BACKGROUND
Ehlers-Danlos syndrome (EDS) is the name given to a group of monogenic
conditions with variable systemic manifestations that predominantly
affect the skin, joints, ligaments, vasculature, and internal
organs.1 Common clinical features among different
types of EDS include joint hypermobility, frequent joint dislocations,
and skin hyperextensibility. Although various mutations and types of EDS
exist, most forms of EDS result from a genetic mutation in collagen
proteins or enzymes involved in collagen biosynthesis or
organisation.2 Inheritance is usually autosomal
dominant, with de novo mutations being relatively common, and
estimates of prevalence range from 1 in 20,000 to nearly 10 in
5,000.3–5
Considering the multisystemic effects of EDS on the body, it is not
surprising that the condition complicates pregnancy and delivery. A
recent population-based retrospective study examining EDS in pregnancy
suggests that the overall prevalence is 7 per 100,000 births on average
during the period studied, with prevalence increasing every year –
likely due to recent advances in EDS classification and genetic
techniques.6 In this cohort examining 1,042 pregnant
patients with EDS, pregnancy in EDS was associated with intrauterine
growth restriction and higher rates of maternal death and obstetric
complications, including prematurity, cervical incompetence, antepartum
haemorrhage, and placenta praevia.6 Despite the higher
prevalence of complications associated with EDS in pregnancy, there is
limited evidence and guidance regarding the optimal management of
individuals with EDS. This piece aims to provide an overview of the
obstetric implications of the most common forms of EDS, namely the
classical, hypermobile, and vascular types, and review the current
literature regarding their optimal obstetric management.
CLASSIFICATION OF EDS
Categorization of the Ehlers-Danlos syndromes began in the late 1960s
and was formalized in the Berlin nosology. Over time, it became apparent
that the diagnostic criteria established previously did not discriminate
adequately between the different types of Ehlers-Danlos syndromes. With
advances in technology, the genetic and molecular basis of several
Ehlers-Danlos syndromes were uncovered, adding a new dimension to the
classification of this group of disorders. Consequently, a revised
classification named the “Villefranche Nosology” was published in 1997
with defined diagnostic criteria and laboratory findings whenever
possible for each type.7 This simplified
classification has facilitated an accurate diagnosis of the
Ehlers-Danlos syndromes and has contributed to the delineation of
phenotypically related disorders. Except for the hypermobility type, the
genetic mutations involved have been
identified and can be precisely identified by specific testing. Since
then, with the development of genetic analysis techniques, such as
next-generation sequencing, and greater research into EDS, new mutations
and subtypes have been discovered. These new findings have culminated in
the new 2017 international classification of EDS, which is summarised in
Table 1.2
TYPES OF EDS AND EFFECTS OF EDS ON
PREGNANCY
Classical and Hypermobile
EDS
Classical EDS (cEDS) and hypermobile EDS (hEDS) account for most
individuals diagnosed with EDS. cEDS is an autosomal dominant disorder
typically caused by a mutation in collagen type V (COL5A1, and COL5A2),
although some patients may have abnormalities in collagen type I
(COL1A1).2 Collagen type V is mainly found as a
heterotrimer along with collagen type I in various tissues, including
skin, tendon, bone, and the cornea.8 Consequently, the
dominant clinical manifestations include skin hyperextensibility,
atrophic scarring, poor wound healing, and joint hypermobility.
Similarly, hEDS is an autosomal dominant condition characterised by
joint hypermobility, although the exact genetic mechanisms are yet to be
discovered.5 As the molecular mechanisms are largely
unknown, diagnostic criteria for hypermobility EDS (hEDS) is based on
strict clinical findings of generalized joint hypermobility and evidence
of syndromic features (skin hyperextensibility, smooth velvety skin,
atrophic scarring), musculoskeletal complications, and/or family
history.2
Although pregnancy is generally well-tolerated in patients with cEDS and
hEDS, the conditions have wide-ranging obstetric implications for the
mother and the foetus. For the mother, the pregnancy-related release of
relaxin can exacerbate joint hypermobility and pain, especially within
the pelvic region.9,10 Interestingly, it was found
that prematurity and premature rupture of membranes were twice as more
common in foetuses with EDS with healthy mothers, compared to foetuses
without EDS in EDS-affected mothers. This suggests that amnion-related
abnormalities could mediate higher rates of prematurity, especially in
cEDS as collagen types I and V are known components of the
amnion.8,11 Cervical insufficiency could also
contribute, with collagen types I and V playing a key role in the
structural integrity of the cervix.12 Finally, with
pelvic connective tissue hypermobility and poor tissue healing, cEDS and
hEDS pregnancies experience higher rates of perineal tearing, postpartum
haemorrhage, pelvic prolapse and incontinence following
delivery.13–15 For the foetus, although no formal
studies on intrauterine growth restriction (IUGR) in specifically cEDS
or hEDS have been performed, large population studies on EDS in general
and case studies have demonstrated IUGR in both
conditions.6,16,17 This is thought to be associated
with placental defects, with a case study demonstrating IUGR in cEDS
related to abnormal placental vascular resistance.17Further research needs to be done to elucidate the prevalence and
mechanisms of IUGR in cEDS and hEDS.
