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:

• 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 1 0.2 Dermatosparaxis 0 0

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

Population as a whole (n=437) 2.4

Classic EDS (n=102) 2.5

Hypermobile EDS (n=331) 2.4

Kyphoscoliosis EDS (n=6) 2

Arthrochalasia EDS (n=1) 1

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)

Miscarriage (<20 wks)

18 17.6 20a 0.326

Stillbirth (20-24 wks)

0 0 0.622b 0.529

Premature delivery (24-36 wks)

13 12.7 12.18c 0.475

Hypermobile (n=331)

Miscarriage (<20 wks)

64 19.3 20a 0.413

Stillbirth (20-24 wks)

2 0.604 0.622b 0.661

Premature delivery (24-36 wks)

47 14.2 12.18c 0.15

a Buss et al., 2006 b MacDorman & Kirmeyer, 2009 c Kochanek et al., 2012

Timing of Miscarriage 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)

First trimester (<13 wks)

9 8.9 16a 0.058

Second trimester (13-19 wks)

8 7.9 4a 0.099

Hypermobile& (n=327)

First trimester (<13 wks)

52 15.9 16a 1

Second trimester (13-19 wks)

8 2.4 4a 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 Complication 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 <0.001

Joint dislocation* 125/330 37.9 <1d <0.001

Post-partum severe bleeding from womb/uterine hemorrhage*

11/332 3.3 1d <0.001

Premature rupture of membranes*

66/343 19.2 3e <0.001

*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 Complication 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 <0.001

Joint dislocation* 27/83 32.4 <1c <0.001

Post-partum severe bleeding from womb/uterine hemorrhage

2/78 2.6 1 d 0.183

Premature rupture of membranes*

13/86 15 3e <0.001

*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 Complication 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 <0.001

Joint dislocation* 96/244 39.3 <1d <0.001

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 <0.001

*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 Frequency (n)

Percent (%)

P-value Frequency (n)

Percent (%)

P-value

Abnormal fetal delivery position

5.4a 55/346 15.9 <0.001*

13/81 16.0 <0.001*

41/261 15.7 <0.001*

Incomplete epidural efficacy

12b 100/191 52.4 <0.001*

25/39 64 <0.001*

74/150 49.3 <0.001*

Joint dislocation

<1c 125/330 37.9 <0.001*

27/83 32.4 <0.001*

96/244 39.3 <0.001*

Post-partum severe bleeding from womb/ uterine hemorrhage

1 d 11/332 3.3 <0.001*

2/78 2.6 0.183 9/251 3.6 0.001*

Premature rupture of membranes

3e 66/343 19.2 <0.001*

13/86 15.0 <0.001*

51/253 20.1 <0.001*

* 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 5.4a 0.011

Premature delivery (<37 weeks)

Yes* (n=161)

19 18.0 12.18b 0.02

No (n=111)

18 16.2 12.18b 0.126

Premature rupture of membranes

Yes* (n=149)

35 23.5 3c <0.001

No* (n=110)

15 13.6 3c <0.001

*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 5.4a 0.011

Premature delivery (<37 weeks)

Yes* (n=161)

19 18.0 12.18b 0.02

No (n=111)

18 16.2 12.18b 0.126

Premature rupture of membranes

Yes* (n=149)

35 23.5 3c <0.001

No* (n=110)

15 13.6 3c <0.001

*Rate is significantly higher than the general population a Martin et al., 2006 b Kochanek et al., 2009 c Goldenberg et al., 2008

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 19 b 0.476

Classic Arterial rupture during delivery or post-partum*

1/79 1.3 8.6 a <0.001

Premature delivery (<37 wks)

13/102 12.7 19 b 0.064

Premature rupture of membranes

13/86 15.0 19 b 0.221

Hypermobile Arterial rupture during delivery or post-partum*

9/253 3.6 8.6 a 0.001

Premature delivery* (<37 wks)

47/284 14.2 19 b 0.013

Premature rupture of membranes

51/253 20.2 19 b 0.343

*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

Additional Complications Provided Complication

(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.