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Abstract
Objectives Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study.
Methods Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes.
Results In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B—one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months)
Conclusion There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.
- pregnancy
- marfan and associated disorders
- aortic dissection or intramural hematoma
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Introduction
Marfan syndrome (MFS) is an autosomal-dominant condition caused by a mutation in the FBN1 gene encoding fibrillin,1 causing connective tissue fragility. Internationally recognised criteria define MFS.1 2 Cardiovascular complications associated with MFS are responsible for the associated increased mortality, predominantly related to aortic dissection (AoD). Several series of pregnancy in women with MFS are described, most small, lacking detail with regards to maternal and neonatal complications.3–5
Pregnancy appears to increase the risk of AoD in women with MFS, which is furthermore increased by pregnancy-related complications such as hypertension.6 Both the European Society of Cardiology (ESC) and the American Heart Association provide pregnancy management guidance, drawing from a limited number of studies.7 8 From the modified WHO risk classification (ESC guidance), women without evidence of aortic root (AoR) dilatation are category II (small increased risk of maternal mortality). Increasing to category III (high risk) with an AoR diameter between 40 mm and 45 mm and category IV (highest risk/contraindication for pregnancy), with an AoR diameter >45 mm. They suggest delivery by caesarean section) with an AoR of >45 mm (level C evidence). While it is logical to assume those with greater AoR diameters are at greatest risk of AoD, there are few data to support such arbitrary cut-offs; furthermore, factors like family history of dissection need to be considered as is advised in recent ESC guidelines.9
A retrospective study of 69 women with MFS in pregnancy suggests an increase in aortic dimensions failing to return to baseline following pregnancy.10 In contrast, a prospective study by Meijboom et al 11 of 23 pregnant women (33 pregnancies) before and after pregnancy found no difference in aortic dimensions compared with 22 matched childless women. Beta-blocker use in MFS in pregnancy to reduce the risk of AoD is unproven.12 13 Outside pregnancy, the beneficial effect of beta-blockers is unclear, with one published randomised trial.14 Shores et al showed a significant reduction in the rate of aortic dilatation in those receiving beta-blockers, but no significant reduction in AoD rates. Lacro et al did appear to show that beta-blocker use retarded aortic growth, but this was not in a placebo controlled study.15 Similarly, beta-blocker use during pregnancy is associated with lower birth weight (BW) and can impair the neonatal response to hypoglycaemia.15 16 The 2011 ESC guidance recommended beta-blocker use in MFS during pregnancy.7
We performed a multicentre study of pregnant women with MFS to investigate: (1) the occurrence of cardiovascular complications and possible related factors, (2) fetal outcomes and BW, (3) the impact of pregnancy on aortic diameters and (4) evidence of preconception counselling (PCC).
Methods
All 14 specialist UK centres providing joint care for pregnant women with congenital heart disease were invited by email in September 2017 to participate. Twelve centres identified pregnancies in women with an established diagnosis of MFS according to modified Ghent criteria, including assisted conceptions and miscarriages/terminations, either through interrogation of prospectively collated databases or through local datasets using relevant ICD-10 codes. . Cases were identified from January 1998 to March 2018 with data collated from review of case notes. Pseudoanonymised (personal identifiers omitted) data were amalgamated into a single dataset. No patient identifiers were used meaning individual patient consent was not required.
Demographic data collected included maternal age, race/ethnicity, New York Heart Association class, height, weight and body mass index. Data were obtained on family history of MFS and family history of AoD or death attributed to MFS. Information was obtained on previous surgical interventions and medication use prepregnancy. Data on echocardiographic assessment of aortic dimensions up to 1 year prepregnancy and 6–12 weeks postpartum were obtained whenever possible. We looked for documented evidence of PCC.
