Inherited aortopathies and risk of aortic dissection and aortic syndrome in pregnancy

Abstract

Acute aortic dissection related to pregnancy is rare, however represented the third most common cause of pregnancy-related cardiovascular death in the 2017 UK-MBBRACE report. The majority of women with pregnancy-related aortic dissection have an underlying inherited syndromic aortopathy, though this is often not recognised until an event. Data regarding the immediate and long-term effects of pregnancy on aortic outcome are not uniform due to publication and ascertainment biases, small sample sizes, inclusion of women whose dissection was the first presentation of the underlying disease, and incompleteness of collected data. Management recommendations are based on relatively low levels of evidence, and there is some variation between society guideline recommendations. This article seeks to review the available evidence regarding pregnancy-related aortic dissection in women inherited syndromic aortopathies, highlighting the importance of pre-conception counselling, genetic testing and a multi-disciplinary team approach to management.

Introduction

Acute aortic dissection (AAD) complicates only 4–5 per million pregnancies, however is associated with maternal and fetal mortalities of 6–12% and 10–28% respectively, and accounted for 11–15% of maternal cardiovascular deaths during pregnancy in the MBBRACE 2017 report.^1–4 Inherited syndromic aortopathies, or a family history of AAD have been identified in 60–70% of women with pregnancy-related AAD.^5,6 Less than 50% of women with AAD in pregnancy were known to have an inherited aortopathy at the time of dissection. ⁵

The risk of AAD in pregnancy has been estimated to be 4–25-fold higher than in the non-pregnant state.^5,7 Postulated contributing factors include increased shearing forces because of the pregnancy-related physiological increase in cardiac output, increased blood volume and heart rate, hypertrophy of smooth muscle and loss of corrugation fibres in the aortic wall, and increased matrix metalloproteinases resulting in fragmentation of the tunica media in large vessels. Studies examining aortic diameter in healthy pregnant women during pregnancy have revealed inconsistent results. In healthy pregnant women, Easterling et al. found a small increase in aortic diameter from 26 weeks’ gestation which fell when re-measured at six weeks postpartum, while remaining larger than in early pregnancy. ⁸

Inherited aortopathies include Marfan (MFS), vascular Ehlers-Danlos (vEDS), Loeys-Dietz (LDS) and Turner syndromes (TS), as well as bicuspid aortic valve (BAV), and non-syndromic hereditary thoracic aortic disease (nsHTAD). Individuals with osteogenesis imperfecta have not been shown to be at increased risk of arterial dissections or aneurysms in the absence of an EDS-overlap syndrome. ⁹ The estimated prevalence and risk factors for pregnancy-related aortic dissection in each inherited aortopathy, summarised in Table 1.

Table 1.

Hereditary thoracic aortopathies and pregnancy.

