Factors Associated with Increased Pain in Primary Dysmenorrhea: Analysis Using a Multivariate Ordered Logistic Regression Model

Accepted Manuscript Factors associated with increased pain in primary dysmenorrhoea: analysis through a multivariate ordered logistic regression model María I. Tomás-Rodríguez, PhD, Antonio Palazón-Bru, PhD, Damian RJ. Martínez-St. John, PhD, Felipe Navarro-Cremades, MD, PhD, José V. Toledo-Marhuenda, PhD, Vicente F. Gil-Guillén, MD, PhD PII:

S1083-3188(16)30177-2

DOI:

10.1016/j.jpag.2016.09.007

Reference:

PEDADO 2044

To appear in:

Journal of Pediatric and Adolescent Gynecology

Received Date: 29 July 2016 Accepted Date: 20 September 2016

Please cite this article as: Tomás-Rodríguez MI, Palazón-Bru A, Martínez-St. John DR, NavarroCremades F, Toledo-Marhuenda JV, Gil-Guillén VF, Factors associated with increased pain in primary dysmenorrhoea: analysis through a multivariate ordered logistic regression model, Journal of Pediatric and Adolescent Gynecology (2016), doi: 10.1016/j.jpag.2016.09.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT TITLE PAGE Title: Factors associated with increased pain in primary dysmenorrhoea: analysis through a multivariate ordered logistic regression model.

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Authors: María I Tomás-Rodríguez, PhD1, Antonio Palazón-Bru, PhD2,3, Damian RJ Martínez-St. John, PhD2, Felipe Navarro-Cremades, MD, PhD2, José V Toledo-Marhuenda, PhD1, Vicente F Gil-Guillén, MD, PhD2,3.

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1: Department of Pathology and Surgery, Miguel Hernández University, San Juan de

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Alicante, Alicante, Spain.

2: Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Alicante, Spain.

3: Research Unit, Elda General University Hospital, Elda, Alicante, Spain.

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Corresponding author: Prof. Antonio Palazón-Bru, PhD. Department of Clinical Medicine, Miguel Hernández University, Carretera de Valencia - Alicante S/N, 03550 San Juan de Alicante, Alicante, Spain. Telephone: +34 965919449. Fax: +34 965919450. E-mail:

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[email protected].

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Conflict of interest statement: Nothing to declare.

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ACCEPTED MANUSCRIPT ABSTRACT Study objective: In the literature about primary dysmenorrhoea (PD), either a pain gradient has been studied just in women with PD or pain was assessed as a binary variable (presence

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or absence). Accordingly, we decided to carry out a study in young women to determine possible factors associated with intense pain. Design: A cross-sectional observational study.

Participants: A total of 306 women, aged 18-30 years.

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Setting: A Spanish University in 2016.

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Interventions: A questionnaire was filled in by the participants to assess associated factors with dysmenorrhoea.

Main outcome measures: Our outcome measure was the Andersch and Milsom scale (grade from 0 to 3). Definition: Grade 0 (menstruation is not painful and daily activity is

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unaffected), Grade 1 (menstruation is painful but seldom inhibits normal activity, analgesics are seldom required, and mild pain), Grade 2 (daily activity affected, analgesics required and give relief so that absence from work or school is unusual, and moderate pain) and Grade 3

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(activity clearly inhibited, poor effect of analgesics, vegetative symptoms and severe pain). Results: Factors significantly associated with more extreme pain: a higher menstrual flow

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(OR=2.11, p<0.001), a worse quality of life (OR=0.97, p<0.001) and use of medication for PD (OR=8.22, p<0.001).

Conclusions: We determined factors associated with extreme pain in PD in a novel way. Further studies are required to corroborate our results. KEYWORDS: Dysmenorrhea; Menstruation; Women's Health.

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ACCEPTED MANUSCRIPT INTRODUCTION

Primary dysmenorrhoea (PD) is a frequent gynaecological disorder in young women that can be a cause for absence from work or school.1-3 Nevertheless, only a few women seek medical

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help for this disorder.4. The epidemiology of PD is difficult to establish due to the different influencing

factors, the subjective nature of the symptoms and the variety of diagnostic criteria. As for

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the prevalence, a great variation is reported, between 11% and 90%, depending on the study.5A great number of factors have been associated with this gynaecological disorder, notably

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psychological factors (anxiety, depression and stress), a family history of PD, lifestyle (smoking, alcohol, diet and physical activity), menstrual characteristics (menstrual bleed and cycle duration, menstrual regularity and menstrual flow), and other factors, like obesity, age and quality of life.9-25 In addition, great variation exists in the pain reported by the women,