The primary outcome was occurrence of AoD during pregnancy or up to 6 months postpartum. Secondary cardiac outcomes included occurrence of cardiac surgery or stroke. Obstetric outcomes included gestational hypertension (GH; ≥140 mm Hg systolic or ≥90 mm Hg diastolic after 20 weeks’ gestation), pre-eclampsia (GH with proteinuria >0.3 g/24 hours/protein creatinine ratio (PCR) ≥30), preterm delivery (delivery at <37 weeks of gestation), postpartum haemorrhage (PPH; blood loss ≥500 mL at delivery) and venous thromboembolism. Neonatal outcomes were small for gestational age (SGA; BW <10th centile for sex and gestational age by Aberdeen centiles (birthweight centile (BWC))), stillbirth (fetal demise ≥24 weeks’ gestation) and neonatal unit admission. We assessed practice with regard to 2011 ESC guidelines, determining the number of women receiving PCC, aortic imaging in pregnancy, beta-blockers and delivery by caesarean section.
Statistics
Data were analysed using SPSS V.23/25 for Windows. Data are presented as medians with IQRs. Correlations were calculated using Spearman’s rank-order correlation because none of the data studied had a Gaussian distribution. Differences between continuous variables were assessed with the Mann-Whitney U/Wilcoxon rank-sum tests. All tests were two tailed, and p<0.05 was considered statistically significant.
Results
Twelve centres provided data on 151 pregnant women with MFS. In total there were 255 pregnancies; 223 pregnancies ≥24 weeks (three sets of twins), 20 miscarriages and 12 terminations of pregnancy.
The following data refer to the 142 women having pregnancies ≥24 weeks’ gestation at delivery. Eighty-three women (55.0%) had one recorded pregnancy, 44 (29.1%) had two recorded pregnancies, 13 (8.6%) had three recorded pregnancies and 2 (1.3%) had four recorded pregnancies. There were 213 live births, 3 stillbirths and 2 neonatal deaths; 131 women were white European, 7 were South Asian, 2 were black African and 2 were mixed race. Median gestational age at delivery was 39 weeks (IQR 37–39, range 24–42 weeks, data missing in five cases). Table 1 shows the demographics of women having their first pregnancy (nulliparous) ≥24 weeks.
Baseline maternal characteristics at first pregnancy (nulliparous) delivering at ≥24 weeks (total n=116)
Data on PCC were recorded in 238 pregnancies. Sixty-five of 136 (47.8%) women in their first recorded pregnancy had documented PCC; before 2011 guidelines, the rates of PCC for first recorded pregnancies was 27/63 (42.8%) and afterwards was 38/73 (52.1%), an insignificant change (p=0.306).
Two women had assisted conception using preimplantation genetic diagnosis ensuring they had a baby unaffected by MFS. Five women had invasive testing during 10 pregnancies. One pregnancy was terminated as result of a positive test. Two further tests were positive, but the women continued with their pregnancy.
There were 35 pregnancies in 21 women who had had a prior ascending aorta replacement (2/19 were for acute type A dissection; all others were prophylactic procedures). One of these women had a type B dissection in the first trimester (see table 2).
Details of dissection during pregnancy and postpartum
Associations with AoD
There were five acute AoD: one type A and four type B. Table 2 provides information relating to these events. Analysis of factors including family history of AoD, use of beta-blockers, AoR size prior to delivery, prior Aortic Root Replace (ARR), pre-eclampsia and GH showed none of these factors were significantly associated with dissection, although small numbers means that even moderate associations cannot be excluded.
Other cardiac complications
Table 3 shows the other cardiovascular complications recorded.
All other cardiovascular complications during pregnancy and postpartum
Echocardiography
Echocardiographic assessments were conducted as per each unit protocol. Excluding women with prior ARR, there were 58 women who had AoR assessment prior to pregnancy and at postnatal follow-up. Median AoR size prior to pregnancy was 36 mm (IQR 33–39mm) and following was 37 mm (IQR 35–39mm). There was small but significant increase in AoR size at follow-up compared with the prepregnancy value – median increase 1 mm (IQR −0.25 to 2, minimum −15 and maximum 8) (p=0.01 Wilcoxon signed-rank test) (figure 1). This change was not significantly modified by beta-blockers; median increase in the 17 women not using beta-blockers was 1 mm (IQR 0–2, minimum −2 and maximum 4) compared with 1 (IQR −1 to 2.5, minimum −15 and maximum 8) in the 41 women using them (p=0.863 Wilcoxon signed-rank test). Following 2011 guidelines, more women had aortic imaging prior to pregnancy, 81/125 (64.8%) versus 51/98 (52%) (p=0.06, Fisher’s exact test).