Condition	Prevalence	Proportion of pregnancy-related aortic disease/dissections	Overall risk of dissection in pregnancy/related to aortic root size	Extreme risk/pregnancy C/I	Pre-conception root replacement recommended#	Other features significant in pregnancy
Bicuspid aortic valve (BAV)	1:50 to 1:100	10%	Rare Higher with ‘aortic root’ phenotype	>50 mm or >27 mm/m2 BSA	≥50 mm or ≥27 mm/m2 BSA	Aortic stenosis or regurgitation
Non-syndromic hereditary thoracic aortic disease		3%	Overall 6% Dissection with smaller aortic diameters with ACTA2 and MYLK variants	Regardless Ao	Based upon family history and pathologic gene variant	Coronary artery disease with ACTA2 variants
Marfan syndrome	1:5000	65%	Overall 3-7% 1 < 40 mm 1% > 40 mm 10% Increased risk with progressive aortic dilatation, hypertension, family History dissection	Ao > 45mm	>45mm >40 mm if >3 mm/year, family history dissection, rapid aortic growth	Dural ectasia Mitral regurgitation Arrhythmias LV dysfunction Scoliosis Chest wall deformities OSA (21–34%)
Turner syndrome	1:2500	0-8%	1.25% 0–2% With OOD	ASI ≥ 25 mm/m2 Increased risk with BAV, hypertension, coarctation, dilated aorta ASI ≥ 20 mm/m2 if BAV, coarctation, history aortic dissection or elongation transverse aorta	ASI≥25 mm/m2	Bicuspid aortic valve (15–30%) Chronic Hypertension Preeclampsia Ascending aortic dilation (33%) Coarctation of aorta (7–18%) OSA (48–90%)
Vascular EDS	1:50000-100000	0–2%	5–9% Unrelated aortic size Risk relates to specific COL3A1 variant Risk lower with null variants	Maternal mortality 5–20% regardless aortic diameter	Rapid growth is indication for replacement No data to guide size for intervention	Dural ectasia Uterine rupture 2.6% OSA (32–42%)
Loeys-Dietz syndrome	1:100000	10%	1.5–19% unrelated to aortic diameter with TGFBR1, TGFBR2 and SMAD3 variants 67% if previous aortic root replacement Less aggressive aortic disease with TGFB2, TGFB3 variants	Regardless Ao	≥ 40 mm if TGFBR1, TGFBR2, SMAD3 variants	Dural ectasia Mitral regurgitation OSA (23%) Cerebral aneurysms (10–18%) Uterine rupture (0.4%) Postpartum haemorrhage (2%) Other vessel dissection (0.7%)

Abbreviations: Ao: aortic root diameter; BSA: body surface area; OSA: obstructive sleep apnoea.

* No aortopathy diagnosis and family history of aortic aneurysm with no genetic variant made up 38% of thoracic dissections.

^#family Hx dissection, and aortic root growth > 3 mm/year, coarctation, chronic arterial hypertension are modifying factors.

A study of 38 pregnancies in women with inherited aortopathies (MFS 9, TS 7, BAV 22), 12 (32%) of whom were treated with a beta-blocker during pregnancy, showed significant aortic dilatation during pregnancy compared with a control group of women with uncomplicated pregnancy, which persisted five years after delivery. ¹⁰ Pre-existing systemic hypertension was associated with larger aortic diameters prior to pregnancy, but did not influence the overall trajectory during pregnancy.

Pre-pregnancy care

The diagnosis of inherited aortopathy is only known in 25–50% of women with MFS, and 10.6% of women with vEDS prior to pregnancy.^3,5,11 Each routine visit to health professionals in women of child-bearing age with known inherited syndromic aortopathy represents an opportunity for preconception counselling. Discussion of the wishes of the woman with regard to future pregnancy, the potential risks of pregnancy for mother and baby, genetic testing and discussion of inheritance, contraception, consideration of preconception surgery, imaging of the aorta, the option of surrogacy (where available) for women of more severe phenotype, and investigation for co-morbidities such as hypertension which may increase the risk of AAD should be considered. Magnetic resonance imaging from head to pelvis should be considered in all connective tissue disorders rather than echocardiography alone. The benefits of maintaining a healthy weight should also be discussed given the increased risks of teratogenicity, gestational hypertension, preeclampsia, and obstructive sleep apnoea (OSA) with maternal obesity.

MFS, vEDS, LDS and nsHTAD are autosomal dominant disorders, although nsHTAD is associated with reduced penetrance, particularly in women. Twenty-five percent of families with nsHTAD have a detectable genetic mutation. BAV is a heterogenous disorder primarily inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. Some families may have easily identifiable genetic mutations, but many do not. ¹² Genetic screening for inherited aortopathy should be considered in individuals with BAV where there is a history of early onset thoracic aortic aneurysm, familial thoracic aortic aneurysm, aortic root aneurysm, or syndromic characteristics. ¹² Next-generation DNA sequencing is available for more than 67 disease-causing genes for connective tissue disorders using saliva. ¹³ Genetic testing is crucial as the risk of AAD depends on the specific pathogenic variant. LDS with TGFBR1, TGFBR2, and SMAD3 variants is associated with greater risk of AAD, and at a smaller aortic size, than TGFB2 and TFGB3 variants. The risk of AAD with vEDS relates to the specific COL3A1 variant, being lower with null variants.

