Accepted Manuscript Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation Daniel L. Picchietti, Jennifer G. Hensley, Jacquelyn L. Bainbridge, Kathryn A. Lee, Mauro Manconi, James A. McGregor, Robert M. Silver, Claudia Trenkwalder, Arthur S. Walters PII:

S1087-0792(14)00119-1

DOI:

10.1016/j.smrv.2014.10.009

Reference:

YSMRV 841

To appear in:

Sleep Medicine Reviews

Received Date: 11 August 2014 Revised Date:

27 October 2014

Accepted Date: 28 October 2014

Please cite this article as: Picchietti DL, Hensley JG, Bainbridge JL, Lee KA, Manconi M, McGregor JA, Silver RM, Trenkwalder C, Walters AS, On behalf of the International Restless Legs Syndrome Study Group (IRLSSG), Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation, Sleep Medicine Reviews (2014), doi: 10.1016/j.smrv.2014.10.009. 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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Original Article

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Consensus Clinical Practice Guidelines for the Diagnosis and Treatment of Restless Legs Syndrome/Willis-Ekbom Disease During Pregnancy and Lactation

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Daniel L. Picchiettia,*, Jennifer G. Hensleyb, Jacquelyn L. Bainbridgec, Kathryn A. Leed, Mauro Manconie, James A. McGregorf, Robert M. Silverg, Claudia Trenkwalderh, and Arthur S. Waltersi On behalf of the International Restless Legs Syndrome Study Group (IRLSSG) a

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University of Illinois School of Medicine and Carle Foundation Hospital, Urbana, IL, USA b College of Nursing, University of Colorado Denver, Denver, CO, USA c Department of Clinical Pharmacy and Department of Neurology, University of Colorado Denver, Aurora, CO, USA d Department of Family Health Care Nursing, School of Nursing, University of California San Francisco, San Francisco, CA, USA e Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland f Department of Obstetrics and Gynecology, Women's and Children's Hospital, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA g Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA h Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, Germany i Department of Neurology Vanderbilt University School of Medicine, Nashville, TN, USA

* Corresponding author: Dr. Daniel Picchietti, MD, University of Illinois School of Medicine and Carle Foundation Hospital, Department of Sleep Medicine, 602 W. University Avenue, Urbana, IL 61801; Tel: 217-383-3311; Fax: 217-383-4468; E-mail: [email protected] 1

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Summary Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting

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approximately one in five pregnant women in Western countries. Many report moderate or severe

symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition. Accordingly, a task force was chosen by the

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International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of

RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics

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developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including exercise and avoidance of

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exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated “may be considered” when RLS/WED is refractory to more conservative approaches. An algorithm summarizes

research.

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the recommendations. These guidelines are intended to improve clinical practice and promote further

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Keywords: Restless legs syndrome; Willis-Ekbom disease; Sleep disorder; Pregnancy; Lactation; Consensus

Introduction

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is 2 to 3 times more

prevalent during pregnancy than in the general population, affecting about 15 to 25% of pregnant women in Western countries [1-3]. There is a peak in the number of women affected by RLS/WED in the third trimester and resolution of symptoms for many by one month after delivery [1, 4]. Independent predictors

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of RLS/WED during pregnancy are a past history of RLS/WED when not pregnant (odds ratio (OR) 12.91), a family history of RLS/WED (OR 8.43), a history of RLS/WED during prior pregnancy (OR 53.74), and hemoglobin ≤ 11 g/dL (OR 2.05) [5]. Preexisting RLS/WED also predicts greater severity

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during pregnancy than before pregnancy [6]. Interestingly, women are 1.5 to 2 times more likely than men to have RLS/WED [7]. The gender difference is explained at least in part by parity, with nulliparous women at the same risk of RLS/WED as age-matched men, but increased risk for women after one

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pregnancy (OR 1.98), two pregnancies (OR 3.04), and three or more pregnancies (OR 3.57) [8, 9].