Change in aortic root size.
Only 32 women had assessment of their AoR prior to pregnancy by MRI; in seven cases, there was no accompanying echo assessment. Of the 132 prepregnancy echo assessments, only 25 (18.9%) had an MRI result. Median difference in the measurement was zero, IQR −1 to 0.5 mm, minimum −3 mm and maximum +3 mm. Therefore, for the purposes of analysis, we have standardised on the ultrasound value.
Delivery
There was no statistically significant association of maximum AoR diameter prior to pregnancy and t gestation at delivery. However, there was a marked effect on the mode of delivery. If the maximum AoR diameter prior to pregnancy was <40 mm, the elective caesarean section rate (ELCS) rate was 26.0% (25/96), compared with 70.6% (24/34) if it was ≥40 mm (p<0.001). Excluding women with previous ARR (and patient with an AoR of 81 mm), ELCS rate was 26.4% if AoR diameter was <40 mm (23/87), compared with 64% if it was ≥40 mm (16/25) (p=0.001).
Data on postpartum blood loss were available in 175/223 deliveries (78.5%). Median blood loss at 55 spontaneous vaginal births was 350 mL (IQR 150–400, minimum 50 mL and maximum 2300 mL), at 39 assisted vaginal births was 450 mL (IQR 300–600, minimum 100 mL and maximum 3000 mL), at 21 emergency casarean sections (CSs) was 600 mL (IQR 400–820, minimum 220 mL and maximum 2000 mL) and at 60 elective CSs was 600 mL (IQR 500–800, minimum 233 mL and maximum 1800 mL). Incidence of PPH (blood loss ≥500 mL) was 12/55 (21.8%) for vaginal birth, 19/39 (48.7%) for assisted vaginal delivery, 13/21 (61.9%) for emergency CS and 51/60 for elective CS (85.0%) (p<0.001).
BW was known in 202/223 babies born (90.6%). There were three sets of twins (six babies) born at 32, 35 and 36 weeks of gestation, median BWs of 2230 g (IQR 1655g to 2695 g, minimum 1460 g and maximum 2890 g). In 196 singletons, median birth weight was 3125 g (IQR 2700–3507.5 g, minimum 850 g and maximum 4400 g). Median birth weight centile (BWC) was 41 (IQR 16–70); 27 infants were SGA (13.8%). Gestational age at delivery was known in 209 cases (96.3%) of singletons. Median gestational age of singletons was 39 weeks (IQR 37–39, minimum 24 and maximum 42). Preterm birth occurred in 28 cases (14.3% of singletons); 17/221 (8%) surviving neonates were admitted to the special care baby unit. Table 4 lists obstetric and neonatal complications.
Obstetric and perinatal complications
Beta-blocker use was known in 218/223 (97.8%) Pregnancies ≥24 weeks and were used in 140 (64.2%) of these pregnancies. Beta-blockers were more likely be prescribed to women with larger AoR size (figure 2). Median root diameter prior to pregnancy with no beta-blocker was 33 mm (IQR 31–36.25 mm, minimum 24 and maximum 44 (n=46)) compared with a median of 38 mm (IQR range 35–41 mm, minimum 25 mm and maximum 81 mm (n=85)) with beta-blocker use (p<0.001 by Wilcoxon rank-sum test).
Box and whisker plot showing distribution of aortic diameter in relationship to use of beta-blockers during pregnancy.
Table 5 shows the different beta-blockers used. Excluding twin pregnancies, median BW and BWC were significantly lower in women taking beta-blockers (3024 g (IQR 716, n=125) vs 3310 g (IQR 810, n=68), p=0.002; BWC 39.7 (IQR 49, n=125) vs 50.9 (IQR 48, n=68), p=0.008) (figure 3). Figure 4 shows the distribution of BWs with different beta-blockers; women taking atenolol had infants with the lowest BWs.