Post-mortem genotyping is also important in individuals who die because of AAD regarding counselling of relatives.

Additional risk factors for AAD in inherited aortopathies include aortic diameter, the rate of aortic growth, hypertension, and a family history of dissection. ³ In TS the presence of BAV, coarctation of the aorta, and hypertension increase the risk of AAD.

Inherited aortopathies are associated with increased risk of sleep disordered breathing (SDB). The prevalence of SDB in MFS, LDS, vEDS and TS in non-pregnant individuals are 21–34%, 23%, 32–42% and 48–90% respectively.^14–19 OSA in non-pregnant MFS is associated with increased aortic root diameter, and shorter event-free survival. ¹⁴ OSA may be associated with masked and nocturnal hypertension, as well as high levels of sympathetic drive. The prevalence and severity of OSA increases during pregnancy. Clinical practice guidelines suggest screening for OSA through history and/or validated instruments throughout the lifespan in TS. ²⁰ The Epworth Sleepiness Scale (ESS), however, is a poor predictor of OSA in MFS and EDS. ²¹ Additionally, the ESS, Berlin questionnaire, STOP-BANG questionnaire and American Society of Anaesthesiologist checklist are poor predictors of OSA in the general population in pregnancy, and pregnancy-specific OSA screening criteria have not been validated for use in women with inherited syndromic aortopathy.^22,23

Observational studies have reported a prevalence of hypertension of 21–40% in girls and adolescent females with TS, and up to 58% in adult TS. ²⁴ Several studies have shown a high prevalence of masked/nocturnal hypertension in TS, and clinical practice guidelines for the care of girls and women with TS recommend annual 24-h ambulatory blood pressure monitoring (ABPM). ²⁵ ABPM should be considered as part of preconception assessment in women with inherited syndromic aortopathies.

Contraception should be discussed with a view to avoiding unplanned pregnancy. Progestogens (oral or implantable) or an intrauterine contraceptive device may be preferable to an oestrogen-containing oral contraceptive pill, as oestrogen may cause a rise in blood pressure in approximately 10% of women, and theoretically may have similar effects on vessel walls as pregnancy. ²⁶ In women with TS and complete ovarian failure requiring hormone replacement, topical oestrogen should be used in view of the risk of oral oestrogen increasing blood pressure and thromboembolic risk. ²⁷

Studies of pregnancies in women with TS found that 10–30% of women had an underlying BAV, 2–30% had previous surgery for coarctation, and 6.8–20% had hypertension pre-conception.^28–31 There is considerable variability in recommendations with regard to the safety of pregnancy in women with TS.^29,30 Women with TS should have cardiovascular imaging, ideally cardiac magnetic resonance imaging or computerised tomography, performed at least once within two years before a planned pregnancy, and repeated sooner if necessary. ²⁰ The 2023 Clinical Practice Guidelines recommended a cut-off threshold for women with aortic dilatation Z-score of >2.5 to receive peripartum cardiovascular care in centres with expertise in aortic surgery, and that those with a Z-score >4 to avoid assisted reproductive technologies or spontaneous conception. ²⁰

Based upon four studies, the risk of gestational hypertension and preeclampsia with oocyte donation in TS were 32% and 9.7% respectively, compared with 13.3% and 6.7% with spontaneous pregnancy.^32–35

Where assisted fertility is required, single embryo transfer should be performed, given the greater physiological haemodynamic changes and risk of hypertensive disorders of pregnancy with multiple pregnancies. In a systematic review of 10 cases of AAD in pregnancy in TS, two (20%) occurred in women with multiple gestations. ³⁰ Ovarian hyperstimulation should also be avoided.