Symptoms of RLS/WED during pregnancy range from very mild to quite severe. Severe to very

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severe symptoms, as assessed by the International Restless Legs Syndrome Study Group (IRLSSG) rating scale, were reported in 45% and 54% of pregnant women in two recent studies [2, 10], with a third study reporting only 14% at this level but 75% with at least moderate symptoms [11]. Negative impact on sleep is common, affecting both sleep onset and maintenance [2, 3, 11-14]. RLS/WED is reported as the third most common reason for insomnia during pregnancy [15]. This is relevant to emerging data that

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show an association between sleep disorders and adverse pregnancy outcomes [16-18]. Thus far, increased rates of preeclampsia, cesarean delivery, and depressed mood have been reported in women with RLS/WED but data are limited and further research is needed [11, 19-21].

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Although the pathophysiology of RLS/WED has been defined, with genetics, the brain dopamine system, and iron found to play important roles [7, 22-25], factors specific to pregnancy have not been

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adequately delineated. Familial predisposition, iron deficiency, iron availability, folate deficiency, estrogen status, and stretch/compression of nerves with fetal growth have all been implicated but much of the limited evidence is conflicting [26, 27]. Because RLS/WED is common during pregnancy and may negatively impact maternal and fetal

well-being, the IRLSSG Executive Committee appointed a committee to develop guidelines for the diagnosis and management of RLS/WED during pregnancy and lactation. This report summarizes the rationale and recommendations of the committee. These conclusions have been officially endorsed by the IRLSSG Executive Committee and the WED Foundation Medical Advisory Board. 3

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Methods A panel of experts was approved in November 2011 by the IRLSSG Executive Committee to provide recommendations on the diagnosis and treatment of RLS/WED during pregnancy and lactation.

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The committee was composed of the authors of this paper, with emphasis on multidisciplinary representation, including maternal-fetal medicine, clinical sleep medicine, restless legs research, pharmacology, nurse-midwifery, patient advocacy, and international sleep medicine.

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The committee had monthly teleconferences for over one year and a single face-to-face meeting in June 2012. Consensus questions were agreed upon and subsequently discussed in depth. The 12

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questions covered prevalence, diagnosis, treatment, and research recommendations (Supplementary Table S1) with responses elaborated in the next section.

To help integrate the medical literature into the recommendations, the committee conducted a formal literature review. Using the PubMed database, first in December 2011 and updated in February 2014, the key words "restless legs AND pregnancy" identified a total of 156 articles. Abstracts from

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these were reviewed to determine if the articles included information on pregnancy, and if they contained original data and/or any diagnosis or treatment recommendations. To be inclusive, no minimum number of subjects was applied. Review articles that did not focus specifically on RLS/WED during pregnancy

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were not retained. Based on the literature search and pearling (checking of reference sections for any articles otherwise missed) 50 original research papers were found: 24 reported prevalence, only 6 reported

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treatment data, and none reported data on lactation. Also, in depth safety/risk reviews of potential treatments for RLS/WED during pregnancy and

lactation were done. The following resources were utilized: PubMed searches for data on other uses of these treatments during pregnancy; "Drugs in Pregnancy and Lactation," Briggs, et al [28]; "Medications and Mothers' Milk," Hale [29]; Motherisk [30]; the Organization of Teratology Information Specialists (OTIS) [31]; LactMed [32]; and Micromedex [33]. Published safety categories for vitamins, minerals, and medications reviewed are summarized in Table S2. Of note, the United States Food and Drug

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Administration (FDA) is retiring its letter risk category system for pregnancy and lactation [34]. Due to numerous concerns about this system, the committee decided not to emphasize it in this review [28]. The committee considered several published rating systems for this project. The majority of

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these emphasize data from large, randomized clinical trials, none of which have been performed for this clinical situation and are unlikely to be done for most medications during pregnancy. However, there is a substantial literature on the efficacy of treatments for non-pregnancy RLS/WED and substantial data on

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the safety of some medications when used during pregnancy for another indication, e.g., carbamazepine and gabapentin for epilepsy. In addition, members of the committee have a significant combined clinical

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experience managing pregnancy-related RLS/WED. Thus, instead of simply stating that little to no highlevel evidence exists, the committee decided to take a more integrative approach to the existing literature and our accumulated clinical experience. That said, we acknowledge and present these results as clinical guidelines, rather than high-level standards. In addition, we hope these guidelines present enough of a framework to promote further research in this area and thereby improve the level of evidence for the

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clinical management of RLS/WED during pregnancy and lactation.

