dr. joseph ernest, eds and pregnancy (2011)

EDNF 2011 Conference 7/28/11

All rights reserved. 1

Ehlers-Danlos Syndrome and

Pregnancy 2011

J. M. Ernest, MD Chair, Department of Obstetrics and Gynecology

Carolinas Medical Center Charlotte, NC

Member, Professional Advisory Network EDNF

Pregnancy and EDS ! At the end of the presentation, the

attendee should be able to: n  Discuss the genetic and collagen changes of

EDS n  Discuss the health risks of EDS in women n  List 5 complications of pregnancy that are

more common in patients with EDS n  Discuss preconceptional counselling for the

patient with EDS n  Discuss the evaluation of the pregnant patient

with EDS



Whale sharks are … vegetarian

Collagen molecule

• X and Y are amino acids

• X generally is proline • Y generally is hydroxyproline

From: Molecular Biology of the Cell, 4th ed; 2002. Chapter V.



A closer look…

Collagen fibril from rat cartilage




Connective tissue under epithelium


Collagen bundles in chick embryo skin

Collagen bundles run at right angles to each other

From C. Ploetz, E.I. Zycband, and D.E. Birk, J. Struct. Biol. 106:73–81, 1991



Steps in synthesis of collagen fiber

EM of collagen fibril


Multiple enzymatic steps provide multiple sites for genetic problems

! If type I collagen abnormality: n  Osteogenesis imperfecta - affects bones

! If type II collagen abnormality: n  Chondrodysplasia - affects cartilage, bones

! If type III, V collagen abnormality: n  EDS - affects skin, blood vessels, GI tract



NEJM 357;11. Sept 13, 2007

EDS and Collagen

! EDS caused by abnormalities in synthesis, metabolism of collagen

! Collagen is essential component of extracellular matrix

! Collagen family includes >20 proteins encoded by at least 35 non allelic genes scattered on 15 different chromosomes



Online Mendelian Inheritance in Man

How does a collagen defect affect a woman’s health?

! Prepubertal ! After child-bearing ! During pregnancy

n  Maternal effects n  Fetal effects



EDS and women

! Propensity for EDS to affect women n  90% of EDS-HT were female in recent review

! Why? n  Muscle pain perception differs in women, men n  Muscle size and ligament/tendon structure

differ in women, men n  At puberty, sex hormones increase pain

perception in women, muscle strength in men

Castori et al. A J Med Genetics Part A. doi:10.1002/ajmg.a.33585

How may EDS affect pregnancy?



Physiology of pregnancy

! Hormonal changes ! Hematologic changes ! Cardiovascular changes ! Genitourinary changes





Progesterone levels during pregnancy

Why are increasing progesterone levels important?

! Progesterone is a smooth muscle relaxant n  Esophagus-more reflux n  Stomach-delayed emptying time n  Intestinal tract-increased transit time n  Uterus-less tone n  Blood vessels-vasodilatation n  Bronchioles-dilatation





Blood volume during pregnancy

Note dilutional effect of extra plasma volume on hematocrit before RBC production increases





Cardiac output increases





Uterine size increases during pregnancy



Uterine blood flow increases during pregnancy


! Hormonal changes n  Increasing levels of progesterone n  Delayed intestinal transit n  Increased relaxin and joint laxity

! Hematologic changes n  Increasing plasma volume

! Cardiovascular changes n  Increasing cardiac output

! Genitourinary changes n  Enlarging uterus with increasing blood flow



How may pregnancy impact the patient with EDS?

! …it depends

Classification of EDS

Current designation Type Classic I, II Hypermobility III Vascular IV Kyphoscoliosis VI Arthrochalasia VIIA, VIIB Other



Classification of EDS

Other Type n  Human dermatosparaxis VIIC n  X linked V n  Assoc. with periodontitis VIII n  Fibronectin-deficient X

Types of EDS and gene abnormality



Classic EDS (Types I, II)

! Majority of reported cases

! Autosomal dominant ! Varying degrees of

hyperextensibility of large, small joints

! Skin fragility ! Easy bruisability

Modified from Wynne-Davies R. J Bone Joint Surgery Br 52: 704, 1970




! Complications that may impact pregnancy: n  Mitral valve prolapse/tricuspid insufficiency n  Aortic root dilation (also seen in Type III) n  Thoracolumbar kyphoscoliosis n  Cervical dysfunction n  Premature rupture of membranes n  Anesthetic issues during labor/delivery n  Preterm birth n  Extension of episiotomy/perineal laceration n  Slowly healing cesarean section incision n  Prolapse of uterus/bladder


! Complications that may impact pregnancy: n  Mitral valve prolapse/tricuspid insufficiency n  Aortic root dilation (also seen in Type III) n  Thoracolumbar kyphoscoliosis n  Cervical dysfunction n  Premature rupture of membranes n  Preterm birth n  Anesthetic issues during labor/delivery n  Extension of episiotomy/perineal laceration n  Slowly healing cesarean section incision n  Prolapse of uterus/bladder



Stenotic lesions are more risky than MVP or tricuspid insufficiency





Aortic root dilation ! With Marfan’s

syndrome, aortic root dilation >40mm imposes an increased risk of aortic dissection and maternal mortality

