- Loeys-Dietz syndrome is an autosomal-dominant disorder with a known risk of aortic and arterial aneurysm and dissection; this risk is thought to be elevated in the peripartum period. Although the third trimester and postpartum period are the times of greatest risk, the optimal gestational age for delivery and delivery method have not yet been determined.
- Loeys-Dietz syndrome is characterized by vascular, skeletal, craniofacial, and cutaneous features; however, the minimum clinical diagnostic criteria have not been established. A family history of aortic dissection and molecular testing of TGFBR1, TGFBR2, SMAD3, and TGFB2 contribute to the diagnosis. A clinical suspicion for Loeys-Dietz syndrome warrants a referral to a cardiovascular geneticist.
- Vessel tortuosity in the head and neck is a hallmark finding for this disorder and may extend to the uterine vessels. Identification of women with Loeys-Dietz syndrome before or early in pregnancy is important to allow for adequate surveillance of aortic disease and to ensure delivery at a tertiary care center with expertise in aortic surgery.
Loeys-Dietz syndrome is an autosomal-dominant connective tissue disorder caused by mutations in the TGFβR1, TGFβR2, TGFβ2, TGFβ3, and SMAD3 genes. The syndrome is characterized by vascular, skeletal, craniofacial, and cutaneous features (Box 1).1 However, the minimum clinical criteria for diagnosis of Loeys-Dietz syndrome have not been defined, and there is a broad spectrum of features and severity.2 Because some individuals have minimal characteristics, a family history of aortic dissection and genetic testing are additional diagnostic criteria.
Clinical Findings Associated With Loeys-Dietz Syndrome Cited Here...
- Dilatation or dissection of the aorta or other arterial aneurysms
- Arterial tortuosity
- Pectus excavatum or pectus carinatum
- Scoliosis or cervical spine malformations or instability and dural ectasia
- Joint laxity or contracture (mostly in fingers)
- Arachnodactyly (long, slender fingers)
- Talipes equinovarus (clubfoot)
- Hypertelorism (widely spaced eyes)
- Bifid uvula or uvula with wide base or prominent ridge
- Cleft palate
- Malar hypoplasia or retrognathia
- Blue sclera
- Translucent skin
- Easy bruising
- Dystrophic scarring
Limited data derived from Loeys-Dietz syndrome registries, case series, and case reports indicate that the rate of aortic dissection in women with Loeys-Dietz syndrome is elevated during pregnancy, likely as a result of hemodynamic and hormonal changes, and may be as high as 1.5–6%.2,3 This rate is much higher than the rate in the general population (0.0004%) and comparable with the rate in women with Marfan syndrome.4 The European Society of Cardiology and the American College of Cardiology acknowledge that pregnancy is a high-risk time for women with aortic disease, with most dissections occurring in the third trimester (50%) or postpartum (33%).5,6 Because aortic dissection in pregnancy is associated with a high mortality rate, it is essential to identify these high-risk women preconception or early in pregnancy. In this specific case, we highlight the obstetric management of Loeys-Dietz syndrome.
A 16-year-old primigravid girl was referred to our tertiary care center at 18 weeks of gestation with a possible history of some form of Ehlers-Danlos syndrome based on arachnodactyly and hypermobile joints as well as aortic root dilation and a small perimembranous ventricular septal defect. Her family history was significant for aortic dissections in two distant maternal relatives. On physical examination, the patient was petite (height 155 cm, prepregnancy weight 44 kg) and had minor dysmorphic features, including dolichocephaly, arachnodactyly, malar hypoplasia, soft translucent skin, and hypertelorism. By echocardiography, her aortic root measured 3.6 cm (Z-score, which accounts for body size, of 4.1 SDs above the mean). Other findings included a small restrictive perimembranous ventricular septal defect, mild pulmonary artery dilation (2.8 cm, Z-score 2.8), normal estimated right ventricular pressure (16 mm Hg plus right atrial pressure), no evidence of mitral valve prolapse, and trivial mitral and tricuspid regurgitation. Based on these features, a family history of aortic dissection, and genetic testing of a maternal relative with aortic dissection revealing a pathogenic TGFβ2 mutation (c.988C>T), a diagnosis of Loeys-Dietz syndrome was suspected. The patient then had molecular testing, which revealed that she was heterozygous for the known familial pathogenic variant. Of note, although her mother and maternal grandmother were obligate carriers of the same mutation, they had only mild aortic root dilation and no history of aortic events.
A multidisciplinary team including members from maternal–fetal medicine, genetics, cardiology, cardiovascular surgery, anesthesia, neonatology, transfusion medicine, and nursing met to plan the method and timing of delivery and to make contingency plans in the case of aortic dissection. A noncontrast magnetic resonance angiogram was ordered from head to pelvis to evaluate for additional aneurysms; however, this could not be completed secondary to patient anxiety. In accordance with American College of Cardiology and European Society of Cardiology guidelines, the size of her aortic root was followed with transthoracic echocardiography every 4–8 weeks and remained unchanged.5,6 She was also treated with metoprolol for heart rate control. Fetal growth scans every 4 weeks confirmed normal fetal growth. The patient underwent a fetal echocardiogram secondary to the concern for congenital cardiac anomalies; no significant cardiovascular findings were seen.
The third trimester was complicated by sudden chest pain and dyspnea on several occasions. Each time the patient was in normal sinus rhythm with a stable aortic root size (3.6 cm). A computed tomographic angiogram identified tortuous vertebral vessels, with a vertebral tortuosity index of 19 (normal less than 10). Although these episodes were felt to be caused by anxiety and panic attacks, because of the complex care required for this patient, inconsistent compliance, and her living 2 hours from the tertiary care center, the decision was made to hospitalize the patient at 32 weeks of gestation until her planned delivery. She underwent magnetic resonance imaging of the spine for anesthesia preparation, which showed dural ectasias at the S1–S2 level.