Table S3 lists criteria the committee used to assess potential treatments: published evidence for effectiveness and safety for non-pregnancy RLS/WED; direct evidence of effectiveness and safety for

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RLS/WED during pregnancy and lactation; overall safety/risk profile during pregnancy and lactation; and expert clinical opinion. For the sections on general comments and guidelines, diagnosis, and

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severity/impact assessment, most, but not all of the recommendations are based on expert clinical opinion. Where there is published evidence, this is noted. For example, there are multiple studies on prevalence and clinical course but no validation studies on the IRLSSG diagnostic criteria or severity scale during pregnancy. There was a high level of committee consensus for these sections. For the purpose of these guidelines, “refractory RLS/WED” is defined as an inadequate response to at least one nonpharmacologic intervention and iron (if ferritin 30 on the IRLSSG rating scale (IRLS) and failure to respond at least one nonpharmacologic intervention, iron (if ferritin > Embryo-Fetal Risk There may or may not be human pregnancy experience, but the potential maternal benefit far outweighs the known or unknown embryo-fetal risk. Animal reproduction data are not relevant. Human Data Suggest Low Risk There is limited human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action, including the 1st trimester, suggesting that the drug does not represent a significant risk of developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) at any time in pregnancy. The limited human pregnancy data outweighs any animal reproduction data. No (Limited) Human Data - Animal Data Suggest Low Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug does not cause developmental toxicity (at doses that did not cause maternal toxicity) in all animal species studied at doses ≤10 times the human dose based on body surface area (BSA) or AUC*. No (Limited) Human Data - Animal Data Suggest Moderate Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in one animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*. No (Limited) Human Data - Animal Data Suggest Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in two animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*. No (Limited) Human Data - Animal Data Suggest High Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in three or more animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*. Contraindicated - 1st Trimester Human exposures in the 1st trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug should not be used in the 1st trimester. Contraindicated - 2nd and 3rd Trimesters Human exposures in the 2nd and 3rd trimesters, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavior deficits, or death). The drug should not be used in the 2nd and 3rd trimesters. Contraindicated Human exposures at any time in pregnancy, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). Animal reproduction data, if available, confirm the risk. The drug should not be used in pregnancy. No (Limited) Human Data - No Relevant Animal Data There is no human pregnancy data or relevant data in animals, or the human pregnancy experience, that may or may not include the 1st trimester, is limited. The risk in pregnancy cannot be assessed. Human Data Suggest Risk in 1st and 3rd Trimesters Evidence (for the drug or similar drugs) suggests that there may be an embryo-fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 1st and 3rd trimesters but not in the 2nd trimester. The human pregnancy data outweigh any animal reproduction data. Human Data Suggest Risk in 2nd and 3rd Trimesters Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 2nd and 3rd trimesters but not in the 1st trimester. The human pregnancy data outweigh any animal reproduction data.

