Osteogenesis imperfecta/ Ehlers-Danlos overlap syndrome (COL1-related disorder) and pregnancy

Osteogenesis imperfecta/ Ehlers-Danlosův syndrom (COL1-asociované onemocnění) v těhotenství

Ehlers-Danlosův syndrom je označení pro skupinu onemocnění pojivových tkání, které může během gravidity vést k řadě komplikací. Manifestuje se hyperextensibilní kůži, špatným hojením, hyperflexibilitou nebo vyšším rizikem poškození různých orgánů (ruptura dělohy, disekce aorty). Kombinace Ehlers-Danlosova syndromu a osteogenesis imperfecta je velmi zřídkavá (dle Orphanetu < 1/1 000 000). Prezentujeme kazuistiku gravidity, u pacientky s osteogenesis imperfecta/Ehlers-Danlosovým syndromem, komplikovanou dilatací aorty. Naší kazuistikou chceme poukázat na možné komplikace související s graviditou u tohoto velmi raritního, ale extrémně závažného syndromu.

Klíčová slova:

těhotenství – osteogenesis imperfecta – disekce aorty – Ehlers-Danlosův syndrom – COL1-asociované onemocnění

Authors: A. Šinská ;  E. Hostinská ;  R. Pilka
Authors place of work: Department of Obstetrics and Gynecology, Faculty of Medicine, Palacky University and University Hospital Olomouc
Published in the journal: Ceska Gynekol 2022; 87(6): 396-400
Category: Kazuistika
doi: 10.48095/cccg2022396


Ehlers-Danlos syndrome is in a group of connective tissue disorders that can result in a range of complications during pregnancy. Clinical manifestations include skin hyperextensibility, atrophic scarring, poor wound healing, hyperflexibility or higher risk of organ ruptures (uterine rupture, aortal dissection). The combination of Ehlers-Danlos syndrome and osteogenesis imperfecta is very rare (< 1/1,000,000 according to Orphanet). We are presenting a case of woman with osteogenesis imperfecta/Ehlers-Danlos overlap syndrome and her pregnancy complicated by aortal dilatation. Our case has attempted to highlight the potential obstetric complications and to attract the attention of clinical physicians to the rare but extremely dangerous syndrome.


osteogenesis imperfecta – Ehlers-Danlos syndrome – pregnancy – COL1-related disorder – aortal dissection


Osteogenesis imperfecta (OI) is a group of conditions, which shares an etiology related directly or indirectly to type I collagen mutations. The most common clinical features of OI include bone fragility and deformity and growth deficiency [1]. Dominant mutations in collagen type I (encoded by COL1A1 and COL1A2 genes) are generally stated to be responsible for 90% of cases [2].

The Ehlers-Danlos syndrome (EDS) is a group of clinically genetically het­erogeneous connective tissue disorders. Skin hyperextensibility and joint hypermobility are the clinical signs of EDS. Vascular type of EDS is characterized by the presence of thin, translucent skin, and a remarkable vascular fragility that leads to spontaneous rupture of blood vessel walls or aneurysm formation [3,4].

According to Orphanet, the combination of EDS and OI is very rare (> 1/1,000,000) and it is not included in the 2017 International classification of EDS.

We present a case of pregnancy in  19-year old woman previously dia­g­nosed with COL1A2 mutation and phenotype of OI/EDS overlap syndrome. Only a few cases of OI/EDS have been described, and to our best knowledge this is the first published case of pregnancy in OI/EDS overlap syndrome.

Case report

Our patient was born in 2002 at the 38th gestational week with intrauterine growth restriction (birth weight of 2,500 g). Her father was healthy, but her mother was observed for muscle weakness during her life with an uncertain dia­gnosis.

Patient’s psychomotor development was retarded in her first years, and her family started complaining of joint hypermobility and spontaneous knee luxation. She was referred to genetic consultation and her consultant was very suspicious of EDS; however, genetic testing for EDS was not available in the Czech Republic at that time (2007), so an echocardiographic examination was recommended. The exam showed an atrial septal defect and dilatation of the aortic isthmus; therefore, she had been referred for a thoracic scan using magnetic resonance imaging (MRI).

Before the MRI was performed, the patient suffered from two different fractures (2007 and 2008) followed by osteosynthesis and was not able to undergo the examination.

In 2009, directly following the extraction of the osteosynthetic material, the patient underwent an MRI examination with the finding of dilatation of the ascendant aorta. With two fractures occurring only after a mild trauma and the finding of aortal dilatation, the patient was referred to a genetic consultant once again with the suspicion of OI/EDS overlap syndrome.

Finally, in 2014, a heterozygous mutation in the COL1A2 gene (responsible for encoding the alpha chain of type I collagen) was identified, which the patient inherited from her asymptomatic  father.

