Non-Vascular Ehlers-Danlos Syndrome and Pregnancy: What are the Risks? EDNF Learning Conference August 10-11, 2012

NV-EDS & Pregnancy Case reports of OB complications : Abnormal fetal presentation at delivery Incompetent cervix Joint dislocation during delivery Standing erect becoming increasingly difficult Uneventful

Question What is the obstetrical experience of women with non-vascular Ehlers-Danlos syndrome? Aim #1: Identify the obstetrical complications women with non-vascular EDS experience Aim #2: Compare the observed rate of obstetrical complications in women with non-vascular EDS to the General population Vascular EDS population

METHODS

Recruitment Participants recruited through the EDNF Monthly electronic newsletter EDNF homepage EDNF Facebook page Study packet distributed at annual national education meeting July 21-23, 2011 2011 meeting had >500 members in attendance Inclusion criteria: Woman with a diagnosis of NV-EDS Had at least one pregnancy At least 18 years of age

Questionnaire 22 questions - 6 sections: Demographics General pregnancy questions Prenatal care Pregnancy Maternal health during pregnancy Labor and delivery All sections other than demographic could be answered one time per pregnancy, for up to four pregnancies Open comment boxes provided throughout

Data Analysis Descriptive statistics for demographics and complication rates Means, frequencies, percentages One-tailed binomial test To compare observed complication rate to published rates when available Open-ended responses were categorized and tabulated

RESULTS

Responses Response method: Excluded responses Received by mail: 34 Received online: 484 Total # received: 517 Excluded responses Type of EDS: 40 Vascular: 1 Don’t know: 34 Skipped question: 5 Never pregnant: 6 Incomplete questionnaires: 34

Included Population # of surveys: 437 (84.5%) # of first trimester miscarriages: 61 Included second trimester miscarriages and stillbirths in analysis of complications Final # of participants included in obstetrical complication analysis: 376

Demographic Information   Frequency (n) Percent (%) Age (n=435)* 18-19 1 0.2 20-29 58 13.1 30-39 186 42.9 40-49 123 28.2 50-59 54 12.6 Over 60 13 3.0 EDS subtype (n=437) Classic 102 23.3 Hypermobility 331 75.7 Kyphoscoliosis 3 0.7 Arthrochalasia Dermatosparaxis Had Genetic Testing for EDS (n=113) DNA analysis 8 7.3 Protein analysis 38 34.9 Don’t know 68 62.4 Answer missing 4 3.7 *Two participants did not report their year of birth

Pregnancy Information   Frequency (n) Total # of Pregnancies Population as a whole (n=437) 1061 Classic EDS (n=102) 258 Hypermobile EDS (n=331) 796 Kyphoscoliosis EDS (n=3) 6 Arthrochalasia EDS (n=1) 1 Average # of Pregnancies per Woman 2.4 2.5 Kyphoscoliosis EDS (n=6) 2

1st Pregnancy Outcomes EDS Subtype Outcome Frequency (n) Percent (%) General Pop Rate (%) P-value Non-vascular (n=437) Miscarriage (<20 wks) 82 18.8 20a 0.281 Stillbirth (20-24 wks) 2 0.458 0.622b 0.496 Premature delivery (24-36 wks) 63 14.4 12.18c 0.09 Classic (n=102) 18 17.6 0.326 0.529 13 12.7 0.475 Hypermobile (n=331) 64 19.3 0.413 0.604 0.661 47 14.2 0.15 Tell why we only analyzed first pregnancy: Confounding factor of multiple pregs in one individual a Buss et al., 2006 b MacDorman & Kirmeyer, 2009 c Kochanek et al., 2012