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Human Data Suggest Risk in 3rd Trimester Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 3rd trimester, or close to delivery but not in the 1st or 2nd trimesters. The human pregnancy data outweigh any animal reproduction data. Human (and Animal) Data Suggest Risk The human data for the drug or drugs in the same class or with the same mechanism of action, and animal reproduction data if available, suggest there may be a risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) throughout pregnancy. Usually, pregnancy exposure should be avoided, but the risk may be acceptable if the maternal condition requires the drug. DEFINITIONS OF BREASTFEEDING RECOMMENDATIONS Compatible Either the drug is not excreted in clinically significant amounts into human breast milk or its use during lactation does not, or is not expected to, cause toxicity in a nursing infant. Hold Breast Feeding The drug may or may not be excreted into human breast milk, but the maternal benefit of therapy far outweighs the benefits of breast milk to an infant. Breastfeeding should be held until maternal therapy is completed and the drug has been eliminated (or reaches a low concentration) from her system. No (Limited) Human Data - Probably Compatible Either there is no human data or the human data are limited. The available data suggest that the drug does not represent a significant risk to a nursing infant. No (Limited) Human Data - Potential Toxicity Either there is no human data or the human data are limited. The characteristics of the drug suggest that it could represent a clinically significant risk to a nursing infant. Breastfeeding is not recommended. No (Limited) Human Data - Potential Toxicity (Mother) Either there is no human data or the human data are limited. The characteristics of the drug suggest that breastfeeding could represent a clinically significant risk to the mother such as further loss of essential vitamins Contraindicated There may or may not be human experience, but the combined data suggest that the drug may cause severe toxicity in a nursing infant, or breastfeeding is contraindicated because of the maternal condition for which the drug is indicated. Women should not breastfeed if they are taking the drug or have the condition. Comparison of Agents within the Same Pharmacologic Class The Appendix arranges the drugs by their pharmacologic category. This allows the reader to identify all of the drugs that have been reviewed within a specific category, thus allowing, if desired, a comparison of the drugs. For example, the subsection Antihypertensives lists together those agents used for this purpose under the general heading Cardiovascular Drugs. To assist the reader in locating an agent in the Appendix, page numbers (in parentheses) referring to the location in the Appendix have been added to the generic names (shown in bold) in the Index. FDA Risk Categories Definitions Although the FDA risk categories have been excluded from this edition, readers wanting this information can obtain it from the manufacturer’s product information. *AUC = area under the plasma concentration vs time curve; a measure of the systemic exposure of a drug.

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HALE’S CLASSIFICATIONS OF DRUGS FOR LACTATION Lactation Risk Category L1 Safest Drug which has been taken by a large number of breastfeeding mothers without any observed increase in adverse effects in the infant. Controlled studies in breastfeeding women fail to demonstrate a risk to the infant and the possibility of harm to the breastfeeding infant is remote; or the product is not orally bioavailable in an infant. L2 Safer Drug which has been studied in a limited number of breastfeeding women without an increase in adverse effects in the infant. And/or, the evidence of a demonstrated risk which is likely to follow use of this medication in a breastfeeding woman is remote. L3 Moderately Safe There are no controlled studies in breastfeeding women, however the risk of untoward effects to a breastfed infant is possible; or, controlled studies show only minimal non-threatening adverse effects. Drugs should be given only if the potential benefit justifies the potential risk to the infant. L4 Possibly Hazardous There is positive evidence of risk to a breastfed infant or to breast milk production, but the benefits from use in breastfeeding mothers may be acceptable despite the risk to the infant. (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). L5 Contraindicated Studies in breastfeeding mothers have demonstrated that there is significant and documented risk to the infant based on human experience, or it is a medication that has a high risk of causing significant damage to an infant. The risk of using the drug in breastfeeding women clearly outweighs any possible benefit from breastfeeding. The drug is contraindicated in women who are breastfeeding an infant.

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Supplementary Table 3. Consensus recommendation criteria and levels.

Criteria: • • • • •

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Published evidence of effectiveness for non-pregnancy RLS/WED Published evidence of safety for non-pregnancy RLS/WED Published evidence of effectiveness for RLS/WED during pregnancy and lactation Published evidence of safety for RLS/WED during pregnancy and lactation Overall safety/risk profile during pregnancy and lactation  Teratogenicity (major/minor congenital malformations)  Effects on pregnancy (premature labor, birth weight, etc.)  Neonatal withdrawal symptoms  Neurodevelopmental considerations • Expert clinical experience ___________________________________________________________________ Levels:

1) Recommended (high level of evidence for safety/effectiveness) 2) May be considered (evidence for safety/effectiveness) 3) Insufficient evidence to reach consensus 4) Probably should not be considered (evidence for risk/ineffectiveness) 5) Not recommended (high level of evidence for risk/ineffectiveness)

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Abbreviations: RLS, restless legs syndrome; WED, Willis-Ekbom disease.

