Original Study

Rett Syndrome and Menstruation

Amy Hamilton BA 1, Michael P. Marshal PhD 2, Gina S. Sucato MD, MPH 3, Pamela J. Murray MD, MHP 3,*1University Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA2Department of Psychiatry, University Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA3Division of Adolescent Medicine, Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

a b s t r a c t

Objective: Describe the experience that girls with Rett syndrome h

ave with menstruation including menstrual hygiene, dysmenorrhea,premenstrual syndrome (PMS), and attempts at treatment.Design: Anonymous web-based survey.Setting: Convenience sample recruited from Rett syndrome LISTSERV in July of 2009.Participants: Mothers of girls with Rett syndrome between the ages of 10e25 who have had at least one menses.Main Outcome Measures: Prevalence, frequency, and severity of dysmenorrhea and PMS; hygiene concerns; and treatments attempts andperceived effectiveness.Results: Dysmenorrhea and PMS are common problems among young women with Rett syndrome. Despite their frequency and severitythey do not routinely limit activities. Multiple treatment attempts are common. Hormonal contraception is used mostly for menstrual cyclecontrol with oral contraceptive pills the most commonly used method.Conclusions: Young women with Rett syndrome have standard symptoms of dysmenorrhea and PMS as well as autism spectrum specificPMS symptoms. Hormonal contraception is commonly used for menstrual management.Key Words: Rett syndrome, Menstruation, Developmental disability, Dysmenorrhea, Premenstrual syndrome

Introduction

Rett syndrome is an X-linked dominant neuro-developmental disorder, primarily seen in girls, that resultsin severe developmental disability with limited self-careand verbal communication skills.1 Other features includerepetitive and distinctive hand and eye movements,stereotypical behaviors, and seizures. It is currently classi-fied in the Diagnostic and Statistical Manual of MentalDisorders (revised 4th ed.) (DSM IV-TR) under autismspectrum disorders.2 Estimated prevalence is 0.44/10,000with equal prevalence across racial and ethnic groups.Patients with Rett syndrome experience puberty and mostsurvive into adulthood. Menstrual cycles may influencetheir physical care needs and their behavioral management.There is limited literature on the sexual development andexperiences of girls with Rett syndrome. Menstrual hygiene,dysmenorrhea, and premenstrual syndrome (PMS) arecommon issues inwomen of reproductive age.Womenwithneurodevelopmental disabilities may face different chal-lenges when affected by these common problems. Thisstudy, exploring the experiences of young womenwith Rettsyndrome, may provide a useful framework to apply to thegrowing population of young adults with chronic condi-tions and neurodevelopmental disabilities.

The authors indicate no conflicts of interest.* Address correspondence to: Pamela J. Murray, Department of Pediatrics, 1

Medical Center Drive, Morgantown, WV 26505-9214E-mail address: pmurray@hsc.wvu.edu (P.J. Murray).

1083-3188/$ - see front matter � 2012 North American Society for Pediatric and Adoledoi:10.1016/j.jpag.2011.11.002

Dysmenorrhea is well documented among femaleadolescents with prevalence rates ranging from 40e90%.3 Inthe United States, dysmenorrhea is the leading cause ofabsenteeism from school and work for adolescents.4 PMSand premenstrual dysphoric disorder (PMDD) are alsocommon among menstruating women. The DSM IV-TRreports that up to 75% of women report premenstrualchanges, with PMS prevalence rates ranging from 20e50%,and PMDD at an estimated prevalence of 3e5%. In a largepopulation-based sample from Switzerland, 91% of womenreported at least one premenstrual symptom and 10.3% ofwomen fulfilled PMS criteria according to the DSM IV-TR,and another 3.1% fulfilled PMDD criteria.5

Developmental disability oftenmakesmenstrual hygienechallenging and may lead families to seek menstrualsuppression from health care providers.6 One single centerretrospective chart review of 72 of adolescent girls (agerange 8e17 years) with developmental disability presentingto a gynecological clinic found that 67% were seekingmenstrual suppression, most commonly because of hygieneand coping concerns.7 Menstrual hygiene issues couldpotentially cause school absenteeism, negatively impactingthe girl’s ability to learn and creating additional pressureson her caregivers. Dysmenorrhea and PMS are additionalproblems for this population and can be harder to diagnosisusing standard self-reported symptoms and more difficultto manage due to the inability of these young women toadequately communicate their symptoms and needs. Oneretrospective clinic based study of 522 developmentallydisabled women of reproductive age (10e52 years) found

scent Gynecology. Published by Elsevier Inc.