Considering these complications, it may be beneficial to advise pregnant
women with cEDS and hEDS about the risks of IUGR, PROM and premature
labour, and adequate screening for the former should be done. Cervical
length screening and cervical cerclage may be helpful in managing
cervical insufficiency. Echocardiography should be completed to monitor
for known aortic root dilation, considering its high prevalence in both
cEDS and hEDS, and the cardiovascular stresses of
pregnancy.18 Early identification can lead to a prompt
referral and appropriate management, minimising further risks. Regarding
delivery options, no clear evidence for or against vaginal or caesarean
sections currently exist in the literature.15,19 For
vaginal delivery, prompt episiotomy should be considered to prevent
excessive perineal damage and should be repaired by an experienced
individual due to the tissue fragility in cEDS and
hEDS.15 Furthermore, considering the joint
hypermobility and propensity for dislocation, special care must be taken
to prevent hip or knee dislocation in the peripartum period, especially
when regional anaesthesia is utilised. It must also be noted that
studies have demonstrated reduced efficacy of regional anaesthesia in
hEDS, and careful anaesthetic input is advised.20,21For hEDS specifically, additional attention may be needed in individuals
who suffer from postural orthostatic tachycardia syndrome (PoTS),
characterised by orthostatic tachycardia without hypotension and
symptoms. PoTS can complicate delivery due to haemodynamic instability,
especially in vaginal delivery with epidural anaesthesia and in
caesarean sections. Karthikeyan and Venkat-Raman recommend combined
spinal-epidural anaesthesia for caesarean delivery.15Finally, considering the risk of postpartum haemorrhage in cEDS and
hEDS, prophylactic desmopressin (DDAVP) and tranexamic acid, along with
postpartum oxytocin may be beneficial.15 However, it
is important to note the effectiveness of these interventions has not
yet been examined in clinical trials, and the extent of the benefit is
unclear. Further work needs to be done in order to formalise management
guidance in patients with cEDS and hEDS.
Vascular EDS
Vascular EDS (vEDS) is arguably the most life-threatening form of EDS.
It is an autosomal dominant disorder of connective tissue caused by
mutation of the COL3A1 gene which encodes the pro-alpha-1 chains of type
III collagen.22 Type III collagen is found within the
skin, vessel walls and viscera, and is responsible for structural
integrity.23 As such, individuals with vEDS are prone
to vascular rupture (i.e. aortic dissection), organ rupture (i.e. bowel
perforation, uterine rupture) and fistulae formation (i.e.