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and it is important to determine what factors are associated with greater pain in PD, because this will enable us to know whether differences exist according to a pain gradient. As far as we are aware one study has been undertaken involving a sample consisting exclusively of

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women suffering from PD, though it just analysed a single associated factor (quality of sleep) in relation to the degree of pain. Nevertheless, the authors assessed both primary and

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secondary dysmenorrhoea.13 Another study undertaken in women who all had PD (mild, moderate or severe) determined factors associated with an increase in pain,21 defined as a greater mean score on a visual analogue scale. This study, though, did not include women who used pain medication and excluded those who had no type of pain. Therefore these exclusion criteria likely change the median pain ratings. This creates a sub-sample of patients with PD that already tends to have more severe symptomatology. Accordingly, we carried out a study in a Spanish province involving young women (18-30 years of age) without eliminating those who may have taken medication for menstrual pain and including those

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ACCEPTED MANUSCRIPT who reported no pain. In all these women we evaluated the factors associated with greater

intensity of pain using the Andersch and Milsom scale,26 which defines 4 stages according to work activity, the systemic symptoms and the taking of medication. Unlike most other

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authors,9-25 who evaluated the presence of pain in a binary manner, we used an ordinal regression model to determine how the factors studied affect a greater intensity of pain. This

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gives our study its innovative character.

MATERIALS & METHODS

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Study population

The study population comprised young women (18-30 years of age) studying at the School of Health Sciences at Miguel Hernández University (Alicante, Spain). Study design and participants

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This was a cross-sectional observational study. To obtain the study sample we divided the School of Health Sciences into degree courses and each of these into subjects. With this grouping we then undertook a stratified random sampling in two stages to determine which

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subjects from which degree course would be selected. After selection, we asked the professors in charge of each subject for permission to explain our study to their students. In

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each of the chosen classes we asked for the cooperation of women and we gave them a questionnaire to detect which women fulfilled none of the exclusion criteria. Use of this type of sampling procedure (random) means that our study participants have similar characteristics to those of the general population. The exclusion criteria were: not having regular menstrual cycles (typical cycle between 21 and 35 days,27 because an abnormal menstrual duration could be associated with other gynaecological disorders), having an intrauterine device fitted, using oral contraceptives, having given birth, presence of secondary dysmenorrhoea, not having

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ACCEPTED MANUSCRIPT undergone a general gynaecological evaluation within the past 18 months, undergoing surgery during the study, and a diagnosis of any serious disease, e.g., cardiovascular disease, dementia, malignant tumour, metastasis.28 This study was completed between the 17th of

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February and the 30th of April 2016. Variables and measurements

The main variable was the grade (from 0 to 3) on the Andersch and Milsom scale.26 The

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women were questioned about each one of the three categories on this scale (work activity, systemic symptoms and need for analgesics). Definition of the grades: Grade 0 (menstruation

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is not painful and daily activity is unaffected), Grade 1 (menstruation is painful but seldom inhibits the woman’s normal activity, analgesics are seldom required, and mild pain), Grade 2 (daily activity affected, analgesics required and give relief so that absence from work or school is unusual, and moderate pain) and Grade 3 (activity clearly inhibited, poor effect of

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analgesics, vegetative symptoms and severe pain). Although this scale to determine menstrual pain was developed in the 1980s, it is still used in studies to assess factors associated with PD.14-16

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The secondary variables were menstrual cycle length (21-27, 28-31 and 32-35 days), menstruation duration (1-3, 4-6 and 7-9 days), family history of PD (mother, sisters and

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grandmothers), menstrual flow (low, medium or high), personal history of smoking, use of medication for PD (yes or no), quality of life measured by the EuroQol-5D questionnaire (EQ-5D) (%),29 body mass index (BMI) (kg/m2) and age (years). All the variables were measured using an original self-administered questionnaire, except for the Spanish version of the EQ-5D. The variables concerning the duration of the menstrual cycle and the duration of menstruation were categorised in order make it easier for the participants to complete the questionnaire. This same process has also been used in other studies.11,13,18,19 Our

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ACCEPTED MANUSCRIPT categorisation of the menstrual cycle duration was based on the fact that its normal duration is 21-35 days, more usually between 28 and 31 days.27 For the duration of menstruation, though, there are no established criteria. Accordingly, we used three-day ranges, to make it

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simpler to answer, given that the range can vary slightly between periods. Sample size

The sample size was calculated to estimate the proportion of severe PD. We assumed an

parameters gave a sample size of 265 participants.

