“Pregnancy in adult-onset idiopathic inflammatory myopathy”: Report from a cohort of myositis patients from a single center

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“PREGNANCY IN ADULT-ONSET IDIOPATHIC INFLAMMATORY MYOPATHY”: Report from a cohort of myositis patients from a single center PINAL-FERNANDEZ IAGO MD, SELVAO’CALLAGHAN ALBERT MD, PhD, FERNANDEZCODINA ANDREU MD, MARTINEZ-GOMEZ XAVIER MD, RODRIGO-PENDAS JOSE, PEREZLOPEZ JORDI MD, PhD, VILARDELL-TARRES MIQUEL MD, PhD

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Cite this article as: PINAL-FERNANDEZ IAGO MD, SELVA-O’CALLAGHAN ALBERT MD, PhD, FERNANDEZ-CODINA ANDREU MD, MARTINEZ-GOMEZ XAVIER MD, RODRIGO-PENDAS JOSE, PEREZ-LOPEZ JORDI MD, PhD, VILARDELL-TARRES MIQUEL MD, PhD, “PREGNANCY IN ADULT-ONSET IDIOPATHIC INFLAMMATORY MYOPATHY”: Report from a cohort of myositis patients from a single center, Seminars in Arthritis and Rheumatism, http://dx.doi. org/10.1016/j.semarthrit.2014.05.004 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 galley proof before it is published in its final citable 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.

TITLE: “PREGNANCY IN ADULT-ONSET IDIOPATHIC INFLAMMATORY MYOPATHY” Report from a cohort of myositis patients from a single center

AUTHORS: PINAL-FERNANDEZ, IAGO, MD SELVA-O’CALLAGHAN, ALBERT, MD, PhD FERNANDEZ-CODINA, ANDREU, MD MARTINEZ-GOMEZ, XAVIER, MD(1) RODRIGO-PENDAS, JOSE(1) PEREZ-LOPEZ, JORDI, MD, PhD VILARDELL-TARRES, MIQUEL, MD, PhD

CENTER: SYSTEMIC AUTOIMMUNE DISEASES UNIT. DEPARTMENT OF INTERNAL MEDICINE. VALL D’HEBRON UNIVERSITY HOSPITAL. (1)

DEPARTMENT OF EPIDEMIOLOGY AND PREVENTIVE MEDICINE.

UNIVERSITAT AUTONOMA DE BARCELONA. BARCELONA. SPAIN.

SOURCE(S) OF SUPORT: NONE.

CORRESPONDING AUTHOR AND REPRINT REQUESTS: IAGO PINAL-FERNANDEZ ADDRESS: C/HEDILLA Nº5 1º 3ª BARCELONA, SPAIN, 08031 TELEPHONE NUMBER: 0034-678865826 E-MAIL: [email protected]

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ABSTRACT Background and Purpose: Idiopathic inflammatory myopathies (IIM) are systemic diseases, characterized by the presence of an inflammatory muscle infiltrate. Although more frequent in women, its relationship with pregnancy has not been extensively studied. Our goal was to analyze the interaction between pregnancy and myositis in a cohort of IIM women from a single center. Methods: Fifty-one patients from a historical cohort of IIM diagnosed between 1983 and 2013 were interviewed with a specific questionnaire. Comparisons between pregnancies occurring before and after the onset of the disease were performed using generalized mixed-effect models with normal and binomial distributions adjusted for confounding factors and clustering. Results: One-hundred and two pregnancies from 51 patients (41 dermatomyositis and 10 polymyositis) were analyzed. Fourteen pregnancies from 8 patients occurred after disease onset; statistically significant (p=0.02) clinical improvement during gestation was evident in 7 pregnancies (4 patients), 5 of them (from 2 patients) experienced a relapse of IIM symptoms afterwards, while in the rest there was no influence of pregnancy on the disease. No disease flare associated with pregnancy was observed. Two patients were diagnosed within the first 6 months after delivery and none during pregnancy. No evidence was found to support pregnancy as a trigger for myopathy (p=0.71). Conclusions: Pregnancy does not seem to carry a worse prognosis for the mother nor for the fetus in patients with IIM; on the contrary, near half of the patients in our series improved clinically when they became pregnant, a relapse of IIM symptoms being common afterwards. Pregnancy does not appear to be a trigger for IIM.