A. Hamilton et al. / J Pediatr Adolesc Gynecol 25 (2012) 122e126 123

that 18% presented to their gynecologist with the primarycomplaint of cyclic behavioral changes.8

A few studies have demonstrated that girls with autismspectrum disorders suffer from PMS andmay bemore likelyto have PMS concerns than the general population. A surveyof parents of girls with developmental disability included12 girls with autism. Among these individuals, 62.5%experienced pain with menses and 75% endorsed symp-toms of PMS.9 A prospective observer-rated study askedcaregivers who were blinded to menstrual status to recordbehavior and mood changes for 26 institutionalized girlswith autism. The investigators compared these changes tomenstrual calendars and found a rate of PMDD of 92%.10

Both of these studies had small sample sizes and neitheraddressed the impact of menstruation on the subjects’ dailyactivities or on the family members and caregivers. Ina retrospective case series of patients presenting to onegynecological clinic for girls with developmental disabil-ities, the 14 girls with autism were found to be more likelyto present with cyclical mood or behavior changes whencompared to girls with Downs syndrome or cerebral palsy.11

In a survey of caregivers of young women with autismspectrum disorder (ASD) rates of dysmenorrhea andpremenstrual symptoms were 91% and 96% respectively.Additionally, 33% reported ASD specific menstrual symp-toms such as self-injury, increased social withdrawal, andincreased repetitive movements.12

There are no studies describing the menstrual experi-ence of girls with Rett syndrome. We hypothesize thatthese young women have menstrual concerns and conse-quences that are different from the healthy population.This investigation may contribute to developing a modelfor the evaluation of menstrual problems and treatmentresponses for young women with severe developmentaldisability.

Methods

Design

The investigators developed an anonymous web-basedquestionnaire after a review of the literature regardingmenstruation, dysmenorrhea, PMS, as well as autism,developmental delay, and mental disability. The surveyincorporated standard symptoms used to diagnosedysmenorrhea and PMS, according to the American Collegeof Obstetricians and Gynecologists13 and the DSM-IV-TR,2

along with autism specific symptoms generated from theliterature and the authors’ clinical experiences. Theseincluded symptoms such as cramps, headaches, abdominalpain, fatigue, anxiety, sadness, and anger, as well as autismspecific symptoms such as increased repetitive movements,self-injury, and aggression. Additional input on question-naire design was sought from the Clinical and TranslationalScience Institute at the University of Pittsburgh. The insti-tutional review board at the University of Pittsburghapproved the study with exempt status. The questionnairebeganwith a letter to participants explaining the goal of thestudy and its voluntary nature as well as providing contactinformation for the study investigators.

The questionnaire collected general demographic infor-mation, self-report of underlying neurodevelopmentaldiagnosis, and detailed information on menstrual history,menstrual hygiene, dysmenorrhea, and PMS. The ques-tionnaire included 44 to 46 questions, because there weretwo additional questions for those respondents whosedaughter was currently using hormonal contraception. Thequestionnaire otherwise asked the same questions of allrespondents with the exception that for those girls whoused hormonal contraception, respondents were asked todescribe periods prior to treatment with hormonalcontraception. The questionnaire used several types ofquestions including multiple choice, free response, andLikert scales. The questionnaire took approximately 10e15minutes to complete, and although it could not be savedand returned to, those taking it could walk away for a periodof time and come back to it as long as they did not close theweb page. The questionnaire was pretested by parents ofadolescent girls with appointments at the Adolescent Clinicat Children’s Hospital of Pittsburgh of UPMC for compre-hension and face validity. Frequency and severity of symp-toms, the impact of the symptoms on daily life, attempts attreatment, and perceived effectiveness of treatments wereall assessed.

Recruitment

The questionnaire was placed on SurveyMonkey, anonline survey tool, and a link was created. The question-naire is no longer available online but hard copies areavailable by request. Initially it was part of a larger surveyon girls with autism spectrum disorders (ASD), which wasdistributed to various physician, community, and schoolbased LISTSERVs. Additional recruitment was through anestablished patient panel LISTSERV sponsored by theInternational Rett Syndrome Association (IRSA). Werecruited a convenience sample of parents/caregivers ofgirls with Rett syndrome between the ages of 10e25 whohad had at least onemenses. The survey link remained openfrom June 2009 to May 2010. However, all responses fromcaregivers of girls with Rett syndrome were collected in themonth of July 2009, 48 hours after the IRSA LISTSERVposting, after which there were no additional responses forpatients with Rett syndrome.