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Statistical methods

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expected proportion of 29.60%,21 a type I error of 5% and an estimation error of 5.5%. These

The variables are described using frequencies and percentages for qualitative variables, and median and interquartile range for quantitative variables. We determined the relationship between higher grade in our outcome and the secondary variables using the JonckheereTerpstra test. To determine factors associated with the outcome (grade in the Andersch and

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Milsom scale),26 we constructed multivariate ordered logistic regression model to estimate the adjusted odds ratio (OR). The goodness-of-fit of the model was determined by the

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likelihood ratio test, with a previous parallel lines testing. All the analyses were performed with a statistical significance of 5% and each relevant parameter was calculated with an

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associated confidence interval (CI). We used IBM SPSS Statistics 19 to perform all the analyses.

Ethical consideration

Each participant handed in her informed consent in writing. All answers were anonymous, individual and with no interaction between participants. The Ethics and Experimental Research Committee of Miguel Hernández University approved the study protocol. All the procedures followed were in accordance with the ethical standards of the Helsinki

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ACCEPTED MANUSCRIPT Declaration of 1975, as revised in 1983.

RESULTS

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Of 374 women invited to participate in the study, 20 were excluded because they declined to participate and 48 were excluded for prescription of oral contraceptives. Thus, the final

sample comprised 306 women (>265, the calculated sample size), 25 of whom had grade 0

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pain (8.2%, 95% CI: 5.1-11.2%), 77 grade 1 (25.2%, 95% CI: 20.3-30.0%), 153 grade 2 (50%, 95% CI: 44.4-55.6%) and 51 grade 3 (16.7%, 95% CI: 12.5-20.8%).

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The distribution of the secondary variables according to the Andersch and Milsom grades (26) is shown in Table 1. This shows the variability according to grade, with significant differences found for the following variables: menstrual cycle length (p=0.007), menstruation duration (p<0.001), family history of primary dysmenorrhoea (p<0.001),

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menstrual flow (p<0.001), medication (p<0.001) and EQ-5D (p<0.001). Factors significantly associated with more extreme pain (Table 1) were higher menstrual flow (OR=2.11, 95% CI: 1.44-3.09, p<0.001), a worse quality of life (OR=0.97,

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95% CI: 0.96-0.99, p<0.001) and use of medication for PD (OR=8.22, 95% CI: 4.62-14.64, p<0.001). The model was significant (p<0.001) and the p-value for the parallel lines

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assumption was 0.883.

DISCUSSION Summary

This study is innovative in its approach, as no study has yet reported this issue (pain gradient in women with and without PD),9-25 examining factors associated with extreme pain. The factors found to be associated (significantly) with extreme pain were a higher flow of menstruation, use of medication for PD, and a lower quality of life.

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ACCEPTED MANUSCRIPT Strengths and limitations of the study The main strength of the study relates to its clinical concept. Our literature review revealed no studies reporting extreme pain (gradient) in a sample composed of women with and

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without PD. This potentially makes our results novel. Regarding the limitations, the most important bias in this study was selection bias, as we only included women from a university community. It would therefore be of interest to

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replicate this study in a random sample from the general population. Concerning information bias, the participants measured the variables in a self-administered fashion. This is the most

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used method in the relevant studies published by others.9-25 Furthermore, apart from smoking, no other healthy lifestyle factors were analysed, nor other factors like seeking care for this disorder. It would be interesting to include factors like these in future studies. Nonetheless, the women were able to take medication. This bias has to be assumed, as we were analysing

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women who experienced great pain and it would not be ethical to stop the medication, which would also have reduced the participation rate. Finally, as the participants determined their menstrual flow completely subjectively, it would be interesting to repeat the study measuring

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this variable with an objective measure, such as the number of pads or tampons used. Comparison with the existing literature

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Comparison of our results with those of other studies is difficult because all the other studies either included pain as a variable (presence or absence of PD) or analysed a pain gradient after excluding those women who had no pain or those who took medication.13,21 Thus, the lack of studies with similar designs, populations and outcomes as ours prevents meaningful comparisons. The first finding in our study was the association between extreme pain and lower quality of life. Although this has not been analysed in the same way in other studies, several authors have shown that symptoms associated with the menstrual cycle, such as depression,

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ACCEPTED MANUSCRIPT irritability or mood changes, are associated with a worse quality of life.31-33 In addition, we

found that women with a higher menstrual flow were more likely to suffer from extreme pain. This result agrees with what has been suggested by other authors.9 Finally, as expected, we

Implications for research and/or practice

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found that the women who used medication experienced the most intense pain.