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INTRODUCTION Idiopathic inflammatory myopathies (IIM) are acquired systemic diseases of probable autoimmune nature characterized by proximal and symmetrical muscle weakness, and inflammatory infiltrates on muscle biopsy. Polymiositis (PM) and dermatomyositis (DM) are the most common forms of IIM.(1, 2) The incidence of IIM is 5-10 new cases/million population/year, with females affected twice as often as males.(3, 4) It is estimated that only 14% of patients with IIM present during reproductive years.(5) In these cases it can occur before, during or immediately after gestation. Although several studies, mainly case reports or observational case series and reviews, have been published about the prevalence and outcomes of pregnancy in patients with IIM,(6-9) data related to the influence of pregnancy on myositis activity, or to mother/fetal complications during pregnancy in patients diagnosed with IIM, is scarce or uncertain. Moreover, some authors have postulated that pregnancy could be viewed as a possible trigger of IIM. Our objective was to analyze the interaction between pregnancy and myositis in a large cohort of women with IIM from a single-center. Specifically we tried to assess both newborn and maternal complications associated with pregnancy in those patients with IIM, the influence of pregnancy in IIM and study if pregnancy could act as an IIM trigger. PATIENTS AND METHODS Patient population In this retrospective cohort study, seventy-one female live patients under routine outpatient follow up during data collection were identified from our cohort of patients diagnosed with DM or PM at Vall d´Hebron General Hospital in Barcelona, 3

Spain, between 1983 and 2013. From this group, 51 female patients were personally interviewed by one of the investigators with a specific questionnaire to assess their gestation history and its relationship with myositis. The other 20 cases were not included because of patient refusal (14 patients) or due to insufficient reported data (6 patients). The diagnoses of DM and PM were based on the Bohan and Peter criteria,(10, 11) and only patients with definite or probable disease were included. Muscle enzime, muscle weakness, electromyography, muscle biopsy and skin rash data to assess Bohan and Peter criteria have been prospectively collected by one of the authors (ASO) from 1983. Patients who were interviewed gave informed oral consent, and the study was approved by our Institutional Review Board. Data on clinical (basic demographic data, date of IIM onset, and treatment) and serologic features (specific and associated myositis antibodies) were obtained by review of the patients’ medical records and laboratory databases. Disease activity was evaluated in an unstructured way and used as a complement of the structured interview with a descriptive purpose by means of clinical assessment -strength measuring of the different muscle groups, skin rash inspection, lung examination and symptoms of esophageal dysfunctionand creatinine kinase serum values. A structured interview was conducted (Appendix 2), registering the following variables of each pregnancy: epidemiological data (delivery date, sex, weight and height of the newborn); abortion (spontaneous or induced and its cause); pregnancy duration (considering a preterm birth when the pregnancy ended before the 37th week); delivery duration and type (natural or cesarean); postpartum period (defined as 6 weeks after delivery); disease symptoms and the time of appearance: before (up to 6 months before pregnancy), during and after pregnancy (up to 6 months after pregnancy); the subjective influence of disease on pregnancy and vice 4

versa; and the treatment of the disease, type and dose of the drugs received, before, during and after pregnancy.

Serologic assays Serum samples had been screened by indirect immunofluorescence for antinuclear autoantibodies using HEp-2 cells, and by enzyme-linked immunosorbent assay (ELISA) for autoantibodies directed against extractable nuclear antigens (anti-Ro, -La, -RNP and -Sm autoantibodies), anti-his-tRNA synthetase (anti–Jo-1), and antiTIF1

autoantibodies. Sera from all patients in this series were additionally tested by

protein and RNA immunoprecipitation, which allows detection of other anti-synthetase and other myositis-specific autoantibodies (MSA), such as anti-Mi-2 and anti-signal recognition particle (SRP), and myositis-associated autoantibodies (MAA), such as antiRo 52/60, anti-La, anti-PM-Scl, and anti-RNP autoantibodies that may have not been detected by ELISA, and to confirm ELISA results.

Statistical analysis Qualitative variables were expressed as percentages and absolute frequencies and continuous variables as median, first and third quartiles (Q1-Q3). We compared pregnancies occurring before and after the onset of the disease. Knowing that different numbers of pregnancies were registered for every patient, a generalized random mixedeffect model was used to adjust for clustering. Normal and binomial distributions were used to compare continuous and dichotomous variables respectively. Confounding variables unevenly distributed in the univariate analysis were introduced into the regression model as factors.