Analysis

The data were analyzed using SPSS statistical software(version 17.0). Descriptive statistics were calculated on alldata. There were some questions with a low response rate,particularly in the table of non-hormonal PMS treatments.The list of treatment options included many complemen-tary treatments that are cited in the literature. The non-response rate for these items ranged from 0% to 100%.Statistical analysis was guided by the investigators’ previouswork on ASD and menses and t test was used to comparelength of periods, number of periods, and number ofhygiene concerns in relation to hormonal menstrual cyclemanagement. A P value of !0.05 was considered statisti-cally significant.

A. Hamilton et al. / J Pediatr Adolesc Gynecol 25 (2012) 122e126124

Results

Demographics

A total of 21 caregivers of the young women with Rettsyndrome, all mothers, responded to the questionnaireabout their daughters. Most were Caucasian, 86% (18/21),and non-Hispanic, 92% (19/21). Most of the young women,86% (18/21), lived at home with their primary caregiver. Allwere non-verbal. The average age of the youngwomenwithRett syndrome was 17.1 years and their average weight was80.1 lbs. Mean age of menarche was 11.7 years (SD 5 2.0years). The majority, 62% (13/21), reported periods thatlasted 3e7 days and 38% (8/21) reported 10 or more periodsa year with 24% (5/21) reporting 7e10 periods a year. Allwere completely dependent on their caregiver formenstrual hygiene care. While there was no measurementof time spent on hygiene during menses, the majority, 57.2%(12/21), reported that hygiene concerns never/rarely causeda problem at home.

Hormonal Contraception Use

A majority, 62% (13/21), had ever tried hormonalcontraception and 48% (10/21) were using hormonalcontraception at the time of the survey. Those with longerperiods, defined as greater than 7 days, were more likely touse hormonal contraception (t test, P 5 0.018), see Table 1.Of those using hormonal contraception, 50% (5/10) wereusing the hormonal contraceptive to eliminate periods, 30%(3/10) to have fewer periods, and 30% (3/10) to reducedysmenorrhea. Oral contraceptive pills were used by 70%(7/10) of those currently on hormonal contraception and20% (2/10) were using medroxyprogesterone injection. Norespondents were using other long-acting reversiblecontraception. A large percentage, 80% (8/10), reported thattheir method of hormonal contraceptionwas ‘very effective’in addressing their menstrual concernwhich for most of therespondents was menstrual cycle control.

Table 2Most Frequently Reported Premenstrual Syndrome Symptoms

Premenstrual Syndrome Symptoms Number Reporting SymptomsN 5 21

Fatigue/Feels tired 14Cries 12Sleeps more 11Irritability/anger 11Sadness 8

Dysmenorrhea

At least one symptom of dysmenorrhea was reported by76% (16/21) with 67% (13/21) reporting ‘frequent’ symp-toms, defined as at least one symptom of dysmenorrhea‘often’ or ‘almost always’ during her menstrual cycle and57% (12/21) reporting at least one ‘moderate’ or ‘severe’symptom of dysmenorrhea. Cramps and low back painwerethe most frequently reported symptoms with 38% (8/21)reporting cramps ‘almost always’ and 24% (5/21) reportinglow back pain ‘almost always.’ Half, 48% (10/21), reportedthat menstrual symptoms never prevented attendance at

Table 1Current Hormonal Contraception Use versus Length of Periods

Current HormonalContraception Use

Length of Periods (Days) Total Number ofRespondents

!3 3e7 O7

Yes 0 6 2 8No 4 7 0 11

school or other scheduled activities and 33% (7/21) said itnever caused a problem at home.

Premenstrual Syndrome

At least one symptom of PMS was reported by 71% (15/21) with 62% (13/21) reporting ‘frequent’ symptoms,defined as at least one symptom ‘often’ or ‘almost always’and 48% (10/21) reporting at least one ‘moderate’ or ‘severe’symptom. Autism specific symptoms, Table 2, were re-ported by 43% (9/21). In an open-ended response questionregarding other symptoms 9.5% (2/21) reported increasedseizure activity premenstrually. When asked about inter-ference with usual activities, 19% (4/21) reported that PMSsymptoms ‘never’ and 19% (4/21) reported that PMSsymptoms ‘rarely’ prevented attendance to school or otherscheduled activities. Furthermore, 14% (3/21) reported thatPMS symptoms ‘never’ and 24% (5/21) reported that they‘rarely’ caused a problem at home.

