523 (1.4)

21 (1.9)

23 (6.0)

1343 (1.6)

Missing, n (%) Chronic diseasesd Yes, n (%)

1638 (15.1)

3977 (11.8)

4447 (12.3)

240 (21.9)

65 (16.9)

10 367 (12.6)

No, n (%)

9225 (84.9)

29 717 (88.2)

31 659 (87.7)

858 (78.1)

318 (82.6)

71 777 (87.4)

0 (0.0)

2 (0.5)

331 (30.1)

55 (14.3)

Missing, n (%)

0 (0.0)

0 (0.0)

0 (0.0)

2 (0.0)

Occupational status Higher grade professionals, n (%)

1437 (13.2)

6690 (19.9)

11 209 (31.0)

19 722 (24.0)

Lower grade professionals, n (%)

2657 (24.5)

10 744 (31.9)

11 902 (33.0)

278 (25.3)

106 (27.5)

25 687 (31.3)

Skilled workers, n (%)

3732 (34.4)

10 104 (30.0)

8310 (23.0)

237 (21.6)

109 (28.3)

22 492 (27.4)

Unskilled workers, n (%)

2539 (23.4)

5120 (15.2)

3496 (9.7)

170 (15.5)

78 (20.3)

11 403 (13.9)

Students, n (%)

231 (2.1)

678 (2.0)

891 (2.5)

59 (5.4)

21 (5.5)

1880 (2.3)

Unemployed .1 year, n (%)

207 (1.9)

257 (0.8)

177 (0.5)

19 (1.7)

9 (2.3)

669 (0.8)

60 (0.6)

101 (0.3)

121 (0.3)

4 (0.4)

7 (1.8)

293 (0.4)

Missing, n (%)

The DNBC 1996 –2002. a Irregular cycle is defined as ≥7 days of variation. b Cycle length was only reported by the women reporting regular cycles, n (%): 67 873 (82.6) [Abstainers; 8694 (80.0), Low; 27 813 (82.5), Moderate; 30 177 (83.6), High; 893 (81.3) and Missing; 296 (25.2)]. c Tobacco smoking was reported during pregnancy. d Chronic diseases included; metabolic disorders, eating disorders and psychiatric disorders. e As the alcohol variable is generated by adding the weekly consumption of beer, wine and spirits, a missing value in one of these variables resulted in a missing value of the total alcohol variable. Of the 385 women with missing alcohol exposure, 293 had missing in only one of the three, 64 had missing values in two, while 28 had missing values in all three.

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Short cycle (≤24), n (%) Long cycle (≥32), n (%)

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Alcohol intake and the menstrual cycle

Table II ORs for irregular, short or long cycles according to weekly alcohol consumption before pregnancy (n 5 82 146). Weekly alcohol consumption (drinks per week)

Irregular cycle (≥7 days)

Short cycle (≤24 days)

Long cycle (≥32 days)

................................................

................................................

................................................

Crude OR (95% CI)

Crude OR (95% CI)

Crude OR (95% CI)

Adjusted OR (95% CI)

Adjusted OR (95% CI)

Adjusted OR (95% CI)

............................................................................................................................................................................................. Abstainers (0) Low (0.5–2)

1.18 (1.11;1.25) 1.0 (ref.)

1.11 (1.04;1.18)

1.22 (1.11;1.35)

1.0 (ref.)

1.0 (ref.)

1.13 (1.03;1.25) 1.0 (ref.)

0.91 (0.82;1.01) 1.0 (ref.)

0.94 (0.84;1.04) 1.0 (ref.)

Moderate (2.5– 14)

0.92 (0.89;0.96)

0.99 (0.95;1.04)

0.85 (0.79;0.92)

0.90 (0.84;0.98)

1.00 (0.94;1.07)

1.02 (0.95;1.09)

High (.14)

1.06 (0.90;1.25)

1.10 (0.93;1.29)

0.93 (0.69;1.26)

0.90 (0.66;1.22)

0.92 (0.69;1.22)

1.00 (0.75;1.34)

1.00 (0.99;1.00)

1.01 (1.00;1.01)

0.98 (0.97;1.00)

0.99 (0.98;1.00)

1.00 (0.99;1.01)