Because dissection has been reported with an aortic root of 3.5 cm in patients with Loeys-Dietz syndrome, and in consideration of the increased vertebral tortuosity index and increased risk of aortic dissection with third-trimester hemodynamic changes, the consensus of the multidisciplinary team was to recommend delivery by planned cesarean at 36 weeks of gestation so that delivery could occur under controlled conditions with maximum resources available. Recovery and postpartum care was planned to occur in the cardiac intensive care unit with telemetry, owing to the risk of postpartum cardiac arrhythmia that has been described in women with Marfan syndrome (odds ratio 10.64), and in close proximity to the cardiac operating rooms.7
After arterial and central line placement, the patient underwent a primary low transverse cesarean delivery at 36 weeks of gestation, with a slowly titrated epidural to avoid hemodynamic fluctuations. She delivered a liveborn female neonate (1- and 5-minute Apgar scores 8 and 9, respectively; birth weight 2,689 g), with an estimated blood loss of 750 mL. Intraoperatively, significant uterine vessel tortuosity was noted (Fig. 1). After delivery, the patient was started on losartan in addition to metoprolol as prophylaxis against further aortic root dilation. She had an echocardiogram on postoperative day 1 and a magnetic resonance angiogram on postoperative day 4, which showed no evidence of further aortic root dilation or dissection. She was offered long-term reversible contraception but declined. She was discharged on postoperative day 5. The neonate was tested for the TGFβ2 mutation and was negative. Although cardiology follow-up was scheduled at 6 weeks and 3 months postpartum, the patient did not attend the visits despite being contacted several times. By report of other family members, she has not had any aortic events 18 months after delivery.
This case demonstrates that a patient with Loeys-Dietz syndrome can have a successful pregnancy when closely monitored by a multidisciplinary team. Additionally, this case suggests that, although not previously reported, uterine vessel tortuosity may be an additional phenotypical finding in Loeys-Dietz syndrome.
Arterial tortuosity, defined as an artery that has multiple turns, is present in head and neck vessels in 84–100% of individuals with Loeys-Dietz syndrome.1,2 A quantitative measure of vertebral tortuosity, the vertebral tortuosity index, has been examined in patients with Loeys-Dietz and Marfan syndrome with a higher tortuosity score associated with earlier age of aortic dissection and death.2,8 Our case suggests that vascular tortuosity extends to the uterine vessels and may be an additional phenotypical finding, although isolated uterine vessel tortuosity is nondiagnostic because it can occur in the general population. One of the limitations with a qualitative assessment of tortuosity is that interpretation can vary between observers. Thus, future studies to determine whether increased tortuosity of the uterine arteries is seen in the majority of women with Loeys-Dietz syndrome and to develop a quantitative measurement of uterine artery tortuosity on imaging, similar to other developed indices, should be considered.8 This quantified tortuosity score, if found to be associated with poor cardiovascular outcomes during pregnancy or in the long-term period, could potentially be used for preconception counseling about the risk of pregnancy in that individual or be used in the planning for timing and method of delivery.
Pregnancy management in women with Loeys-Dietz syndrome requires a multidisciplinary team with knowledge of connective tissue disorders, including access to cardiac surgeons with expertise in aortic surgery; the management guidelines are outlined in Table 1. In Marfan syndrome, the greatest risk of pregnancy-associated aortic events occurs when the maximum aortic dimension is 4.0–4.5 cm or greater, bu aortic diameter criteria have not been well studied in pregnant women with Loeys-Dietz syndrome, and aortic dissections have been reported at diameters as small as 3.1 cm in a patient with prior aortic surgery and 3.5 cm in a patient without prior surgery.2,4 Therefore, until more data are available to estimate aortic dissection risk in patients with Loeys-Dietz syndrome, caution should be taken in pregnant women with aortic dilation and this syndrome.
Treatment with β blockers and angiotensin receptor blockers, outside of pregnancy in children and young adults, reduces the rate of aortic root dilation and improves survival; however, a recent meta-analysis refutes these benefits.9,10 Angiotensin receptor blockers cannot be used during pregnancy secondary to teratogenic risks. Beta blocker use in pregnancy is associated with fetal growth restriction; metoprolol is specifically recommended because it is thought to have the least detrimental effect on fetal growth.11
The method and timing of delivery in women with Loeys-Dietz syndrome are controversial, and no guidelines have been established. Because of an early study reporting uterine rupture before term (2/12 women [17%]), some experts recommended early cesarean delivery to avoid this potential risk.1 These patients generally tolerate surgical manipulation and thus differ from patients with vascular Ehlers-Danlos syndrome, who have poor tolerance for surgery and fragile tissues. However, larger and more recent studies in Loeys-Dietz syndrome have not shown that vaginal delivery increases the risk of uterine rupture; thus, vaginal delivery may be considered.2,3 Because of the lack of rigorous data, a consensus of a multidisciplinary team should determine the timing and mode of delivery for each patient individually until there is more information. Because of the peripartum risk of aortic dissection and cardiac arrhythmias, postpartum observation in a higher level of care setting should be considered. The American College of Cardiology and the European Society of Cardiology recommend cardiovascular imaging postdelivery and at 6 months postpartum.5,6 Contraception should be offered to the patient before discharge, although minimal data are available regarding the ideal contraceptive methods in women with Loeys-Dietz syndrome.
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