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A sign test was performed to address whether pregnancy changes the course of the disease in terms of its symptoms. Percentage of missing values in reported maternal and newborn complications were compared through a two-proportion z-test to assess the possibility of a recall bias between those pregnancies occurring before and after the onset of IIM To assess the plausibility of pregnancy as a trigger for IIM we calculated the expected percentage of patients with the onset of the disease within the period between conception and 6 months after delivery. If pregnancy was a trigger for IIM, the onset of the disease should occur more frequently during or immediately after gestation. To test this hypothesis we performed an exact binomial between the expected (Appendix 1) and the observed percentage of patients with IIM pregnancy-related onset. Microsoft Office Access 2007 was used to design the database and make a controlled data entry (limit de range of values allowed for the different variables, creation of logical algorithms to avoid data entry errors, design of a clear interface to allow an easy data entry…) while IBM SPSS Statistics 20.0 and Stata 12 were used to perform the statistical analysis.

RESULTS Seventy-one patients met the entry criteria of the study and 51 of them were available for the interview; 41 (80.4%) dermatomyositis (DM) and 10 (19.6%) polymiositis (PM). The number and percentages of patients with myositis specific or associated antibodies were as follows: fourteen patients (27.5%) were positive for antysinthetase autoantibodies (12 anti-Jo-1, 1 anti-PL12, and 1 anti-PL7), 8 (15.7%) for 6

anti-PM/Scl, 6 (11.8%) for anti-TIF1 , 5 (9.8%) for anti-Ro52, 2 (4%) for anti Mi2, 2 (4%) for anti-La, 2 (4%) for anti-SRP, 1 (2%) for anti-MDA5, and 1 for anti-Ku antibody. Ten patients (16 pregnancies) were detected as having pregnancies temporally related with the myositis process; in 8 (5 DM, 3 PM, 14 pregnancies) pregnancy occurred after the diagnosis of the disease and in 2 (2 pregnancies) dermatomyositis started after delivery. The diagnosis or symptoms onset of IIM did not appear in any case during the pregnancy period. Regarding the modulation of disease activity through pregnancy, 3 patients (2 DM, 1 PM, 6 pregnancies) reported resolution or marked improvement of the disease during gestation, one of them (1 pregnancy) remained asymptomatic and the other two (5 pregnancies) relapsed afterwards. In another 4 patients (2 DM, 2 PM, 5 pregnancies) there was no influence of pregnancy on the disease symptoms as they were asymptomatic or mildly symptomatic before pregnancy. One patient reported no changes in the disease symptoms during of after the first pregnancy -an induced abortion-, referring resolution of the symptoms associated to IIM during the second pregnancy, remaining asymptomatic afterwards, including during her third pregnancy. The sign test showed that the improvement in symptoms during pregnancy was statistically significant (p=0.02). On the contrary, influence of disease on pregnancy was reported mostly as absent or mild. Of the 14 pregnancies beginning after the onset of the disease, 11 were completed without complications for the fetus but in 3 cases pregnancy ended in abortion (2 induced and one spontaneous). All patients with active disease at the time of pregnancy were treated with low dose glucocorticoids exclusively, except one of the induced abortions, which was because of methotrexate treatment and one of the 7

patients with a successful pregnancy, which received also immunoglobulins. Treatment changes were not registered during pregnancy. Three pregnancy complications (two cases of high risk of premature birth because of vaginal bleeding and one intrauterine growth restriction), 4 delivery complications (an episode of fever and anemia, a brain hematoma post-epidural anesthesia, an emergency cesarean for lack of cervical dilatation and an umbilical cord knot), 3 postpartum complications (a mastitis, an uterine prolapse and hypertension after delivery) and 2 preterm births (34 and 36 weeks of pregnancy, this last one corresponding with the reported case of intrauterine growth restriction) were detected in these 14 pregnancies. All this data is summarized in Table 1. Univariate analysis comparing pregnancies occurring before and after the onset of the disease showed marked differences on two well known confounding variables: maternal age at delivery (medians 28.3 vs. 36.6 years) and time since delivery (median 31.5 vs. 5 years). Multivariate analysis, adjusted for the confounding variables did not detect differences in children weight, height, sex, pregnancy planning or duration, number of pregnancies, abortions, need of infertility treatment, cesareans, maternal smoking habit, premature delivery, pregnancy, delivery, postpartum or newborn complications (Table 2). The expected proportion of patients with IIM onset during the pregnancy-related period was calculated to be 3.7%. Two patients (3.9%) actually had the onset of the disease during this period. The binomial exact test showed that the observed and the expected proportion of patients were not significantly different (p=0.71).