! No definitive quantified risk in EDS

! Recommendation:

Consider echocardiagram prior to pregnancy for all patients with EDS at risk for aortic root dilation





Kyphoscoliosis in pregnancy

! Increasing lordosis as pregnancy progresses ! Most pregnant women have low back pain in

third trimester ! May be exacerbated with pre-existing

kyphoscoliosis ! Should not affect delivery ! Recommendation:

n  Pre-labor anesthesia consult to discuss regional (epidural) anesthetic

n  Consider pulmonary function tests to document baseline





Collagen in cervix during pregnancy

First trimester cervix Third trimester cervix

Iwahashi M et al. J Clin Endocrinol Metab 88: 2231–2235, 2003



Ultrasound appearance of cervix in pregnancy

Normal Dysfunction

AF AF

Ultrasound appearance of cervix in pregnancy

Normal Dysfunction

AF AF



Cervical dysfunction

! Collagen content of cervix important for maintaining integrity

! With decreased/ abnormal collagen, cervical dilation may occur prematurely

! Result: preterm birth

Recommendation: Consider baseline ultrasonic cervical length at 16-20 weeks gestation





Structure of the amnion and chorion (fetal membranes)

! Amnion: n  Single cell layer thick n  Avascular n  Has basement membrane composed of Type

III collagen (contributes elasticity, strength) ! Chorion

n  2-10 cell layers thick n  Vascular

Risk factors for preterm premature rupture of the fetal membranes

! Prior preterm delivery ! Cigarette smoking ! Antepartum bleeding

! Cervical incompetence ! Bacterial vaginosis ! Overdistended uterus

! Alpha-1-antitrypsin deficiency ! Sickle cell disease ! Ehlers-Danlos syndrome

2x risk of PROM

Increased risk of PROM



Premature rupture of membranes

! Increased risk if fetus has EDS n  (50% vs 20% if mother has EDS)

! May result in preterm birth ! May result in intrauterine/fetal infection

! Recommendation: n  Treat vaginal infections aggressively n  Carefully evaluate signs of PROM n  Observe appropriate protocols if PROM occurs





Preterm birth

! 23 weeks: First routine survival ! 28 weeks: 90% survival ! 34 weeks: Latest to offer betamethasone ! 36 weeks: Lung maturity usually complete ! 37 weeks: Term ! 40 weeks: “Due date”





Anesthetic issues during labor

! Regional vs general anesthesia ! With regional (spinal or epidural), avoid hip

and knee stress to minimize risk of dislocation

! Obtain anesthesia consultation PRIOR to labor/delivery





Slowly healing incisions

! Recommendations: n  No routine episiotomies n  Cesarean section for usual obstetrical reasons n  Metal clips vs skin sutures n  Delayed suture removal (6+ days)

Elbow




! Complications that may impact pregnancy: n  Mitral valve prolapse/tricuspid insufficiency n  Aortic root dilation (also seen in Type III) n  Thoracolumbar kyphoscoliosis n  Cervical dysfunction n  Premature rupture of membranes n  Preterm birth n  Extension of episiotomy/perineal laceration n  Slowly healing cesarean section incision n  Prolapse of uterus/bladder

Prolapse of uterus

! Recommendation: n  Avoid excessive

traction on umbilical cord at time of delivery



Classic EDS (Types I, II) ! Postpartum hemorrhage more likely

n  DDAVP (vasopressin) may be useful ! Neonatal complications

n  Prematurity n  Breech presentation n  Hypotonic, floppy baby with articular hyperextensibility n  Recommendation: Avoid operative vaginal delivery (forceps or

vacuum extractor) if fetus likely to be affected

! Prenatal diagnosis n  50% have affected parent; 50% de novo mutation n  No prenatal molecular genetic testing available*

*If linkage established in family, or disease-causing mutation has been identified in a family member, testing on research basis may be available

Hypermobility EDS (Type III)

! Autosomal dominant ! Marked joint, spine

hypermobility

! Recurrent joint dislocations ! Skin may be virtually normal ! May have chronic joint and

limb pain



Hypermobility EDS (Type III)

! Complications that may impact pregnancy: n  Similar to Classic types, as well as… n  Chronic joint and limb pain

! Prenatal diagnosis n  None currently available

Vascular EDS (Type IV)

! Autosomal dominant primarily n  New mutations (50%), germinal mosaicism give rise

to patients with negative family history ! No hyperextensibility of large joints, no

hyperelasticity of skin ! Deficiency in Type III collagen

n  Found in skin, blood vessels, uterus ! Repeated arterial rupture ! Susceptible to rupture of internal viscera,

including uterus





! Complications that may impact pregnancy: n  Bowel rupture n  Liver rupture n  Uterine rupture n  Coronary artery dissection/death n  External iliac artery rupture/aortic disruption n  Vena cava rupture n  Postpartum hemorrhage




PREGNANCY IS EXTREMELY RISKY IN PATIENTS WITH

VASCULAR (TYPE IV) EDS

Maternal mortality in Vascular EDS (Type IV)

