non-vascular ehlers- danlos syndrome and pregnancy: what are the risks?
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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 0.220-29 58 13.130-39 186 42.940-49 123 28.250-59 54 12.6Over 60 13 3.0
EDS subtype(n=437)
Classic 102 23.3Hypermobility 331 75.7Kyphoscoliosis 3 0.7Arthrochalasia 1 0.2Dermatosparaxis 0 0
Had Genetic Testing for EDS(n=113)
DNA analysis 8 7.3Protein analysis 38 34.9Don’t know 68 62.4Answer 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 OutcomesEDS 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 MiscarriageType 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 populationa Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006e 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, 2006e 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 populationa Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006e Goldenberg et al., 2008
Pregnancy Complications Non-vascular EDS
Total N=376Classic EDSTotal N=93
Hypermobile EDSTotal 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 populationa Martin et al., 2006 b Beilin et al., 1998 c Snow & Neubert, 1997 d ACOG Practice Bulletin, Number 76, 2006e 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 populationa 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 populationa Martin et al., 2006 b Kochanek et al., 2009 c Goldenberg et al., 2008
NV-EDS vs. Vascular EDS Type of
EDSComplication 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 PreviaAbruption
Pelvic complications 26 SymphysisInstability
Cardiac issues and fainting
23 POTSChange in heartrate
Swelling and edema 16 Oligohydramnios 18 Gastrointestinal manifestations
14 GERDDysmotility
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
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.
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