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Percentage of missing values of reported maternal and newborn complications occurring before (17.33%) and after (19.15%) the onset of the disease were not significantly different (p=0.76).

DISCUSSION In this retrospective cohort study of female patients with IIM we found that pregnancy is not related with a worse prognosis of the disease, moreover half of the pregnant females with DM presented a clinical, although temporarily, improvement. Our results, also argue against the role of pregnancy as a trigger of myositis, as is clearly demonstrated by means of the exact binomial test. From a clinical point of view, the pregnancy must to be viewed as a favorable situation in patients with IIM. Although described in the literature, the development of a severe myositis flare in pregnant patients, a potential serious situation, is highly uncommon, as is herein reported; on the other hand, the fact that IIM patients have a predisposition to improve the disease activity when pregnant, is a valuable information for the clinician, who has to face with the query about the risk of pregnancy in patients with myositis. These findings have been reported also by other authors(5, 8) Silva et al.(5) found a decrease in the need for treatment during pregnancy, suggesting that hormonal changes during this period may modulate inflammatory activity in IIM. It runs in parallel with other systemic autoimmune disease such as rheumatoid arthritis(12) or Behçet disease(13) where it could be observed amelioration during pregnancy, which is not seen in systemic sclerosis(14) or necrotizing vasculitis.(15) Probably the differences observed between those systemic diseases could be explained by means of the different pathogenesis and how pregnancy affects these mechanisms.

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In our cohort we detected two patients with the onset of the disease soon after pregnancy. Because of the design of our study we were able to calculate the expected proportion of patients with onset of IIM during pregnancy or in the immediate period afterwards, and compare it with the observed proportion. Various authors have pointed to pregnancy as a possible trigger for IIM(6, 7), a claim that cannot be supported by our data. Of course, unmatched retrospective cohort studies cannot be taken as proof of high-level causality and further studies are needed to confirm this assumption. No differences in newborn complications, during the first 6 months of life, or in maternal complications during pregnancy, delivery or postpartum were detected in pregnancies occurring before and after the onset of the disease. Reproductive counseling in order to choose a period of low activity of the disease for pregnancy is key for a good pregnancy outcome and probably explains both the low treatment requirements and the good prognosis of pregnancies in the patients of our cohort. Our study has certain limitations that should be taken into account. The number of pregnancies occurring after the onset of IIM was relatively low. Clustering and confounding factors were detected and consequently adjusted, but the study was not randomized between groups and therefore unaccounted biases may be present. Pregnancies after the onset of the disease were more recent and the mothers were younger; both the time difference between groups(16) and the age of the mother(17) are well known confounders related to fetal and maternal outcome. The cut-off point of 6 months after pregnancy might be criticized; however it was selected as a biologically plausible limit wide enough to include most of the myositis suspected to be induced by pregnancy, knowing that symptoms of IIM may appear gradually and identified on delay. (7) Recall bias was unlikely to affect the study of complications between 10

pregnancies occurring before and after the onset of IIM known that the proportion of missing values in both groups was not significantly different.

CONCLUSION In conclusion, pregnancy does not seem to carry a worse prognosis for the mother nor for the fetus in patients with IIM and may be associated with clinical improving of symptoms, which may reappear after gestation. Pregnancy does not seem to be a trigger for IIM.

ACKNOWLEDGMENTS We thank Dr. Pari Basharat and Dr. Arash Lahoutiharahdashti for their critical review of this manuscript. REFERENCES

1.

Rider LG, Miller FW. Deciphering the clinical presentations, pathogenesis, and

treatment of the idiopathic inflammatory myopathies. JAMA. 2011;305(2):183-90. 2.

Vincze M, Danko K. Idiopathic inflammatory myopathies. Best Pract Res Clin

Rheumatol. 2012;26(1):25-45. 3.