carotid-cavernous sinus fistulae).24 These conditions
form the major criteria for clinical diagnosis of vEDS according to the
2017 EDS guidelines.2 Clinical suspicion can also be
raised on characteristic facial features, thin translucent skin, talipes
equinovarus, congenital hip dysplasia, and increased bruising, although
these features are often recognised in retrospect.2,24
Due to these complications, vEDS is seen as the most life-threatening
form of EDS. The significance of these problems is magnified in
pregnancy and especially during the peripartum period when uterine
contractions begin to appear. The contractions themselves increase
stress on a structurally weaker uterus, increasing the risk of uterine
rupture, and also facilitate increase in blood volume, heart rate, and
blood pressure, which can increase the risk of vessel rupture and
dissection25. Valsalva-associated increases in
abdominal pressure during contractions can also increase vascular and
organ transmural pressures, increasing the risk of vessel and hollow
organ rupture.26 As such, it is not surprising that
pregnancy-related deaths in women with vEDS occur in around 5% of
deliveries, which is nearly 300 times the maternal mortality rate in the
local population studied.27 Interestingly, pregnancy
and delivery do not seem to alter survival rates overall according to
the largest survival analysis to date, contrary to the established
opinion that pregnancy should not be considered in vEDS due to the
mortality risk.27,28
In addition to EDS-specific complications, there is a greater prevalence
of obstetric complications in women with vEDS. Pre-term births have been
reported to occur with a prevalence of 19%, likely associated with
cervical insufficiency and/or preterm PROM.27,29 Due
to the fragility of the skin and connective tissues,
3rd and 4th-degree perineal tears
are almost 20-fold more prevalent in vaginal deliveries in
vEDS27. Finally, postpartum haemorrhage is also
reported to be more common, possibly due to greater vascular rupture,
higher rates of uterine rupture, and problems with haemostasis secondary
to platelet aggregation dysfunction.24,30
Despite the risks associated with vEDS, formal obstetric guidelines on
vEDS do not yet exist, perhaps due to the rarity of the condition making
it difficult to conduct controlled trials and build a solid evidence
base. A multidisciplinary approach, including input from cardiovascular
and genetic specialists, is likely to improve outcomes for patients. The
European Society of Cardiology (ESC) recommends that celiprolol, a
β1-adrenoreceptor antagonist and
β2-adrenoreceptor agonist, be used in
pregnancy.28 Celiprolol has been demonstrated to
reduce vascular complications in an open randomised trial and an
observational study, although both studies have significant
limitations.31,32 In theory, the tocolytic
β2-agonist action could also be beneficial in preventing
premature contractions and delivery associated with vEDS. From a genetic
point a view, it may be valuable to genetically screen for patients with
vEDS in high-risk groups (i.e. positive family history) or on clinical
suspicion. For instance, Murray and colleagues argue that being aware of
the risk associated with vEDS can direct clinicians to manage pregnancy
and delivery in tertiary care settings.27 Moreover,
considering the differences in survival depending on the mutation type,
genetic testing may be able to help guide clinical
decision-making.33 However, this may be difficult to
implement as de-novo mutations in COL3A1 are common, and as the majority
of women are genetically diagnosed after pregnancy.27Many case reports describe the first presentation of vEDS in the
perinatal period. Patients have presented with severe and often deadly
complications including uterine rupture as a primigravida, coronary
artery dissection, aortic dissection, and inferior vena cava
rupture.34–37
In terms of obstetric management, early elective caesarean section, with
prophylactic DDAVP and tranexamic acid to support haemostasis and
sufficient transfusion preparation, is thought to minimise complications
although no empirical studies have been performed to assess
this29. Theoretically, caesarean section would
minimise labour-related risks and enable greater haemostasis control.
However, caesarean section is also not without excess risk in vEDS. With
fragile vessels and organs, arterial damage and haemorrhage are more
likely and bowel rupture can occur during the
procedure.38 The risk of wound dehiscence is likely
increased due to the thin and friable skin.39Anaesthesia choice is also a key factor, with local and generalised
anaesthesia having distinct advantages and disadvantages. Neuraxial
blockade poses a risk of perforation, nerve injury,
hematoma.29,40 Techniques such as single-shot spinal
anaesthsia may not provide sufficient anaesthetic coverage to manage
intraoperative haemorrhage and organ rupture.41 On the
other hand, generalised anaesthesia may face difficulties with
intubation, as atlantoaxial sublaxation has been reported in patients
with vEDS, and a greater risk of ventilation-associated pneumothorax due
to lung tissue fragility.40,42,43 Nonetheless, both
Orphanet UK emergency guidelines and Wiesmann and colleagues’
recommendations for anaesthesia in vEDS suggest the use of generalised
anaesthesia due to the potential risks of neuraxial blockade and lack of
clear evidence of benefit.29,42 If the patient
proceeds with vaginal delivery, epidural anaesthesia may be beneficial
in reducing excess maternal effort and the pain-associated sympathetic
response, which can increase blood pressure.37 Again,
haemostasis support with tranexamic acid and DDAVP is likely to be
beneficial. Orphanet UK guidelines for vEDS recommend that steps be
taken to strengthen the perineum and to strongly avoid using forceps,
considering tissue fragility and risk of severe perineal
tearing.42 Finally, regardless of caesarean or vaginal
delivery, patients should be closely monitored in hospital in the
postnatal period for delayed complications.