1.00 (0.99;1.01)

a

Continuous

median time for completing the interview was at 17 weeks of gestation (range 7– 40 weeks), and 71.8% completed it between 12 and 20 weeks of gestation. By 20 weeks of gestation, 75% had completed the interview (data not shown). Crude and adjusted ORs with 95% CI for irregular, short and long cycles according to exposure levels of weekly alcohol consumption are given in Table II. The results show that women who abstained from drinking alcohol had higher odds of irregular cycle when compared with women who had a low alcohol intake. Also, data showed higher odds of short cycle length among women who abstained from drinking, while women reporting moderate alcohol intake had lower odds of short cycle when compared with the group of women with a low intake. No statistically significant associations were found when comparing women with high alcohol intake to the group of women with a low intake. Further, no statistically significant associations were observed between intake of alcohol and long menstrual cycle. Supplementary data, Table SI shows crude and adjusted ORs from the complete-case analysis. Furthermore, it presents the number of persons in each exposure group as well as the number of cycle characteristics encountered in each of these. Results based on complete-case analysis (Supplementary data, Table SI) were similar to those based on multiple imputation of missing values (Table II). The spline regression analysis (Fig. 1) revealed a somewhat J-shaped association between the weekly alcohol intake and the adjusted OR of irregular cycle, illustrating the relative higher odds for abstainers when compared with women with moderate alcohol consumption. The sub-analysis between continuous alcohol exposure and continuous mean cycle length for women with regular cycles did not show a statistical significant association (data not shown). A sub-analysis stratified by type of alcohol (beer, wine or spirits) is presented in the Supplementary data, Table SII.

Discussion Higher weekly alcohol consumption was not associated with more frequent menstrual cycle disturbances in this study. We observed higher

Figure 1 ORs for irregular cycle according to weekly alcohol consumption before pregnancy. Spline analysis. Estimated ORs with 95% CIs (upper and lower dotted lines) of irregular cycle as a function of the weekly alcohol intake (drinks per week), using an alcohol intake of two drinks per week as reference. Irregular cycle is defined as ≥7 days variation in length. The model is restricted to complete cases (i.e. only subjects with full information on all variables required) with an alcohol intake of ,40 drinks per week. Adjusted for age, age of menarche, tobacco smoking during pregnancy, pre-pregnancy BMI, chronic diseases and occupational status.

odds of irregular and short cycles among abstainers when compared with women with a low weekly alcohol consumption, but found no trends towards more cycle disturbances with higher alcohol consumption. The National Board of Health in Denmark state that a high alcohol consumption is related to menstrual cycle disturbances, while women who stop drinking will experience fewer cycle disturbances. Our results, with a majority of moderate drinkers, do not support that women in the Danish population experience substantially more

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Multiple imputations: logistic regression analysis. The DNBC, 1996– 2002. Short cycles and long cycles are compared with normal cycles as reference (25 –31 days). Adjusted for age, age of menarche, tobacco smoking during pregnancy, pre-pregnancy BMI, chronic diseases and occupational status. CI, confidence interval. a Alcohol ≥0.5 drinks per week as a continuous variable in test for trend irregular cycle is defined as ≥7 days of variation. As only women with regular cycles reported their cycle length, the analyses concerning short and long cycles are reported in relation to women with regular cycles only.

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women not reporting irregularities in cycle length. However, Mumford et al. (2012) reported that menstrual cycle length may be a relevant indicator of estradiol exposure and risk of anovulation among regularly cycling women. Age at menarche is an independent risk factor of menstrual disturbances. Further, some studies have shown that girls with early menarche have a tendency for more abusive behaviour and depression, and an association with alcohol intake is also reported (KaltialaHeino et al., 2011; Richards and Oinonen, 2011). Thus, we find it likely that age of menarche is associated with alcohol exposure and therefore a possible confounder of the association, although one could also speculate that age of menarche could be an intermediate on the causal path between alcohol and time to pregnancy. Residual and uncontrolled confounding cannot be ruled out. It is well known that women with a high alcohol intake have other unhealthy habits and potential alcohol-related diseases that are difficult to adjust for. Also, the group of abstainers probably include women with chronic diseases. In contrast, women with a low-to-moderate intake more often have healthier lifestyles as illustrated in studies reporting shorter time to pregnancy among these women (Juhl et al., 2001, 2003). However, these findings are considered a result of the general healthier lifestyle and thus not considered related to the consumption of alcohol (Schmidt and Pinborg, 2012). Our results with higher odds of cycle disturbances among the group of abstainers and lower odds of short cycle among moderate drinkers compared with women with a low alcohol intake are in line with this. Thus, the results are believed to demonstrate health problems among abstainers rather than an actual effect of alcohol consumption on the menstrual cycle. Strengths of this study include the large population-based study design, the possibility of controlling for a variety of potential confounders and that the study was carried out in a cultural setting where alcohol consumption among women is socially accepted. However, those women who are may be alcoholic cannot be identified in the DNBC and women unable to get pregnant are not represented, limiting the generalizability to women who are able to conceive. For public health matters, it is important to determine whether the intake of alcohol among women might disrupt their menstrual cyclicity and thereby potentially affect their fertility. In this study, we found no dose–response pattern between alcohol consumption and cycle disturbances. In conclusion, our findings suggest that levels of alcohol exposure found in this cohort do not substantially affect the menstrual cycle.