Box and whisker plot showing distribution of birth weight in relationship to use of beta-blockers during pregnancy (three sets of twins excluded).
Box and whisker plot showing distribution of birth weight in relationship to type of beta-blockers used during pregnancy (three sets of twins excluded).
Beta-blockers prescribed prior to and during pregnancy in women not having a miscarriage or termination of pregnancy
Discussion
Dissection during pregnancy and the puerperium was 1.9%, falling to 1.8% including only pregnancies >24 weeks’ gestation. There were no maternal deaths. Dissections were mainly type B. Predicting which women are at particular risk of dissection remains challenging, as no factors were significantly associated, although this is likely due to the low number of dissections. Dissection rate in our study was lower than reported by Roman et al of 3.1%17 and Pacini et al at 4.4%.3 13 It is notable that there were 33 pregnancies where the maternal aortic diameter prior to pregnancy was 40 mm or greater. There were two dissections (one type A and one type B) in this group (rate 6.0%). There were no third trimester or delivery dissections. This maybe because of the greater use of beta-blockers in our cohort compared with other studies such as Lind and Wallenburg.5 In their cohort of 44 women (147 pregnancies >24 weeks’ gestation), there were five dissections; no women took beta-blockers. It may also have been due to chance.
We demonstrated a significant but small increase in AoR size at pregnancy follow-up, in keeping with Donnelly et al and Renard et al.10 18 Renard et al showed that in pregnant women the most profound increase in AoR dimensions was after delivery, plateauing after this point; unfortunately, we only had data on AoD at a single time point after delivery. Interestingly, change in aortic size did not correlate with the use or non-use of beta-blockers, although our study was underpowered to draw definite conclusions. Moreover, the apparent change in some of the cases was not entirely plausible, suggesting that the accuracy of routine ultrasound measurement of aortic diameters needs to be improved. Furthermore, the increase in the frequency of ultrasound imaging prior to pregnancy following the 2011 ESC guidance was disappointingly small (from 52% to 64.8%) and not statistically significant. Improvement in prepregnancy assessment should be a priority.
Only 50% of women had evidence of documented PCC in their first pregnancy. However, we recognise that we could only identify that counselling occurred if there was documentation of this in the medical record and clinicians may not have routinely recorded it. PCC is important because cardiac disease remains the leading cause of indirect maternal death19; clinicians should provide women with cardiac disease with individualised, accurate and contemporary data regarding their risk of a pregnancy.20 For those who have a dilated aorta, prophylactic ARR prior to pregnancy maybe considered, although ARR does not necessarily negate cardiac complications. A Japanese series reported a rate of peripartum type B dissection in women with previous ARRs undergoing pregnancy of 60%; however, in our study, it was 3.4%. A large Dutch study involving 600 patients with MFS reported that prior ARR was an independent risk factor for type B dissection,21 but pregnancy was not included in their predictive model. Although our study is the largest to date of women with MFS and prior ARR, there remain limited data for management of these women. Registries enabling large prospective studies are urgently required.
Our data showed a clear association between beta-blockers and low BW. While the majority of infants born SGA will demonstrate catch up growth, there is an increased lifelong risk of developing the metabolic syndrome in adulthood.22 The 2011 ESC guidance recommended beta-blocker use for MFS, while acknowledging their benefit was uncertain. The 2018 guidance states beta-blockers should be considered, accepting that they are of unproven benefit.9 We found no significant increase in the use of beta-blockers following the 2011 ESC guidance, suggesting that some clinicians consider their use as beneficial while others do not. In another study we showed that women with heart disease generally have smaller infants than healthy women after adjusting for confounding factors, in our study beta-blockers were associated with a 286 g lower BW.23 Atenolol had the strongest association with lower BW, in part because it was the most commonly used beta-blocker. Lydakis et al 22 showed in a cohort of women with GH that when atenolol was compared with other antihypertensive agents to treat GH, women receiving atenolol had infants with significantly lower BWs. Use of beta-blockers to prevent aortic dilatation remains controversial.24 Presently, there are no reported studies in pregnancy assessing the impact of beta-blockers on the rate of dissection. In our study, all women who suffered a dissection had been prescribed beta-blockers during pregnancy. Women should be advised the evidence for beta-blockers use to prevent AoD in pregnancy is limited.