TOTALS: 135 ~256 11.5-25%

Erez et al. Fetal Diagn Ther 2008; 23: 7-9



Vascular EDS (Type IV) ! Recommendations

n  Preconceptional counselling n  If pregnancy continues, elective hospitalization in 3rd

trimester with restriction of physical activity n  Monitor for premature rupture of fetal membranes n  Constant vigilence for vascular, bowel accidents

! Arterial rupture including aorta ! Colon rupture

n  Consider early (32-34 weeks) cesarean delivery to avoid uterine rupture (after steroid administration to enhance fetal lung maturity)

n  Observe for post partum hemorrhage n  Observe for post partum vascular accidents


! Prenatal diagnosis n  Biochemical testing available via chorionic

villus sampling at 10-12 weeks gestation if underlying abnormality of Type III collagen has been identified

n  Molecular testing of DNA from fetal cells obtained by amniocentesis at 15-18 weeks gestation or from CVS tissue at 10-12 weeks AFTER disease-carrying allele of affected family member has been identified



Kyphoscoliosis EDS (Type VI)

! Autosomal recessive ! Deficiency of lysyl hydroxylase results in

hydroxylysine-deficient collagen ! Results include those of other forms of

EDS plus scleral fragility ! Severe kyphoscoliosis may lead to

cardiorespiratory failure

Pulmonary function in pregnancy



Kyphoscoliosis EDS (Type VI)

! Complications that may impact pregnancy: n  Severe kyphoscoliosis may worsen as pregnancy

advances n  Slow wound healing n  Other complications of EDS

! Prenatal diagnosis possible n  Screening fetal DNA for mutations in lysyl hydroxylase

gene when disease-causing mutation has been identified in an affected family member

Arthrochalasia EDS (Types VIIA, B)

! Autosomal dominant ! Pronounced joint hypermobility ! Moderate cutaneous elasticity ! Moderate bruising ! Short stature ! Kyphoscoliosis, muscle hypotonia,

frequent dislocations (esp. large joints)



Arthrochalasia EDS (Types VIIA, B)

! Complications that may impact pregnancy: n  Hip instability during vaginal delivery n  Other typical EDS complications with skin,

joints

! Prenatal diagnosis available

Anesthesia issues with EDS

! Regional (spinal and epidural) and general have been administered to patients with EDS

! Pros and cons need to be discussed BEFORE labor/delivery with anesthesia



Preconceptional counseling with EDS

! Which form of EDS does the patient have? n  Pregnancy extremely risky in vascular type

! How certain is she of the diagnosis? n  Review records/talk with primary MD to

confirm diagnosis ! What problems has she had to date?

n  Wound healing n  Joint dislocations n  Pain n  Kyphoscoliosis

Preconceptional counseling with EDS

! Has she had an echocardiogram? n  MVP/Tricuspid insufficiency/aortic root dilation

! Does she understand the genetics of her particular type of EDS?

! Has she been pregnant before? ! How did the pregnancy progress?

n  Premature rupture of membranes n  Cervical dysfunction n  Prior child with EDS



Prenatal evaluation of the pregnant patient with (non-vascular type) EDS

! Review inheritance and potential for prenatal diagnosis

! Review prior pregnancies n  Cerclage-pros and cons n  Lacerations/poor wound healing

! Discuss premature rupture of membranes/ preterm labor

! Early ultrasound for dating, viability ! Consider echocardiogram for aortic root dilation ! Consider baseline transvaginal cervical length at

16-20 weeks

Prenatal evaluation of the pregnant patient with (non-vascular type) EDS

! Support hose to reduce varicose veins ! Consider pelvic belt for discomfort ! Fluids, fiber to prevent constipation ! Address periodontal disease aggressively ! Discuss vaginal vs cesarean delivery-pros

and cons ! Discuss type of anesthesia before labor



Intrapartum evaluation of the pregnant patient with (non-vascular type) EDS

! Observe for breech presentation ! Avoid excessive abduction of hips ! Avoid episiotomy, forceps when possible (especially when fetus affected) ! Careful incisional repair for vaginal,

cesarean delivery

Postpartum evaluation of the pregnant patient with (non-vascular type) EDS

! Delayed suture removal after c-section ! Notify pediatricians of inheritance pattern ! Observe for postpartum hemorrhage ! Avoid excessive traction on umbilical cord



SUMMARY

! Physiologic changes in pregnancy may impact EDS

! Type of EDS important to document ! Pre-pubertal, preconceptional, pregnancy,

and later life periods affected by EDS ! PREGNANCY EXTREMELY RISKY IN

VASCULAR (TYPE IV) EDS

Unanswered pregnancy issues

! Preimplantation genetic diagnosis n  Gestational surrogate

! Prepregnancy issues n  MRA? n  Begin beta blocker (celiprolol)?

! Pregnancy risks n  Best management with vascular type n  Cervical dysfunction therapy

! Postpartum recommendations n  Oxytocin antagonist to reduce vascular accidents?



Thank you

dr. joseph ernest, eds and pregnancy (2011)

Documents

collagen changes of

eds ednf

collagen defect

metabolism of collagen

collagen family

n chondrodysplasia

genitourinary changes

women n list