Thromboangiitis obliterans in pregnancy – Case report and literature review

Abstract

Thromboangiitis obliterans, also known as Buerger’s disease, is rarely reported in young women in pregnancy. It is an occlusive vascular disorder, characterised by episodic non-atherosclerotic thrombosis of small- and medium-sized blood vessels. Thromboangiitis obliterans predominantly occurs in males aged less than 50 years and is almost exclusively diagnosed in smokers. The small number of published cases have frequently reported worsening of thrombotic symptoms, due to the hypercoagulable state of pregnancy, and potential pregnancy complications of intra-uterine growth restriction and pre-term labour. This report provides a summary of the literature and outlines the case of a pregnant 23-year-old female with thromboangiitis obliterans, who was managed with low-dose enoxaparin and aspirin. Her thrombotic symptoms were stable during pregnancy; however, her pregnancy was complicated by placental malperfusion and intra-uterine growth restriction.

Introduction

Thromboangiitis obliterans (TAO or Buerger’s disease) is an occlusive vascular disorder, characterised by episodic non-atherosclerotic thrombosis of small- and medium-sized blood vessels. It predominantly occurs in males aged less than 50 years and is almost exclusively diagnosed in smokers. It is clinically indistinguishable to cannabis arteritis. Clinically, TAO may manifest as Raynaud’s phenomenon, digital ischaemia, claudication and, less commonly, joint complaints. Diagnosis is made by either histopathology of an affected blood vessel or by typical imaging findings in individuals with distal extremity ischaemia, once other vascular disorders have been excluded.

As TAO more commonly affects older men, there are very few reported cases of young women with TAO in pregnancy. Published cases have reported frequent worsening of thrombotic symptoms, due to the hypercoagulable state of pregnancy, and potential pregnancy complications of intra-uterine growth restriction (IUGR) and pre-term labour.

Case

A 23-year-old Caucasian female in her first pregnancy was seen at 8 weeks’ gestation in the obstetric medicine outpatient department for management of TAO in pregnancy.

She was diagnosed with TAO at the age of 21, on a background of a 5 pack-year smoking history and bipolar affective disorder. She had a history of occasional marijuana use pre-pregnancy, and a distant history of amphetamine use. After initially presenting with an acutely ischaemic left lower limb, she underwent a left tibial bypass graft, and subsequently required a left below knee amputation. Histopathology confirmed TAO. Alternative diagnoses had been excluded, with investigations including negative anti-phospholipid antibodies, and negative antinuclear antibodies (ANA), anti-centromere and Scl-70 antibody, which ruled out scleroderma as a diagnosis. She also had a normal echocardiogram, to rule out thromboembolic disease. The following year, she presented with an occluded right popliteal artery, which was managed with an embolectomy and right popliteal to anterior tibial artery bypass graft.

At her first appointment in pregnancy, her only medication was aspirin 100 mg daily. Clopidogrel had been ceased. She was commenced on enoxaparin 40 mg subcutaneous injection daily, to optimise placental blood flow, although we were unable to verify adherence. The woman was managed with serial fetal ultrasound scans, which showed progressive slowing of fetal growth, with normal placental blood flow (Figure 1). Maternal symptoms of TAO were stable throughout pregnancy, and she had no acute episodes of vascular occlusion. An ultrasound of her right lower limb graft was performed at 36 weeks’ gestation and showed reduced but stable graft function. Smoking cessation was recommended, however, the woman continued to smoke one to six cigarettes daily throughout pregnancy.

Figure 1.

Serial fetal ultrasound scans.

The woman delivered by elective lower segment caesarean section at 38 weeks and two days of gestation. She delivered a live infant weighing 2460 g. Her placenta weighed 364 g (5–10th centile for 38 weeks’ gestation) and showed increased syncytial knots, infarction and membranous hemosiderin on histopathological examination, consistent with maternal vascular malperfusion.

A CT angiogram of her lower limbs was performed postpartum, which showed her right lower limb anastomosis remained patent.

Discussion

There are six women (eight total pregnancies) with TAO reported in the English literature who have had pregnancies resulting in a live birth (Table 1), and for whom neonatal and/or maternal outcomes are described.^1–6 Most (6/8) report worsening of maternal ischaemic symptoms during pregnancy.^1–6

Table 1.

Maternal and neonatal outcomes for published cases of TAO in pregnancy.