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Supplementary Table 4. IRLSSG consensus diagnostic criteria for RLS/WED (2014). _____________________________________________________________________________________

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Restless legs syndrome (RLS)/Willis-Ekbom disease (WED), a neurological sensorimotor disease often profoundly disturbing sleep and quality of life, is diagnosed by ascertaining the following five essential criteria adding clinical specifiers where appropriate.

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Essential Diagnostic Criteria (all must be met) 1. An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.a,b 2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting. 3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.c 4. The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.d 5. The occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).e Specifier for Clinical Significance of RLS/WED The symptoms of RLS/WED cause significant distress or impairment in social, occupational, educational or other important areas of functioning by their impact on sleep, energy/vitality, daily activities, behavior, cognition or mood.

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Specifiers for Clinical Course of RLS/WEDf A. Chronic-persistent RLS/WED: symptoms when not treated would occur on average at least twice weekly for the past year. B. Intermittent RLS/WED: symptoms when not treated would occur on average < 2/week for the past year, with at least 5 lifetime events. _______________________________________________________________

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Footnotes: a Sometimes the urge to move the legs is present without the uncomfortable sensations and sometimes the arms or other parts of the body are involved in addition to the legs. b For children, the description of these symptoms should be in the child’s own words. c When symptoms are very severe, relief by activity may not be noticeable but must have been previously present. d When symptoms are very severe, the worsening in the evening or night may not be noticeable but must have been previously present. e These conditions often referred to as “RLS/WED mimics”, have been commonly confused with RLS/WED particularly in surveys because they produce symptoms that meet or at least come very close to meeting criteria 1-4. The list here gives some examples that have been noted as particularly significant in epidemiological studies and clinical practice. RLS/WED may also occur with any of these conditions, but the RLS/WED symptoms will then be more in degree, conditions of expression or character than those usually occurring as part of the other condition. f The clinical course criteria do not apply for pediatric cases nor for some special cases of provoked RLS/WED such as pregnancy or drug-induced RLS/WED where the frequency may be high but limited to duration of the provocative condition. _____________________________________________________________________________________________ Abbreviations: IRLSSG, International Restless Legs Study Group; RLS, restless legs syndrome; WED, WillisEkbom disease. Reproduced with permission from Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria – history, rationale, description, and significance. Sleep Medicine. 2014;15:860-73.

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Supplementary Table 5. Prevalence of restless legs syndrome/Willis-Ekbom disease during pregnancy. Location of study

N

Prevalence rate (%)

Interviews & questionnaires 1 day PP. IRLS, ESS, H/H. Matched-controls after RLS identified.

Peru

18.4

NIH/IRLSSG

Interview within 2 days of delivery. IRLS scale.

Iran

218 consecutive women admitted in labor 443 consecutive women admitted in labor

Minár [3]

NIH/IRLSSG

Slovak Republic

300 total

2013

Hubner [4]

NIH/IRLSSG

Switzerland

501 total

2012

Ko [5]

NIH/IRLSSG

2012

Sarberg [6]

NIH/IRLSSG

Self-administered questionnaires on admit for delivery. IRLSSG criteria “slightly modified for pregnancy.” Interview if + RLS. TC 4 months PP. Prospective, face-to-face interviews. IRLS, PSQI. Most severe cases got IV iron and were excluded. Leg actigraphy for PLMs; estradiol, Hgb, ferritin, CRP. Prospective cohort study, self-administered questionnaires in 8 offices over 3 months. PSQI, WHIIRS, Berlin, JHTDIF, ESS. Prospective study in ∆s 1-23 and up to 3 years PP. Snoring symptoms, ESS.