Mastaglia FL, Phillips BA. Idiopathic inflammatory myopathies: epidemiology,

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Vargas-Leguas H, Selva-O'Callaghan A, Campins-Marti M, Hermosilla Perez E,

Grau-Junyent JM, Martinez Gomez X, et al. [Polymyositis-dermatomyositis: incidence in Spain (1997-2004)]. Med Clin (Barc). 2007;129(19):721-4.

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Silva CA, Sultan SM, Isenberg DA. Pregnancy outcome in adult-onset

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pregnancy. Arthritis Rheum. 1984;27(3):291-4. 7.

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dermatomyositis that developed after delivery: the involvement of pregnancy in the induction of dermatomyositis. Br J Dermatol. 1999;141(5):897-900. 8.

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Engl J Med. 1975;292(7):344-7. 11.

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Dommergues M, et al. Behcet's disease and pregnancy. Arthritis Rheum. 2013;65(9):2450-6. 14.

Taraborelli M, Ramoni V, Brucato A, Airo P, Bajocchi G, Bellisai F, et al. Brief

report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum. 2012;64(6):1970-7.

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Pagnoux C, Le Guern V, Goffinet F, Diot E, Limal N, Pannier E, et al.

Pregnancies in systemic necrotizing vasculitides: report on 12 women and their 20 pregnancies. Rheumatology (Oxford). 2011;50(5):953-61. 16.

AbouZahr C, Wardlaw T. Maternal mortality at the end of a decade: signs of

progress? Bull World Health Organ. 2001;79(6):561-8. 17.

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APPENDIX 1 EXPECTED PERCENTAGE OF PATIENTS WITH THE ONSET OF THE DISEASE DURING PREGNANCY-RELATED PERIOD (EPP):

EPP=Proportion of patients in risk (PPR) × = PPR ×

Pregnancy-related period per patient (years) = Childbearing period (years)

Ppp × (μ PD + 0.5) (MaxDMA + 0.5) − (MinDMA − μ PD)

Where:

PPR=

Patients with the onset of the disease during the childbearing period Total number of patients

Ppp (pregnancies per patient) =

Total number of pregnancies Total number of patients

μPD (mean Pregnancy duration) =

∑ Pregnancy duration per patient Total number of patients

MaxDMA (maximum maternal age at delivery)

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MinDMA (minimum maternal age at delivery)

APPENDIX 2 STRUCTURED INTERVIEW (TRANSLATED FROM SPANISH): STUDY OF PREGNANCY IN ADULT-ONSET IDIOPATHIC INFLAMMATORY MYOPATHY The results of this survey are strictly confidential. Its purpose is to understand the complications associated with pregnancy in idiopathic inflammatory myopathy, so we can do a better reproductive counseling to our patients. Data from this study may be used for scientific purposes, always anonymously, in order to share the findings with the scientific community. PATIENT INFORMATION: -Name: ___________________________________________________________________ -DoB: ________ -Weight: ______ -Height: ________ -Smoker No Yes What age did you start smoking?: ___________________________ -Disease start date.- ____________________________ -Total number or pregnancies (including those occurred before the onset of the disease).- ________________________ -Patient diagnosis (to be completed by clinical staff): _________________________________________________________________________

PREGNANCY, DELIVERY AND POSTPARTUM INFORMATION (including abortions and neonatal deaths) -Weight of the child at birth: __________ -Height of the child at birth: ____________ -Child sex: ___________ -Delivery duration (hours): _____________ -Type of delivery: Natural Cesarean Cause for cesarean: _________________________________________________________________________ -Pregnancy planning: No Yes Time of planning (months): ___________________________________________ -Infertility treatment: No Yes Which one?: _________________________________________________________________________ -Smoked during pregnancy: No Yes Number of cigarettes per day:____________________________________ 14