Many authors have recommended against pregnancy in women with vEDS, given the reported maternal mortality has been reported in 4.3–25%. ¹¹ Maternal mortality was 5.3% with vEDS in pregnancy when women with null mutations were excluded. A recent retrospective review of 121 pregnancies to 43 women with vEDS due to pathogenic (P/LP) COL3A1 variants over a three-year period, however, found no cases of uterine rupture nor life-threatening or fatal vascular events in the perinatal period. ³⁶ The authors acknowledged the absence of adverse events may be partially attributed to a lack of preconception vascular complications in all women studied, a relatively low percentage of glycine substitutions and high percentage of haploinsufficient variants. It was recommended that women with vEDS desirous of pregnancy should be invited for individualised shared decision-making process regrading reproductive options at specialised centres employing a multidisciplinary approach, Surrogacy may also be considered where available, though preimplantation diagnosis is important, as an EDS fetus/nonEDS mother pairing have a greater risk of prematurity and preterm premature rupture of membranes than EDS fetus/EDS mother or nonEDS fetus/EDS mother pairings. ³⁷

Fewer than 350 pregnancies have been described in women with LDS.^38–40 Major clinical features include cardiovascular, craniofacial, neurocognitive and skeletal abnormalities, although the phenotype may be variable within and between families, with minimal clinical features in some individuals. Generalised vascular tortuosity is present in 84–100% of individuals LDS, 10–18% have cerebral aneurysms, cerebral haemorrhage accounting for 7% of deaths in individuals with LDS.^41,42 Uterine rupture has been reported in three cases in pregnancy.^40,43 Rarely, LDS may be complicated by arrythmias and dilated cardiomyopathy. ⁴⁴ Due to scarcity and the substantial phenotypic variability the optimum management strategy is not known. While early reports of uterine rupture and a high risk of aortic dissection independent of aortic diameter with TGFBR1, TGFBR2 and SMAD3 variants led some expert to recommend early caesarean delivery, larger and more recent case series with lower risks of complications have suggested vaginal delivery may be considered. A consensus of a multidisciplinary team in discussion with the pregnant woman taking into account family history of dissection and genetic variant should determine the timing and mode of delivery for each woman individually.^38,40,45,46

While the evidence for efficacy regarding prevention of AAD is limited, and confined to individuals with MFS, most guidelines recommend the use of a beta-blocker and/or angiotensin-receptor blocker (ARB) in individuals with inherited aortopathies. ⁴⁷ A recent small retrospective cohort study found that beta-blocker use prior to conception and during pregnancy was associated with less aortic root dilatation in pregnant women with MFS. ⁴⁸ No fetal growth restriction was seen with a maximal systolic blood pressure of 123 mm Hg in the beta blocker group. Similarly, no difference was found in infant birthweight in women treated with beta-blockers and those who did not in the Registry of Pregnancy and Cardiac disease. ⁴⁷ Atenolol should not be used given the association with fetal growth restriction. Long-acting beta-blockers such as bisoprolol or extended-release metoprolol may be preferable regarding medication adherence, and the significant changes in metoprolol pharmacokinetics potentially requiring increased frequency of administration and total daily dose. ⁴⁹ Celiprolol should be used in women with vEDS in view of the demonstration of reduced vascular complications in non-pregnant individuals.^50,51

ARBs have been shown to have a similar effect as beta blockers on reducing the rate of aortic root dilatation, and rates of AAD, aortic root surgery and death over a three-year period in MFS in non-pregnant individuals. ⁵² Some studies have suggested a greater reduction in aortic root dilatation, surgery, and mortality from AAD with the combination of ARBs and beta-blockers compared with beta-blockers alone.^53,54 While fetotoxic, and contraindicated in second and third trimester, the evidence for teratogenicity of ARBs from studies is confounded by maternal obesity and undiagnosed diabetes mellitus. It may be reasonable to continue ARBs pending conception, ceasing as soon as pregnancy is confirmed.

A case-control study in individuals with MFS demonstrated increased risk of AAD or need for surgery with the use of calcium channel blockers compared with other antihypertensives. ⁵⁵ Mouse models with Fbn1 gene mutations showed accelerated aortic aneurysm growth, AAD and early mortality with verapamil and amlodipine. ⁵⁵ Conversely, the use of hydralazine in a Fbn1 mouse model showed benefits on aorta growth, and improvement in aorta wall architecture, compared with placebo. No consensus or society guidelines, however, recommend avoidance of calcium channel blockers in the general or pregnancy populations with inherited aortopathies and hypertension.

