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

2. 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

3. 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

4. METHODS

5. 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

6. 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

7. 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

8. RESULTS

9. 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

10. 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

11. 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

12. 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

13. 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., b MacDorman & Kirmeyer, 2009 c Kochanek et al., 2012

14. 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

15. 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

16. 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., c Snow & Neubert, d ACOG Practice Bulletin, Number 76, 2006
e Goldenberg et al., 2008

17. 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., c Snow & Neubert, d ACOG Practice Bulletin, Number 76, 2006
e Goldenberg et al., 2008

18. 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., c Snow & Neubert, d ACOG Practice Bulletin, Number 76, 2006
e Goldenberg et al., 2008

19. 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

20. 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

21. 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., b Yen et al., 2006

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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.