Overall, the caesarean section rate was almost 50%, higher than the 41% reported by the Registry of Heart Disease and Pregnancy (ROPAC).25 Many women were managed prior to the 2011 guideline, suggesting delivery by ELCS should be performed if AoR is >45 mm. Our data showed that the overall rate of ELCS remained unchanged in spite of this guidance. Currently, there is no clear evidence suggesting that ELCS. The 2018 guidance suggests a more individualised approach to delivery. It is unclear why dissection is more common postpartum. There is no evidence suggesting labour increases the incidence of dissection. However, cardiac output increases progressively as labour advances, peaking around delivery,26 potentially increasing aortic shear stress.27 Nevertheless, AoD in labour is seldom reported,28 so decisions around mode of delivery should be multidisciplinary.
PPH complicated 40% of deliveries which is double the rate from a systematic review analysing the overall rate of PPH in the general obstetric population.29 Ergometrine, used routinely to reduce bleeding is often avoided in women with MFS because its vasopressor activity results in marked hypertension. As a result, women are likely to experience a greater blood loss at delivery.
Preterm delivery was relatively common being comparable to ROPAC.25 Our data show that 21 (66%) of the infants born preterm were late preterm deliveries (between 34 weeks and 37 weeks), 17 (53%) due to elective early delivery. Decisions regarding delivery should be multidisciplinary, involving the patient, late preterm birth has an adverse effect on child health up to 5 years of age.30
Limitations
This study has limitations. It is retrospective so data may be missing or incomplete. We only included follow-up to 6 months postpartum and did not include nulliparous controls in our analysis. We included patients managed in tertiary centres, so introducing selection bias. Furthermore, while we had data on aortic measurements both before and after pregnancy in 58 cases, these would have been performed by different individuals and not to a standardised proforma. Images were not blindly reviewed by expert echocardiographers/cardiologists to ensure consistency and accuracy of aortic measurements. We aim to design a prospective study to address these points
Conclusion
Risk of AoD in women with MFS in pregnancy, managed within 12 specialist centres in the UK was 1.9%. Ascending aortic size increased significantly by 0.65 mm from prepregnancy to postpregnancy. There were no obvious risk factors, other than MFS itself, that were significantly associated with dissection. Rates of obstetric and neonatal complications was high. Introduction of ESC guidance in 2011 was associated with a small increase in the proportion of women having aortic imaging during pregnancy but no change in the use of beta-blockers (which was associated with lower BW).
Key messages
What is already known on this subject?
The literature suggests that pregnancy increases the risk of aortic dissection in women with Marfan syndrome, yet predicting which women are a greatest risk remains challenging. Furthermore, it remains unclear whether pregnancy impacts significantly on aortic root size.
What might this study add?
Although aortic dissection is a known hazard of pregnancy in women with Marfan syndrome, the absolute risk (1.9%) remains low. In our study, four of five dissections were type B. Beta-blockers were associated with lower birth weight, significantly so in the case of atenolol and bisoprolol. Pregnancy, however, did appear to increase aortic root size in the short term. Rates of preconception counselling were low.
How might this impact on clinical practice?
This study provides reassurance that the majority of women with Marfan syndrome and pregnancy will have a good outcome. The benefit of using beta-blockers in Marfan syndrome in pregnancy remains unclear and is associated with lower fetal birth weight. Prospective randomised trials of their use may be justified.
References
Footnotes
Contributors MC conceived the idea for the study. Data for the study was collated by MC, SLC, LM, AM, SD, HMP, JO, MS, SW, GM, GP, LJF, APB, FS, DW, MS, NW, KH, KT, FB and RM. PS and MC analysed and approved the data. MC, PS, MRJ and FW wrote the first draft, which was reviewed and approved by all authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer No sponsor played any role in the design and conduct of this study, including in data collection, analysis, data interpretation and in the preparation, review or approval of the manuscript.
Competing interests None declared.
Ethics approval The study protocol was approved by the research governance team at Imperial College Healthcare.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.