As no similar studies have been undertaken and in light of our innovative results, other

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studies should be carried out to determine whether the factors found in our study exist in other geographical areas in PD, given that the other studies either excluded women who had

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no pain or those who were taking medication, or used no pain gradient. Conclusion

In this study factors associated with extreme pain in PD were determined. Factors significantly associated with extreme pain were use of medication for PD, a worse quality of

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life and a higher menstrual flow. As the other relevant studies were carried out just in women with PD when a pain gradient was analysed or else assessing the presence of pain as a binary variable (yes/no), further studies are required to attempt to corroborate our results and offer

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more supporting scientific evidence.

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and dysmenorrhea? J Pediatr Adolesc Gynecol 2014; 27: 371-4. 11. Faramarzi M, Salmalian H. Association of psychologic and nonpsychologic factors with

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14. Ozerdogan N, Sayiner D, Ayranci U, Unsal A, Giray S. Prevalence and predictors of dysmenorrhea among students at a university in Turkey. Int J Gynaecol Obstet 2009; 107:

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ACCEPTED MANUSCRIPT 34. 18. Abenhaim HA, Harlow BL. Live births, cesarean sections and the development of menstrual abnormalities. Int J Gynaecol Obstet 2006; 92: 111-6.

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students. Ann Ist Super Sanita 2016; 52: 98-103.

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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS

The authors thank Dr. Kathryn McKenney and Ian Johnstone for their help with the English

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version of this work. No external funding was received for this study.

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dysmenorrhea, 2014 data. Grade 0

Grade 1

Grade 2

n=25

n=77

21-27

13(52.0)

44(57.1)

28-31

10(40.0)

18(23.4)

32-35

2(8.0)

(95% CI)

56(36.6)

16(31.4)

0.007

1.09(0.79-1.49)

0.612

72(47.1)

25(49.0)

25(16.3)

10(19.6)

4-6 7-9

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1-3

<0.001

1.32(0.78-2.23)

0.304

a

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Menstruation duration (days):

15(19.5)

Adj. OR

value

n=153

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Menstrual cycle length (days):

p-

n=51

a

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a

Grade 3

pvalue

Variable a

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Table 1: Descriptive and analytical characteristics for increased pain (Andersch and Milsom scale) in young Spanish women with primary

10(40.0)

12(15.6)

12(7.8)

4(7.8)

11(44.0)

63(81.8)

128(83.7)

41(80.4)

4(16.0)

2(2.6)

13(8.5)

6(11.8)

b

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2

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Family history of primary dysmenorrhoea: 10(40.0)

36(46.8)

116(75.8)

39(76.5)

No

15(60.0)

41(53.2)

37(24.2)

12(23.5)

Low

11(44.0)

24(31.2)

10(6.5)

5(9.8)

Medium

12(48.0)

39(50.6)

99(64.7)

25(49.0)

2(8.0)

14(18.2)

44(28.8)

21(41.2)

15(19.5)

18(11.8)

10(19.6)

62(80.5)

135(88.2)

41(80.4)

No Medication:

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1(4.0)

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Yes

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Personal history of smoking:

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Menstrual flow:

High

<0.001

1.46(0.88-2.41)

0.143

<0.001

2.11(1.44-3.09)

<0.001

0.617

1.11(0.57-2.16)

0.761

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Yes

24(96.0)

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3

3(12.0)

38(49.4)

128(83.7)

49(96.1)

No

22(88.0)

39(50.6)

25(16.3)

2(3.9)

EQ-5D (%)

90(10)

90(10)

80(25)

80(25)

<0.001

0.97(0.96-0.99)

<0.001

BMI (kg/m2)

21.4(2.7)

21.9(3.3)

21.3(3.3)

22.1(4.2)

0.887

1.01(0.99-1.02)

0.552

Age (years)

21(6.5)

20(5.0)

20.5(4.0)

0.124

0.94(0.87-1.01)

0.076

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Yes

20(3.0)

<0.001

8.22(4.62-14.64)

<0.001

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Abbreviations: Adj. OR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; EQ-5D, EuroQol 5D.

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Goodness-of-fit of the model: χ2=131.52, p<0.001. p-value for the parallel lines assumption: p=0.883. a, absolute and relative frequency for qualitative variables, and median and interquartile range for quantitative variables; b, Jonckheere-Terpstra

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test.

category).

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In the multivariate model, menstrual cycle length, duration and flow, were quantified as 0 (lowest category), 1 (medium category) and 2 (highest