Case report	Maternal age	Gravidity	Parity	Treatment in pregnancy	Clinical course in pregnancy	Gestation at delivery (weeks)	Growth restriction	Infant birthweight (grams)	Placental histology
Zelikovsky et al.1	30	3	2	Symptomatic only	Worsening of lower limb ischaemic symptoms and gangrene of left first to third toes post-partum	Not described	Not described	Not described	Not described
Young et al.2	21	1	0	Nil	Worsening lower limb ischaemic symptoms and gangrene of right great toe	37	No	3320	Not described
	22	2	1	Nil	Worsening lower limb ischaemic symptoms	40	No	3350	Not described
Casellas et al.3	38	4	3–2a	Nil	Digital necrosis	32	Yes	1000	Multiple infarcts and calcifications
Kikuchi et al.4	28	1	1	Heparin 10,000 units daily from 12 weeks’ gestation	Lower limb ischaemic symptoms and ulceration and necrosis of left lower limb	36	Yes	1814	Small infarction
Durens and Ang-Sy6	33	5	4	Symptomatic only	Lower limb ischaemic symptoms	Not described	Not described	Reportedly normal	Not described
Ohwada et al.5	33	1	0	Nil	Stable	39	No	2828	Areas of infarction
	36	2	1	Heparin 5000 units twice daily from 27 weeks’ gestation	Stable	38	No	2634	Areas of infarction
Current case	23	1	0	Enoxaparin 40 mg daily from 12 weeks and aspirin 100 mg daily	Stable	38	Yes	2460	Syncytial knots, infarctions and membranous hemosiderin

^aIntra-uterine fetal deaths at 30 and 32 weeks, and case complicated by presence of anti-phospholipid syndrome.

Frequently reported adverse neonatal outcomes include pre-term birth and IUGR. Smoking is an additional contributing factor to IUGR and could potentiate the effect in some cases. All of the published cases that include the details of placental histology demonstrate areas of placental infarction, similar to our case (Table 1).^3–5

Heparin use has been described in two previously published cases that describe maternal and neonatal outcomes.^4,5 A 28-year-old female was treated with 10,000 units of subcutaneous sodium heparin daily from 12 weeks’ gestation, due to development of a left lower limb ulcer and ischaemic pain. ⁴ Her symptoms stabilised after heparin was commenced, although she developed complications of IUGR and a small placental infarct. In the second published case of heparin use for TAO in pregnancy, sodium heparin 5000 units twice daily was commenced from 27 weeks’ gestation, due to an asymptomatic increase in fibrin and D-dimer, which was significantly greater than what was expected physiologically in pregnancy. ⁵

The principle management of TAO is smoking cessation, which substantially reduces the risk of amputation. Complete abstinence is important, as even as little as one or two cigarettes can lead to a flare. Vasodilators, including prostacyclin analogues and phosphodiesterase inhibitors, are the mainstay of medical management, although their use is largely palliative. ⁷ Both of these agents have been successfully used during pregnancy in women with pulmonary arterial hypertension, ⁸ however, there are no reports of their use for TAO in pregnancy. Endothelin receptor antagonists such as bosentan, which are contraindicated in pregnancy, have also been successfully used in patients with TAO. Revascularisation is usually difficult due to the predominantly distal site of disease, although it should be considered if it is anatomically favourable. Other trial therapies have also been considered.

Although there is no evidence for using low molecular weight heparin (LMWH) for thrombus prevention or acute treatment of TAO, it is frequently used for deep vein thrombosis prophylaxis in high-risk pregnant women, due to the pro-thrombotic state of pregnancy. It is also frequently used to reduce the risk of placental complications in high-risk women, although the evidence has been conflicting. An initial meta-analysis of studies using LMWH to reduce recurrent placenta-mediated complications suggested significant improvement in outcome (relative risk reduction 0.52, 95% CI 0.32–0.86), although there was substantial statistical and clinical heterogeneity between patients, trials and outcome measures. ⁹ A subsequent individual patient data meta-analysis were performed by the same group, including 963 women from eight randomised trials, which found no significant benefit. ¹⁰ On the other hand, a recent study found LMWH to be superior to sildenafil citrate for outcomes of birth weight, time from randomisation to delivery and fetoplacental blood flow indices, for pregnant women with placentally mediated fetal growth restriction. ¹¹

This case report outlines the progress of a 23-year-old female with TAO who was managed in pregnancy with aspirin and enoxaparin. Although her ischaemic symptoms remained stable throughout pregnancy, her case was complicated by placental malperfusion and resultant IUGR. Given the limited supporting evidence, it is unclear whether the addition of aspirin and enoxaparin improved pregnancy outcomes; however, given the high-risk nature of her pregnancy the overall outcome was excellent.