Treatment Attempts

Ibuprofen and acetaminophen were the most commonlytried non-hormonal treatments for both dysmenorrhea andpremenstrual symptoms. The average number of non-hormonal treatments tried for dysmenorrhea was 2.4 andfor premenstrual symptomswas 1.9. Ibuprofenwas reportedby 33% (7/21) as ‘very effective’ at treating dysmenorrhea,and 9.5% (2/21) reported acetaminophenwas ‘very effective’for treating dysmenorrhea. For premenstrual symptoms,24% (5/21) reported ibuprofen as ‘very effective’ and 9.5%(2/21) reported acetaminophen as ‘very effective.’

Discussion

Young women with Rett syndrome have menstrualconcerns that are similar to the general population as wellas unique concerns associated with their underlying neu-rodevelopmental disorder. Their slowed somatic growthand small size do not delay menses nor result in infrequentperiods as commonly seen in chronic diseases characterizedby malnutrition or inflammation. The average age ofmenarche was slightly lower than the general population

Tense/anxiety 8Cramps 8Autism spectrum disorder specific symptomsAt least one ASD specific symptom 9Increased repetitive movements 8Worsening of underlying autistic behaviors 4Self injury 3Increased aggression 3Increased social withdrawal 3Increased temper tantrums 3

A. Hamilton et al. / J Pediatr Adolesc Gynecol 25 (2012) 122e126 125

and similar to the age found in a study of six girls with Rettsyndrome where the average age of menarche was 11 years2 months.14 The majority of these young women hadperiods that were comparable to non-affected adolescentgirls in both frequency and length. In previous workinvestigating the menstrual experience of young womenwith other autism spectrum disorders, menstrual hygieneconcerns were shown to be a predictor of hormonalcontraception use.12 However, in this study, hygienewas nota predictor of hormonal contraception use, possibly becausethe young women with Rett syndrome were dependent oncaregivers for regular bowel and bladder eliminationhygiene in addition to menstrual hygiene care.

Approximately half of these young women werecurrently using hormonal contraception with menstrualmanagement the most common reason for its use. Thosewith longer periods were more likely to use hormonalcontraception. When the same questionnaire was used ina study of young women with ASD the same associationbetween longer periods and hormonal contraception usewas found.12 Period length outside the range of normal maytrigger caregivers or health care providers to initiatemenstrual cycle control. Oral contraceptive pills were themost common form of hormonal contraception. The over-whelming use of OCPs was unexpected given our clinicalexperience with depot medroxyprogesterone for menstrualsuppression. Multiple factors and comorbidities may factorinto the choice of hormonal medication that were notexplored in this survey. Limited and long-term dosingroutines, interactions with other medications, concerns forbone health, and frequency of clinic visits for injections mayfactor into the choice of medication for menstrualmanagement. Rett syndrome is associated with seizures,and seizure control may influence menstrual managementchoices. Seizure control was not explored explicitly in thisstudy.

Rates of dysmenorrhea and premenstrual symptoms inyoung women with Rett syndrome are comparable to ratesin the general population. These young women hadfrequent and severe symptoms of both dysmenorrhea andpremenstrual syndrome; however, their caregivers re-portedminimal morbidity in terms of daily activities. This issimilar to previous work on young women with ASD wherehigh rates of dysmenorrhea and premenstrual symptomswere found but did not result in significant morbidity interms of their daily activities and interactions with others.12

For the majority of these young women, neither dysmen-orrhea nor premenstrual symptoms prevented attendanceto school or other scheduled activities or caused a problemat home. Given these young women’s baseline handicapsand needed assistance for activities of daily living, any extraphysical or behavioral burden of menstrual-specificcomplaints may be accommodated by family and school-based care-givers.

Use of non-hormonal treatments for both dysmenorrheaand premenstrual symptomswas similar towhat is found inthe general population. NSAIDs are effective treatment fordysmenorrhea at appropriate doses; however, commonlydysmenorrhea is undertreated with subtherapeutic doses.Information on dosing was not gathered by this survey. This

continues to be an area where providers can guide patientsand families to optimal and appropriate treatment ofmenstrual and premenstrual symptoms.