Timing of Miscarriage First trimester (<13 wks) 61 14.1 16a 0.317 Type of EDS Time of Miscarriage Frequency (n) Percent (%) Gen Pop Rate (%) P-value Non-vascular$ (n=432) First trimester (<13 wks) 61 14.1 16a 0.317 Second trimester (13-19 wks) 16 3.7 4a 0.877 Classic% (n=101) 9 8.9 0.058 8 7.9 0.099 Hypermobile& (n=327) 52 15.9 1 2.4 0.183 a Cunningham et al., 2010, chp 9 $ Five people did not report when miscarriage occurred % One person did not report when miscarriage occurred & Four people did not report when miscarriage occurred

Pregnancy Complications: NV-EDS Frequency (n=376) Percent (%) General Population Rate (%) P-value Abnormal fetal delivery position* 55/346 15.9 5.4a <0.001 Incomplete epidural efficacy* 100/191 52.4 12b Joint dislocation* 125/330 37.9 <1d Post-partum severe bleeding from womb/uterine hemorrhage* 11/332 3.3 1d Premature rupture of membranes* 66/343 19.2 3e *Rate is significantly higher than the general population a Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006 e Goldenberg et al., 2008

Pregnancy Complications: Classic EDS Frequency (n=93) Percent (%) General Population Rate (%) P-value Abnormal fetal delivery position* 13/81 16 5.4a <0.001 Incomplete epidural efficacy* 25/39 64 12b Joint dislocation* 27/83 32.4 <1c Post-partum severe bleeding from womb/uterine hemorrhage 2/78 2.6 1 d 0.183 Premature rupture of membranes* 13/86 15 3e *Rate is significantly higher than the general population a Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006 e Goldenberg et al., 2008

Complications: Hypermobile EDS Frequency (n=279) Percent (%) General Population Rate (%) P-value Abnormal fetal delivery position* 41/261 15.7 5.4a <0.001 Incomplete epidural efficacy* 74/150 49.3 12b Joint dislocation* 96/244 39.3 <1d Post-partum severe bleeding from womb/uterine hemorrhage* 9/251 3.6 1 d 0.001 Premature rupture of membranes* 51/253 20.1 3e *Rate is significantly higher than the general population a Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006 e Goldenberg et al., 2008

Pregnancy Complications   Non-vascular EDS Total N=376 Classic EDS Total N=93 Hypermobile EDS Total N=279 Complication Gen Pop Rate (%) Frequency (n) Percent (%) P-value Abnormal fetal delivery position 5.4a 55/346 15.9 <0.001* 13/81 16.0 41/261 15.7 Incomplete epidural efficacy 12b 100/191 52.4 25/39 64 74/150 49.3 Joint dislocation <1c 125/330 37.9 27/83 32.4 96/244 39.3 Post-partum severe bleeding from womb/ uterine hemorrhage 1 d 11/332 3.3 2/78 2.6 0.183 9/251 3.6 0.001* Premature rupture of membranes 3e 66/343 19.2 13/86 15.0 51/253 20.1 * Rate is significantly higher than the general population a Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006 e Goldenberg et al., 2008

Accounting for Fetus’ EDS Status   Fetus has EDS? Frequency (n) Percent (%) General Population Rate (%) P-value Abnormal delivery position Yes* (n=161) 29 18.0 5.4a <0.001 No* (n=92) 11 12.0 0.011 Premature delivery (<37 weeks) Yes* (n=161) 19 12.18b 0.02 No (n=111) 18 16.2 0.126 Premature rupture of membranes Yes* (n=149) 35 23.5 3c (n=110) 15 13.6 *Rate is significantly higher than the general population a Martin et al., 2006 b Kochanek et al., 2009 c Goldenberg et al., 2008

Accounting for Fetus’ EDS Status   Fetus has EDS? Frequency (n) Percent (%) General Population Risk (%) P-value Abnormal delivery position Yes* (n=161) 29 18.0 5.4a <0.001 No* (n=92) 11 12.0 0.011 Premature delivery (<37 weeks) Yes* (n=161) 19 12.18b 0.02 No (n=111) 18 16.2 0.126 Premature rupture of membranes Yes* (n=149) 35 23.5 3c (n=110) 15 13.6 *Rate is significantly higher than the general population a Martin et al., 2006 b Kochanek et al., 2009 c Goldenberg et al., 2008