Since then, the patient underwent regular intravenous pamidronate treatment for osteogenesis imperfecta, developing thrombosis of the brachiocephalic vein during one cycle. Further testing for thrombophilias was negative.

From 2016 to 2018, the patient suffered 4 more fractures (femurs, metatarsal) and had to undergo spine stabilisation and posterior lumbar interbody fusion (PLIF) due to dysplastic spondylolisthesis (Fig. 1).

Fig. 1. An X-ray showing a patient
after spine stabilisation and bilateral
hip fixation.<br>
Obr. 1. Rentgenový snímek pacienta
po stabilizaci páteře a oboustranné
fixaci kyčle.
Fig. 1. An X-ray showing a patient after spine stabilisation and bilateral hip fixation.
Obr. 1. Rentgenový snímek pacienta po stabilizaci páteře a oboustranné fixaci kyčle.

Regular check-ups with the cardiologist showed progression in aortal di­latation: +4 mm in 2018 and +3 mm in 2020. The patient was referred to a children’s heart center in Prague, where surgical intervention was not fully recommended. The patient was strongly discouraged from becoming pregnant.

She was referred to our clinic in 2022 – in her 17th week of pregnancy. Her I. trimester screening (including screening for preeclampsia and foetal growth restriction) and foetal anomaly scan in the 20th week were both negative. An amniocentesis and prenatal genetic consultation were performed. She was taking low molecular weight heparin (LMWH) since the 20th week due to her previous history of thrombosis. Oral glucose loading test was negative and she had regular follow-ups at the cardiology department. She was instructed to measure her blood pressure regularly and to keep the blood systole under 130 mmHg. Foetal growth restriction (early form, mild placental insufficiency) was dia­g­nosed in her 30th gestational week. Caesarean section was scheduled for the 36th week with cooperation from the cardio surgeon, anaesthesiologist and obstetrician.

A planned caesarean section was performed in the 36th gestation week. Prior to surgery, echocardiography was performed, and an epidural catheter, radial artery catheter and central venous catheter were all secured. The surgery itself was uncomplicated, performed with spinal anaesthesia, along with an estimated blood loss of 500 mL. A healthy baby girl was delivered, with a birthweight of 2,020 g and an Apgar score of 10-10-10. The patient was transferred to the intensive care unit for further treatment in a stable condition.

She was transferred back to our clinic 24 hours after surgery, hemodynamically well compensated. Standard analgesics and LMWH were administered, and her blood pressure was measured regularly.

Approximately 48 hours after surgery, the patient started to complain about blunt pain in her chest, worsening with inspiration. The cardiologist performed an electrocardiography (ECG) and bed-side echocardiography, and no progression in aortal dilatation was noted (Fig. 2).

Fig. 2. An echocardiography examination showing a dilation of the ascending aorta.<br>
Obr. 2. Echokardiografické vyšetření ukazující dilataci ascendentní aorty.
Fig. 2. An echocardiography examination showing a dilation of the ascending aorta.
Obr. 2. Echokardiografické vyšetření ukazující dilataci ascendentní aorty.

The discharge of the patient was scheduled on the 5th day following surgery. During the morning round she didn’t complain of any pain or problems, the laparotomy was healing without any complications and her blood pressure was normal.

A few minutes before discharge, the patient called for a nurse complaining of a sudden strong pain in her chest and dyspnoea. She was pale and hemodynamically unstable, so oxygenotherapy was started and the emergency team was called. Her condition progressed to cardiac arrest within a few minutes and CPR was initiated.

Orotracheal intubation was managed by the anaesthesiologist, the automated external defibrillator (AED) analysed a non-shockable rhythm, and regular i.v. adrenaline was administered. Bed-side echocardiography showed absence of cardiac activity and presence of a thrombus in the right ventricle. The CPR team came to mutual consensus to connect the patient to extracorporeal membrane oxygenation (ECMO).

During the preparation for ECMO, transoesophageal echocardiography revealed a complete Stanford type A aortal dissection. Due to its inauspicious prognosis, CPR was terminated after 90 minutes.


Ehlers-Danlos syndrome is in a group of connective tissue disorders that can result in a range of complications during pregnancy. In a retrospective study by Kang et al examining EDS in pregnancy suggests that the overall prevalence is 7 per 100,000 births and the prevalence increases every year – due to advances in genetic techniques [5,6].

The 2017 EDS classification divides this disorder into several groups (Tab. 1), with three most common types:

classic (cEDS);

vascular (vEDS);

hypermobile (hEDS) [7].