Only 50% of women who were known to have MFS had preconception counselling. ¹² Cauldwell et al. reported that only 57% of women with TS had an echocardiogram within 24 months of conception. ⁵⁶

The benefits of the implementation of guidelines with respect to preconception assessment and cardiology follow-up in TS were demonstrated in a study by Cadoret et al., demonstrating lower rates of hypertension (19% vs 38%), preeclampsia (8%vs 21%), and lower rates of delivery prior to 35 weeks’ gestation (15% vs 38%). ³¹

Pregnancy

Cardiovascular imaging should be performed as soon as possible following confirmation of pregnancy, including assessment of the vascular tree from head to pelvis in women with LDS. ³⁸ Echocardiography assessment of the aortic root should be performed every 4–8 weeks where the aortic root diameter is > 40 mm, and every 8–12 weeks where the diameter is ≤ 40 mm. Non-contrast magnetic resonance imaging should be performed in the setting of aortic dilation. No randomised trials have been performed with respect to targets for pulse rate and blood pressure in pregnancy. Based upon the small study by Roberts et al., it may be reasonable to target a systolic blood pressure < 120–125 mm Hg. ⁴⁸ Aspirin 150 mg nocte should be considered from 12 weeks’ gestation in all women as prophylaxis against preeclampsia, especially those with TS.

Iron studies and full blood count should be measured every 4–8 weeks during pregnancy to avoid anaemia precipitating tachycardia and greater increase in cardiac output. Home blood pressure may be useful to ensure adequate beta blockade with respect to pulse and blood pressure, and for early detection of preeclampsia. Studies investigating the potential role of periodic 24-h ABPM to exclude nocturnal and masked hypertension and nocturnal tachycardia, particularly in women with OSA or TS, may be useful.

vEDS is associated with increased risk of spontaneous preterm labour and preterm premature rupture of membranes, as well as preterm birth due to iatrogenic elective delivery. ⁵⁷ Transvaginal cervical assessment of cervical length should be considered during second trimester. Growth scans should be performed monthly from 28 weeks’ gestation for potential fetal growth restriction.

Anaesthetic review is an important part of pre-conception and pregnancy care. Imaging for dural ectasia (MFS, LDS) and spinal vascular anomalies with non-contrast magnetic resonance imaging may be performed preconception or during pregnancy. Dural ectasia may result in inadequate neuraxial anaesthesia and increased risk of dural puncture. Additional considerations for neuraxial anaesthesia include the presence of kyphosis/scoliosis and Harrington rods, and the increased risk of bleeding with vEDS in the absence of measurable laboratory bleeding abnormalities leading to spinal or epidural haematoma.

Women may pose airway challenges due to temporomandibular joint dysfunction, premature spondylosis, atlanto–occipital joint instability or subluxation. ⁵⁷ Use of video laryngoscopy and fibreoptic intubation should be considered.

The diagnosis and management of AAD during pregnancy or in the postpartum period is similar for that outside pregnancy. Computerised tomography is the imaging modality of choice given its widespread availability and speed of acquisition. Iodinated radiocontrast agents are safe for the fetus, and CT of the chest and abdomen is associated with an estimated fetal dose of less than 10mGy, below the level for fetal harm, or the stochaistic risk for later childhood malignancy. ⁵⁸