2012

Chen [7]

NIH/IRLSSG

2013

Ramirez [1]

RLS/WED diagnostic criteria useda NIH/IRLSSG

2013

Vahdat [2]

2013

Prevalence higher than in general population? Yes

17.8

Yes

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First author and reference

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Methodsb

Year

Overall 31.3 Symptoms started: ∆ 1: 6% ∆ 2: 23% ∆ 3: 71% 12

Yes

Overall 19.4 ∆ 1: 15.6 ∆ 2: 17.1 ∆ 3: 20.8 PP 6 weeks: 21 Overall 32 ∆ 1: 17 ∆ 2: 27.1 ∆ 3: 29.6 PP 3 years: 31 10.4

Yes

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Yes

Face-to-face interviews on admission to hospital. JHRLSSRS. F/U 2 months PP.

Korea

689

Sweden

500

Taiwan

461

Other observationsb

+ RLS had ↑ preeclampsia. + RLS had ↑ ESS scores. + RLS took iron supplements less frequently. 74.7% moderate, 13.9% severe to very severe RLS. ↑ insomnia if RLS. ↑ cesarean section rate if RLS. Pre-existing RLS in 12.7% of those with RLS. Pre-existing RLS in 17% of those with RLS. PP  ↓ IRLS scores for 68.8%. 50% had sleep disturbances. Mimics ruled out by neurologist. + RLS had greater weight gain. Mimics ruled out. Strongest predictors of RLS were positive personal and family history of RLS. 45% had moderate/severe RLS. Severity did not increase over ∆s. 30% had RLS symptoms PP. No significant difference in prevalence by trimester or PP. However, the PP population surveyed was small (n = 47).

Yes

Snoring correlated strongly with ↑ prevalence of RLS in all 3 trimesters. 31% had RLS 3 years PP.

Yes

27% had RLS symptoms 3 months PP. Sleep disturbance in 81.2% of those with RLS. ↑ history of anemia and peptic ulcer disease with RLS.

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2010

Facco [10]

NIH/IRLSSG

2010a

Neau [11]

NIH/IRLSSG

2010b

Neau [12]

NIH/IRLSSG

2010

Alves [13]

NIH/IRLSSG

2010

Ismailogullari [14]

NIH/IRLSSG

2009

Sikandar [15]

NIH/IRLSSG

2008

Harano [16]

NIH/IRLSSG

2007

Tunc [17]

NIH/IRLSSG

2004

Manconi [18]

IRLSSG (1995)

Self-administered questionnaire. Nulliparous women enrolled between 620 weeks with follow-up at 28-40 weeks. Prospective, crosssectional, self-administered questionnaire. IRLS.

Prospective cross-sectional, self-administered questionnaire in ∆ 3, reviewed by provider. F/U mail or telephone 3 months PP. Interview in ∆ 1, ∆ 2, ∆ 3.

22.5

Yes

↑ family history of RLS and history of growing pains in those with RLS.

Norway

251

34 PP 2-3 days: 3

Yes

United States

189

∆ 1: 17.5 ∆ 3: 32.2

Yes

18% affected had pre-existing RLS. 90% had remission of symptoms within 3 days PP (97% if those with pre-existing RLS excluded). ∆ 1: 15.2% had severe RLS symptoms. ∆ 3: 27.1% had severe RLS symptoms.

France

1,022

Overall 23.7 ∆ 1: 8.3 ∆ 2: 18.3 ∆ 3: 38.4

Yes

186

3∆: 32

Yes

524

Yes

983

Overall 13.5 ∆ 1: 5.6 ∆ 2: 43.7 ∆ 3: 50.3 10.5

Yes

Pakistan

271

30

Yes

Pre-existing RLS in 29.6% of those with RLS during pregnancy.

Japan

19,441

2.9

No

Prevalence differs significantly from Suzuki (2003).

Turkey

146

26.02

Yes

Leg cramps and excessive daytime sleepiness were more common in women with RLS.

Italy

642

26.6

Yes

Highest prevalence ∆ 3, with a sharp drop off PP. 20% had symptoms > 2x/week. Significant impact on sleep.