Tab. 1. Clinical subtypes of Ehlers-Danlos syndrome and their main clinical features [7].
Tab. 1. Klinické podtypy Ehlers-Danlosova syndromu a jejich hlavní klinické rysy [7].
Clinical subtypes of Ehlers-Danlos syndrome and their main clinical features [7].<br>
Tab. 1. Klinické podtypy Ehlers-Danlosova syndromu a jejich hlavní klinické rysy [7].
AD – autosomal dominant, AR – autosomal recesive, EDS – Ehlers-Danlos syndrome

Hypermobile EDS (hEDS) is the most prevalent form of EDS. Pregnancy is well-tolerated in hEDS, with minimal excess complications. Recent data suggest that hypermobile EDS and joint hypermobility syndromes do not increase the risk of preterm premature rupture of membranes (PPROM) or preterm birth [8].

Classic EDS (cEDS) is the 2nd most common variant, where dominant clinical manifestations include skin hyperextensibility, atrophic scarring, poor wound healing, and joint hypermobility [6]. Based on the Dutch study from 2002, prematurity and PPROM were at least twice as more common in foetuses with EDS in healthy mothers compared to foetuses without EDS in EDS-affected mothers [9]. It has been shown that the membranes of foetuses with connective tissue disorders have an abnormal collagen content and structure and are weaker than normal  membranes [10].

Vascular EDS (vEDS) is the most life--threatening form of EDS. Patients with vEDS have a higher risk of vascular rupture (i.e. aortic dissection), organ rupture (i.e. uterine rupture, bowel rupture) and fistulae formation [6,11]. Based on the large analysis by Murray et al, which examined 565 deliveries, pregnancy-related deaths in women with vEDS occur in around 5% of deliveries, nearly 300 times more than in the general population [12]. Pregnancy is therefore considered as a very high-risk undertaking and is not advised [13].

As an autosomal dominant disorder, there is a 50% risk of transmitting EDS to the foetus. The foetus of a woman with EDS is at increased risk of prematurity, intrauterine growth restriction, joint luxation or limb abnormalities [14,15].

There is no specific treatment for EDS and there is no consensus in the literature on the timing and mode of delivery for pregnant women with EDS. Theoretically, caesarean section would minimise labour-related risks and enable greater haemostasis control. It might circumvent third and fourth degree perineal lacerations especially in classic and hypermobile EDS.

In the vascular EDS type, consideration should be given to delivery by planned caesarean section. Although there are inadequate data, Volkov et al proposed it might theoretically be beneficial to deliver between the 32nd and 35th gestational week (majority of spontaneous deliveries in EDS occur between 32 and 35 weeks of gestation; plasma volume (which peaks in the 32nd week) might have a role in the severity of vascular complications; caesarean delivery may minimize the fluctuations in maternal cardiac output and blood pressure) [15]. However, caesarean section is connected to an increased risk of perioperative haemorrhage and wound healing may be impaired [15,16].

The choice of anaesthesia is controversial; however, neuraxial techniques using epidural anaesthesia and combined spinal-epidural anaesthesia offer the advantage of extending the anaesthesia for the duration of the surgery and thus avoiding conversion to general anaesthesia [17].

Osteogenesis imperfecta is a rare condition. The main characteristic feature is brittle bones leading to repeated fractures after minimal trauma. Dia­gnosis is mainly clinical [18,19]. Pregnancy can be carried to term especially in mild forms of OI. A good outcome has been reported in pregnant women with OI and their neonates. The pregnancy can be complicated by musculoskeletal problems; common complications are backache, spinal deformity, disc and ligament problems, and non-vertebral fractures. Mode of delivery is chosen for the usual obstetric indications [20].

The combination of osteogenesis imperfecta and Ehlers-Danlos syndrome is very rare (< 1/1,000,000 according to Orphanet). It is not clear if this phenotype could be considered a forgotten type of EDS with a recognized molecular defect, or rather it is implicitly included in OI nosology [21]. Some authors considered that COL1A1-COL1A2 mutations were related to EDS and osteogenesis imperfecta as a distinct form from other EDS or OI variants, termed OI/EDS overlap syndrome [22]. Only a few cases of OI/EDS have been described and to our best knowledge, this is the first published case of pregnancy in OI/EDS overlap syndrome.


Women with EDS are at an increased risk for various complications during their pregnancies; however, with a wide range of phenotypes, the approach to their pregnancies may vary. Patients with a classical or hypermobile variant of EDS may have fewer complications and can usually tolerate pregnancies better. Special care should be taken for women with the vascular type – they should undergo preconceptional counselling and be advised against pregnancy. Our case has attempted to highlight the potential obstetric complications and to attract the attention of clinical physicians to the rare but extremely dangerous syndrome.

ORCID authors

A. Šinská 0000-0001-5584-0398

E. Hostinská 0000-0002-7635-402X

R. Pilka 0000-0001-8797-1894

Submitted/Doručeno: 22. 8. 2022

Accepted/Přijato: 7. 9. 2022

Alexandra Šinská, MD

Department of Obstetrics and Gynecology

Faculty of Medicine

Palacky University and

University Hospital Olomouc

I. P. Pavlova 6 779 00 Olomouc



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