Our questionnaire was offered only online; thus wewereunable to gather responses from families without internetaccess. Different experiences between caregivers who do ordo not actively participate in web-based communities isa source of potential bias in our results. Also, due to thelimited communication abilities of those with Rettsyndrome, the parents/caregivers of the girls were surveyedrather than the girls themselves. However, this study wasconcerned with both the families’ and the girls’ experienceswith menstruation, and hence the parents’ input andperceptions are valuable. In addition, most of the respon-dents were intimately involved in the health care and day-to-day care of their children and presumably are able toprovide an accurate account of the problems faced by theirdaughters and her caregivers. Another limitation of ourstudy is that our question on frequency of periods wouldnot have captured polymenorrhea as those with 10 or moreperiods a year were grouped together. While a standard 28day cycle would produce 12e13 periods a year missing oneto two cycles a year would still indicate fairly regular cyclingparticularly in an adolescent population in which anovula-tory cycles are more common.

Because we surveyed a convenience sample and used ananonymous web-based questionnaire we have no infor-mation about families who were eligible but declined toanswer the questionnaire. Also, families of girls with moresevere menstrual problems may have been more likely tocomplete the questionnaire. We tried to limit this source ofbias by asking in our introduction to the questionnaire thatparents respond to the questions even if their daughter didnot have any problems with menstruation. Additionallytherewas no control group.While a control groupmay haveassisted with assessing validity and reproducibility of thequestionnaire we believe that menstrual issues have beenwell described among neurodevelopmentally normaladolescents.

Recommendations for future investigations includea prospective study evaluating menstrual and premenstrualsymptoms of young women with Rett syndrome and otherneurodevelopmental disorders to better clarify theirsomatic and behavioral symptoms that occur with menses.This could provide clinical tools that reliably measurebaseline symptoms and treatment responses in a pop-ulation with limited capability to express symptoms andresponses to treatment.

Acknowledgments

Supported by a Dean’s Summer Scholarship, Universityof Pittsburgh School of Medicine.

References

1. National Institute of Neurological Disorders and Stroke: NINDS Rett SyndromeInformation Page. Available: http://www.ninds.nih.gov/disorders/rett/rett.htm.Accessed August 20, 2011.

2. American Psychiatric Association: Diagnostic and Statistical Manual of MentalDisorders, (rev 4th ed.). Washington, DC, American Psychiatric Association,2000

A. Hamilton et al. / J Pediatr Adolesc Gynecol 25 (2012) 122e126126

3. Bettendorf B, Shay S, Tu F: Dysmenorrhea: contemporary perspectives. ObstetGynecol Surv 2008; 63:597

4. Klein JR, Litt IF: Epidemiologyofadolescentdysmenorrhea. Pediatrics1981;68:6615. Tschudin S, Bertea PC, Zemp E: Prevalence and predictors of premenstrual

syndrome and premenstrual dysphoric disorder in a population-basedsample. Arch Womens Ment Health 2010; 13:485

6. Quint EH: Menstrual issues in adolescents with physical and developmentaldisabilities. Ann N Y Acad Sci 2008; 1135:230

7. Dizon CD, Allen LM, Ornstein MP: Menstrual and contraceptive issues amongyoung women with developmental delay: a retrospective review of cases atthe Hospital for Sick Children, Toronto. J Pediatr Adolesc Gynecol 2003; 18:157

8. Quint EH, Elkins TE, Sorg CA, et al: The treatment of cyclical behavioral changesin women with mental disabilities. J Pediatr Adolesc Gynecol 1999; 12:139

9. Kyrkou M: Health issues and quality of life in women with intellectualdisability. J Intellect Disabil Res 2005; 49(Pt 10):770

10. Obaydi H, Puri BK: Prevalence of premenstrual syndrome in autism:a prospective observer-rated study. J Int Med Res 2008; 36:268

11. Burke LM, Kalpakjian CZ, Smith YR, et al: Gynecologic issues of adolescents withDown syndrome, autism, and cerebral palsy. J Pediatr Adolesc Gynecol 2010;23:11

12. Hamilton A, Marshall MP, Murray PJ: Autism spectrum disorders andmenstruation J. Adolesc Health 2011; 49:443

13. American College of Obstetricians and Gynecologists: Premenstrual Syndrome.ACOG Practice Bulletin No. 15, April 2000.

14. Holm VA: Physical growth and development in patients with Rett syndrome.Am J Med Genet Suppl 1986; 1:119