-Date of delivery: ___________________________ -Pregnancy duration (weeks): ________________________ -Pregnancy complications: No Yes Which ones?: _________________________________________________________________________ -Delivery complications: No Yes Which ones?: _________________________________________________________________________ -Postpartum complications (during 6 weeks after delivery): No Yes Which ones?: _________________________________________________________________________ -Symptoms during 6 months before pregnancy: No Yes Which ones?: _________________________________________________________________________ -Symptoms during pregnancy : No Yes Which ones?: _________________________________________________________________________ -Symptoms during 6 months after delivery: No Yes Which ones?: _________________________________________________________________________ -IIM specific treatment before pregnancy: No Yes Which one?: _________________________________________________________________________ -IIM specific treatment during pregnancy: No Yes Which one?; _________________________________________________________________________ -IIM specific treatment after pregnancy: No Yes Which one?: _________________________________________________________________________ -Child health problems during 6 months after delivery: No Yes Which one?: _________________________________________________________________________ -¿What influence had the disease on your pregnancy? None Little Fair Important In case you noticed any influence describe it with your own words: ______________ _________________________________________________________________________ -¿What influence had the pregnancy on your disease? None Little Fair Important In case you noticed any influence describe it with your own words: ______________ _________________________________________________________________________ -Observations not included in the interview: ______________________________________ _________________________________________________________________________ _________________________________________________________________________ 15

_________________________________________________________________________ _________________________________________________________________________ ROLE OF THE FUNDING SOURCE No funding source was used for this project.

COMPETING INTERESTS Any of the authors involved in this project had any financial or personal relationships that could potentially and inappropriately influence (bias) the work or the conclusions.

Table 1: Summary of pregnancies related with inflammatory myopathy Patient Age code Type of disease (years) (abc*)

Disease evolution

Pregnancies (G, P**)

Fetal outcome

Therapy (BDA***)

G1, P0

Induced abortion because she was under methotrexate treatment

Methotrexate 5mg/week (BDA) Prednisone 7,5mg/day (BDA)

a1

35

Amyopathic dermatomyositis with intense dermatological affectation. No Dermatomyositis changes in the disease evolution during or after pregnancy

“

36

From a severe muscle and dermatologic Dermatomyositis affectation she turned asymptomatic during pregnancy and afterwards

G2, P1

Healthy female

Prednisone 5mg/day (BDA)

“

38

Dermatomyositis Remained asymptomatic

G3, P2

Healthy female

Prednisone 5mg/day (BDA)

a2

22

Polymyositis

Myalgia, arthritis and asthenia solved during pregnancy which didn´t reappear afterwards.

G1, P1

Healthy male

Cyclosporine 100mg/12h (B) Immunoglobulins monthly (BD) each 2 months (A) Prednisone 7,5mg/day (BDA)

a3

35

Dermatomyositis

Generalized weakness which disappeared during pregnancy and reappeared during the puerperal period with Raynaud phenomenon

G1, P1

Healthy male

Prednisone 2,5mg/day (BDA)

“

36

Generalized weakness which Dermatomyositis disappeared during pregnancy and reappeared during the puerperal period

G2, P2

Healthy male

Prednisone 2,5mg/day (BDA)

a4

38

Articular pain solved during pregnancy Dermatomyositis and reappeared after delivery.

G1, P0

Induced abortion of a female in the first trimester because of anencephaly

Prednisone 7,5mg/day (BDA)

“

39

Dermatomyositis

Articular and muscle pain solved during pregnancy and reappeared 1 month after delivery with a flare of the disease (fever, muscle and articular pain)

G2, P1

Healthy male

Prednisone 7,5 (BDA)

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Patient Age code Type of disease (years) (abc*)

Disease evolution

Pregnancies (G, P**)

Fetal outcome

Therapy (BDA***)

G3, P2

Healthy female

Prednisone 7,5mg (BD) 20mg (A)

“

41

Articular pain solved during pregnancy and reappeared afterwards with less Dermatomyositis intensity. Increased prednisone dose to avoid flare. Better disease control afterwards.

b1

28

Dermatomyositis Disease started 3 months after delivery

G2, P2

Healthy male

Prednisone 60mg/day (A)

b2

32

Dermatomyositis Disease started in the puerperal period

G2, P1 (previous spontaneous abortion)

Healthy female

Prednisone 60mg/day (A)

c1

31

Dermatomyositis

G1, P1

Healthy female

-

“

39

Dermatomyositis Remained asymptomatic

G2, P1

Spontaneous abortion of a male during the first trimester.