France

Brazil

Face-to-face interviews using surveys at delivery and 6 months PP. Interviews within 3 days PP.

Turkey

Self-administered questionnaires in 344 medical clinics. Face-to-face interviews in one facility by same neurologist at 16-36 weeks gestation. Face-to-face interviews at delivery with telephone interviews 1, 3, 6 months PP.

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NIH/IRLSSG

211

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Uglane [9]

Australia/New Zealand

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2011

Case control; questionnaires administered to women in obstetric waiting room in ∆ 3. Questionnaires administered in hospital 2-3 days PP.

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NIH/IRLSSG

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Balendran [8]

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2011

Predictors for RLS included advancing maternal age & ∆ 3. RLS symptoms sooner & more severe in subsequent pregnancies. 44% primparae, 56% multiparae. RLS symptoms abated or diminished dramatically after birth.

53.4% affected with severe or very severe RLS by IRLS ratings. Pre-existing RLS in 9.9% of those with RLS. Significant ↓ to 2.9% 6 months PP.

ACCEPTED MANUSCRIPT Suzuki [19]

IRLSSG (1995)

Self-administered questionnaires in 260 maternity clinics.

Japan

16,528

19.9

Yes

2001

Lee [20]

Single question

Prospective questionnaire preconception, ∆ 1, ∆ 2, ∆ 3, PP. PSG, lab work.

United States

30

Yes

1988

Goodman [21]

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Interview at 32-34 weeks gestation; telephone or mail with follow-up 4 weeks PP.

England

500

Preconception: 0 ∆ 1: 12.5 ∆ 2: 18 ∆ 3: 23 PP 1 mo: 3 19

1960

Ekbom [22]

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Sweden

1953

Jolivet [23]

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Face-to-face interview by author in a women’s clinic, a few days to weeks PP. Random selection, ages 1645. Face-to-face interview.

1945

Ekbom [24]

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Face-to-face interview on obstetrical ward shortly before or after delivery.

Sweden

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2003

France

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Yes

202

12.4

Yes

100

27

Yes

486

11.3

Yes

Prevalence differs significantly from Harano (2008). Use of 1 IRLSSG 1995 based question: Is your sleep interrupted by a sensation of “insects running across your skin” or hot flashes inside your legs after you go to bed at night? An item for secondary analysis was included for prevalence of RLS within the past week: “restless legs as you fell asleep.” 16% of those affected had pre-existing RLS. Severe symptoms in 7%. Marked improvement in the 4 weeks PP. 16% of those affected had pre-existing RLS. All affected women became symptom free after delivery.

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33% of those affected had pre-existing RLS. 97% of those with pregnancy-only RLS had resolution of symptoms PP. a “NIH/IRLSSG” designation indicates the study followed the 2003 International Restless Legs Syndrome Study Group criteria for RLS diagnosis [25]. Studies designated with “IRLSSG (1995)” used the 1995 IRLSSG RLS criteria to diagnose RLS [26]. bRLS used rather than RLS/WED for brevity in the table.

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Abbreviations: Berlin, Berlin Questionnaire for sleep disordered breathing; CRP, C-reactive protein; ESS, Epworth Sleepiness Scale; f/u, follow-up; Hgb, hemoglobin; H/H, hemoglobin/hematocrit; IRLS, International Restless Legs Syndrome Study Group rating scale; IRLSSG, International Restless Legs Syndrome Study Group; IV, intravenous; JHRLSSRS, Johns Hopkins RLS Severity Rating Scale; JHTDIF, Johns Hopkins Telephone Diagnostic Interview Form; NIH, National Institutes of Health; PLMs, periodic limb movements; PP, postpartum; PSG, polysomnogram; PSQI, Pittsburgh Sleep Quality Questionnaire; RLS, restless legs syndrome; TC, telephone call; ; ∆, trimester; WED, WillisElbom disease; WHI-IRS, Women’s Health Initiative Insomnia Rating Scale.

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References

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Willis-Ekbom disease during pregnancy and lactation.

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western coun...
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