Vascular EDS Pop Rate (%) NV-EDS vs. Vascular EDS Type of EDS Complication Frequency (n) Percent (%) Vascular EDS Pop Rate (%) P-value Non-vascular Arterial rupture at delivery or post-partum* 11/335 3.3 8.6 a <0.001 Premature delivery* (<37 wks) 63/437 14.4 19 b 0.007 Premature rupture of membranes 66/343 19.2 0.476 Classic Arterial rupture during delivery or post-partum* 1/79 1.3 Premature delivery 13/102 12.7 0.064 13/86 15.0 0.221 Hypermobile 9/253 3.6 0.001 47/284 14.2 0.013 51/253 20.2 0.343 One-tailed binomial DECREASED rates in NV-EDS population Arterial ruptures: COL3 vs other types of collagen in arterial walls Premature delivery: approached significance in classic EDS population PROM: abnormalities in collagen predispose to PROM, doesn’t matter which type of collagen? Ruptures resulted in death in the vascular population *Rate is significantly lower than the vascular EDS population a Pepin et al., 2000 b Yen et al., 2006

Other OB Complications   Non-Vascular EDS (Total N=376) Complication Frequency (n) Percent (%) Increase in bone and/or joint pain 263/346 75.6 Difficulty standing >5-10 min 210/345 60.9 Ankle instability 183/347 52.7 Skin tingling, prickling, numbness 127/336 37.8 Teeth fragility 118/345 34.2 Heavy vaginal bleeding 139/354 39.3 Amniotic sac complications, not specified 48/344 14.0 Excessive bleeding/Hemorrhage (other than uterus) 38/338 11.2 Blood vessel rupture at any time during pregnancy 18/347 5.2 Cervical cerclage attached 3/346 0.87 Bowel perforation 2/341 0.58 Exacerbations of normal EDS symptoms

Additional Complications Provided (if n>5) Frequency (n) Examples Maternal hypertension and pre-eclampsia 40   Placental problems 28 Previa Abruption Pelvic complications 26 Symphysis Instability Cardiac issues and fainting 23 POTS Change in heartrate Swelling and edema 16 Oligohydramnios 18 Gastrointestinal manifestations 14 GERD Dysmotility Hyperemesis gravidum 13 Emergency c-section 12 Stalled labor 9 Gestational diabetes 7

Study Limitations Self-report General population rates from published literature No control group collected Ascertainment bias Vocabulary of the survey Premature rupture of membranes Hemorrhaging versus excessive bleeding

Directions for Future Research Replication of findings Control group Confirmation of diagnosis & complications via medical records Examine additional complications mentioned by participants Placenta Amniotic fluid levels Maternal blood pressure Correlation studies: Genotype-phenotype correlations Complications in previous pregnancy predict future complications Research on start and duration of complications

Conclusions Results suggest the pregnancy outcomes for women with non-vascular EDS do not differ from those of the general population: Miscarriage Still birth Premature delivery

Conclusions Results suggest women with non-vascular EDS may be at a higher risk than the general population to experience the following obstetrical complications: Fetal malpresentation, regardless of fetus’ EDS status PROM, regardless of fetus’ EDS status Premature delivery, if the fetus is also affected Incomplete epidural efficacy Joint dislocation Uterine hemorrhaging/heavy bleeding

Conclusions Results suggest women with non-vascular EDS may have a lower risk than the vascular EDS population for: premature delivery, if hypermobile EDS a during-delivery or post-partum arterial rupture

Acknowledgements The Ehlers-Danlos National Foundation Participants Statistical Sciences Core, Center for Clinical Investigation, Case Western Reserve University This work has been supported by the Jane Engelberg Memorial Fellowship Student Research Award to Krista Sondergaard, provided by the Engelberg Foundation to the National Society of Genetic Counselors, Inc.