-

c2

36

Dermatomyositis

Invariable cutaneous exanthema during and after pregnancy

G2, P2

Healthy male

Prednisone 5mg/day (BDA)

c3

33

Polymyositis

Asymptomatic pregnancy

G1, P1

Healthy female

Prednisone 7,5mg/day (BDA)

c4

36

Polymyositis

No symptoms or specific treatment since 2 years before pregnancy

G1, P1

Healthy female

-

No symptoms or specific treatment since 2 years before pregnancy

during

and

after

* Patient groups: a) Patients which experienced relieve of the symptoms associated to a previously diagnosed inflammatory myopathy during pregnancy. b) Patients in which the beginning of the disease was chronologically related with pregnancy. c) Patients with previously diagnosed inflammatory myopathy in which no symptom modification was detected during pregnancy. *G= Number of pregnancies; P= Number of deliveries. **B= Before pregnancy; D= During pregnancy; A= After pregnancy.

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Table 2a: Descriptive data of the pregnancies. Before onset of the disease

Total

Medi an

Q1 Q3

Weight of the child (Kg)

3.4

3.1 3.9

Height of the child (cm)

50.5

Delivery duration (h)

6.5

Time of (months)

planification

Duration of pregnancy (weeks)

Number of pregnancies

Time from (years)

delivery

Age of the mother at delivery (years)

2

48. 852 2.8 18. 5 27.5

Medi an

Q1 Q3

N

81

3.5

3.2 4.0

7 0

2.7

42

51

5052

3 1

49

70

6

217. 3

6 0

12

25

2

2-6

1 8

6

N

Medi an

39.5

3640

76

40

3640

6 3

38

3

2-3

10 2

3

2-4

8 8

2

27.5

1238. 7

92

31.5

7 8

5

29

24. 633. 1

92

28.3

7 8

36.6

17. 740. 5 23. 631. 3

*U-GLMEM (ND)= Univariate generalized linear mixed model (normal distribution). **M-GLMEM (ND)= Multivariate generalized linear mixed model (normal distribution).

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UGLM EM (ND)* pvalue

MGLME M (ND)* * pvalue

1 1

<0.01

0.28

1 1

0.31

0.54

1 0

0.65

0.73

7

0.09

0.13

1 3

0.69

0.93

1 4

0.02

0.30

1 4

<0.01

1 4

<0.01

After onset of the disease Q1 Q3 2. 43. 1 47 52 7. 529 .5 416 35 39 .5 1. 83 2. 77. 2 35 38 .7

N

Table 2b: Descriptive data of the pregnancies Before onset of the disease

Total

Disease started before pregnancy

%

n

13.7

14

After onset of the disease

%

n

%

n

U-GLMEM (BD)** p-value

M-GLMEM (BD)*** p-value

Disease related with pregnancy*

15.7

16

Abortion

16.7

17

15.9

14

21.2

3

0.61

0.52

Spontaneous abortion

68.8

11

76.9

10

33.3

1

0.26

0.77

Sex (female)

52.9

46

52.7

39

53.8

7

0.97

0.81

Cesarean

8.0

7

6.6

5

18.2

2

0.25

0.95

Planning

59.6

53

53.9

41

92.3

12

0.07

0.33

Treatment of infertility

3.4

3

0.0

0

25.0

3

0.01

0.08

Smoking during pregnancy

12.2

11

11.7

9

15.4

2

0.61

0.74

Pregnancy complications

13.6

12

11.8

9

25

3

0.44

0.24

Delivery complications

12.6

11

9.3

7

33.3

4

0.11

0.96

Postpartum complications

5.7

5

2.7

2

25

3

0.03

0.20

Newborn complications

5.9

5

6.8

5

0.0

0

0.60

0.35

Premature delivery

18.2

12

18.2

10

0.96

0.69

18.2

2

Symptoms before pregnancy

56.2

9

Symptoms during pregnancy

12.5

2

Symptoms after pregnancy

56.2

9

None

75

12

Little

12.5

2

Fair

6.2

1

Important

6.2

1

None

37.5

6

Little

6.2

1

Fair

12.5

2

43.8

7

Influence of the disease in pregnancy

Influence of the pregnancy in the disease

Important *The onset of the symptoms was before 6 months after pregnancy. **U-GLMEM (BD)= Univariate generalized linear mixed model (bivariate distribution). ***M-GLMEM (BD)= Multivariate generalized linear mixed model (bivariate distribution).

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