Delivery

In the absence of randomised trials, the timing of delivery should be based upon a multidisciplinary team discussion with the pregnant woman. Whelan et al. recommend delivery by 34–37 weeks in vEDS, or other aortopathies with high risk factors including high risk dilatation of aortic root, previous dissection, rapid aortic dilatation, or poor controlled hypertension. ⁵⁹ Delivery should take place at a centre where experienced emergency aortic surgical repair is available. There is no strong evidence-based consensus regarding mode of delivery. In general, vaginal delivery with early epidural by an experienced anaesthetist is reasonable in women with an aortic root and ascending aorta diameter of <40 mm in the absence of high-risk factors as listed previously. In women with an aortic root or ascending aorta diameter > 45 mm or additional risk factors caesarean section is recommended. Low-dose sequential spinal epidural may be a preferable mode of neuraxial anaesthesia for delivery in high-risk women.^60,61 Early fluid loading and vasopressors may be required in the setting of postural orthostatic tachycardia syndrome. Ergometrine/syntometrine should be avoided following delivery because of risk of hypertension, and low-dose incremental syntocinon by infusion considered.

Endocarditis prophylaxis is not required for BAV is the absence of a history of prior endocarditis.

The tissue fragility and bleeding risk with vEDS pose special consideration with respect to delivery. There are no formal guidelines with regard to recommended mode of delivery. The prevalence of third–fourth degree perineal tears is increased 20-fold compared with healthy women. Where women prefer vaginal delivery, early neuraxial anaesthesia should be used, forceps delivery avoided, and an early episiotomy considered avoiding perineal tears. Care also needs to be taken to avoid hip or knee dislocation. Careful positioning with use of adequate padding should be employed to minimise inadvertent injury. With operative delivery, attention is required with the use of adhesive tapes and dressings due to skin fragility. Prophylactic desmopressin and tranexamic acid should be used to reduce the risk of postpartum haemorrhage, and are not associated with increased thromboembolic risk. ⁶²

Postpartum

Beta-blockers and/or ARBs should be commenced. There is adequate safety data for the use of candesartan with lactation. ⁶³ Some authors recommend against breastfeeding as mouse models of MFS and eVDS suggest oxytocin release may influence postpartum AAD risk.^64,65 Initial care postpartum should be in a high dependency or critical care unit as the risk of AAD is probably highest within the first few days post-delivery. It has been recommended the women remain as inpatients for one week postpartum where this is practical, particularly in high-risk women. Remaining in proximity to a centre where aortic surgery can be performed for four to six weeks postpartum is a consideration for women who live in remote locations. The risk of dissection remains elevated for up to six months postpartum. Patients should be educated on the importance of presenting to hospital with concerning symptoms. Effective contraception should be addressed as per the paragraph in prepregnancy care. Echocardiography should be performed prior to discharge post-birth and at six weeks postpartum. ³

Surgical management of aortopathies in pregnancy

The surgical management of AAD during pregnancy is well described. A review by Meng et al. found that Stanford Type A Aortic dissection was more common antepartum, while Stanford Type B dissection was more common postpartum. ⁶⁶ Mode of delivery had no impact on the type of postpartum dissection. Management typically involves emergency delivery and subsequent aortic surgery. ⁶⁶

Traditional methods of aortic root repair such as a Bentall's Procedure (replacement of the aortic root and aortic valve with a composite valve conduit) or a valve-sparing root replacement (David Procedure) remain options for women preconception, however the Bentall's Procedure requires lifelong anticoagulation, and the subsequent complications of management of anticoagulation in pregnancy. Both procedures require cardiopulmonary bypass, with the risk of fetal death, making them a less ideal option for women in whom aortic dilatation is either diagnosed in pregnancy or reaches an unacceptably high risk during pregnancy. Personalised External Aortic Root Support (PEARS) has emerged as an option for MFS women with dilated aortic root. Cases involving PEARS during pregnancy have been reported, both as planned elective management, and in emergencies, but there remains no long-term data.^67,68

Conclusion

The complexity in managing women with inherited aortopathies in pregnancy compels preconception evaluation, counselling, and management by a multidisciplinary team including a cardiologist/vascular physician, cardiovascular surgeon, maternal–fetal medicine specialist, obstetric physician, anaesthetist, geneticist and neonatologist. Cardiologists, vascular physicians, and cardiovascular surgeons seeing adolescent and young women in aortopathy clinics have the opportunity to discuss the benefits of pregnancy planning if desired at each review.