Supplementary data Supplementary data are available at http://humrep.oxfordjournals.org/.

Acknowledgements The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation.

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menstrual disturbances when comparing moderate consumers to women with a low alcohol intake. Data on a possible association between alcohol intake and menstrual cycle disturbances are sparse. Though several animal studies have indicated possible disruptions of the hormonal system controlling the menstrual cycle when exposed to alcohol (Alfonso et al., 1993; LaPaglia et al., 1997), the estrous cycle in rodents may differ too much from human conditions to draw firm conclusions and further, exposure levels are often much higher in these studies compared with exposure in human. The literature concerning alcohol and the female reproductive system is very sparse, and studies are small or focus on a high alcohol intake (Wilsnack et al., 1984; Emanuele et al., 2002). A large American study on 2912 women, reported no association between alcohol intake and irregular periods (Kritz-Silverstein et al., 1999). Yet, they did not control for use of oral contraceptives and only had access to self-reported data on menstrual symptoms such as menses and irregular periods. There are limitations in our study which leaves room for bias: The participation rate among women invited to the study was about 60%. However, to cause selection bias, the decision to participate has to be associated with both alcohol intake and menstrual cycle characteristics, which we believe is unlikely. Studying the association between alcohol intake and the menstrual cycle was not specified as one of the aims of this cohort. Also, it has been shown that the low participation rate does not induce selection bias at baseline in this particular cohort (Nohr et al., 2006). However, generalizability may be affected due to selection related to socioeconomic status (Jacobsen et al., 2010). One of the most serious limitations of the study is its use of retrospective data. Although recall time regarding both exposure and outcome was rather short, use of retrospective data leaves room for recall bias and thus we cannot rule out some misclassification. As for most previous epidemiological studies on alcohol intake, our study relies on self-reported data regarding the amount of alcohol exposure, which is in general assumed to be under-reported. If the proportion of under-reporting is equally distributed among the different exposure groups, the observed results of no effect on menstrual cyclicity might apply to an even higher alcohol intake. If women with a high alcohol consumption were more susceptible to under-reporting alcohol use, this could bias the reported association towards the null. However, the level of alcohol intake investigated in this cohort is considered acceptable by the general Danish population, and a study performed in settings similar to the DNBC found that an interview is a reliable method to obtain information on alcohol intake among Danish pregnant women (Kesmodel and Olsen, 2001). Information on menstrual cycle characteristics was obtained through recall of the period when trying to become pregnant. The accuracy of data on menstrual cycles is not perfect. Recent studies observed a poor-to-moderate agreement between self-reported menstrual cycle length and prospectively observed cycle length (Small et al., 2007; Jukic et al., 2008), while others have shown good correlations between selfreport and the average, actual cycle length (Steiner et al., 2001; Creinin et al., 2004). We determined cut-off points for all three outcome variables based on existing literature (Kolstad et al., 1999; Small et al., 2007), however, several other definitions regarding short, long and irregular cycles have been proposed (Jukic et al., 2008; Fruscalzo et al., 2010; Yang et al., 2011; Mumford et al., 2012). Further, only women with regular cycles reported their cycle length. The relation between cycle irregularities and changes in cycle length is well established and, thus, our results regarding short and long cycle are only valid for

Lyngsø et al.

Alcohol intake and the menstrual cycle

Authors’ roles J.L., G.T., B.B.H., J.O. and C.H.R.H.: Contributions to conception, design, data interpretation. J.L., G.T., B.B.H., J.O., K.G. and C.H.R.H.: Paper revision and approval of the submitted version. J.L., C.H.R.H., B.B.H., J.O. and G.T.: Acquisition of data and data analysis. J.L.: drafting the paper.

Funding Julie Lyngsø’s scholarship was granted by the Aarhus University Research Foundation.

Conflict of interest None declared.

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Lyngsø et al.

Moderate alcohol intake and menstrual cycle characteristics.

Does moderate alcohol intake affect menstrual cycle characteristics among women in the Danish population?...
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