Cutaneous hypersensitivity reaction to low molecular weight heparins in pregnancy, cross reactivity and prednisolone treatment: A case report

Abstract

In pregnant women, low molecular weight heparin is recommended as the preferred agent for venous thromboembolism prophylaxis and treatment. Despite their widespread application, heparin-induced skin lesions are probably under-reported and under-estimated. We present a case report of a primigravida treated with low molecular weight heparin for deep vein thrombosis, who developed a delayed-type hypersensitivity reaction to enoxaparin, tinzaparin and dalteparin. As the patient was pregnant, treatment options were restricted. Tolerance was achieved with dalteparin with adjuvant administration of prednisolone. An attempt to decrease prednisolone dose triggered delayed-type hypersensitivity reaction recurrence that was solved by keeping the initial prednisolone prescription. To the best of our knowledge, there are no described cases using this approach. In cases of delayed-type hypersensitivity reaction to low molecular weight heparin during pregnancy our case suggests that switching low molecular weight heparin and adjuvant administration of prednisolone can be an option.

Introduction

Low molecular weight heparin (LMWH) is a drug used in prophylaxis and treatment of thromboembolic disorders during pregnancy. Both unfractionated heparin (UFH) and LMWH are recommended for pregnant women since they do not cross the placenta.^1,2 Most women use LMWH due to its simple administration in the outpatient setting, better safety profile and lower incidence of adverse drug reactions compared to UFH.^3,4

Nevertheless, there are complications associated with LMWH administration, such as bleeding or rarely hypersensitivity reactions (heparin-induced thrombocytopenia (HIT), immediate anaphylactic reactions and delayed-type hypersensitivity reactions (DTHR)). ³ Hypersensitivity reactions to UFH or LMHW are uncommon.^5,6 In pregnancy, according to a systematic review, allergic skin reactions are reported in only 1.8% of pregnancies. ⁷

Case report

A 32-year-old woman in her first pregnancy was referred for obstetric clinical surveillance after a left iliofemoral deep vein thrombosis (DVT), at 26 weeks' gestation.

Past medical history was not relevant except for infertility for the previous 2 years. The current pregnancy resulted from ovulation induction and was uneventful until at 26 weeks’ gestation, when the DVT was diagnosed and therapeutic dosing enoxaparin (70 milligrams (mg) twice per day) was started.

At 28 weeks’ gestation, she was admitted to the emergency department (ED) with pruritic erythematous indurated plaques with well-defined edges of two weeks duration. The skin reaction was located at the sites of subcutaneous enoxaparin administrations (both upper thighs) (Figure 1). After a multidisciplinary discussion, enoxaparin was switched to tinzaparin 1000 International Unit (IU) per day, and she was discharged. Three days later, she was readmitted at the ED with worsening of the skin lesions. At that time, in addition to the lesions described above, she had developed new pruritic erythematous plaques in the lower quadrants of the abdomen (Figure 2) and erythematous millimetric macules in the pectoral region. Laboratory testing was performed showing normal full blood count, renal and liver function. Dalteparin was started as inpatient care, 6600 IU, twice a day combined with prednisolone without a new allergic reaction. Oral treatment with hydroxyzine and topical diphenhydramine and calamine was administered for symptomatic relief. Four days later, she was discharged on dalteparin 12500 IU per day and prednisolone 20 mg.

Figure 1.

Pruritic erythematous indurated plaques with well-defined edge in the upper thighs.

Figure 2.

Pruritic erythematous plaques in the lower quadrants of the abdomen.

An attempt to reduce the corticosteroid dose was made at 30 weeks, however new skin lesions were reported, and prednisolone dosing was continued until delivery. The affected skin area reduced in size as well as the associated erythema. The follow-up was unremarkable.

At 36 weeks and 6 days generalized pruritus developed, predominantly on the palms, soles and lower limbs, without new cutaneous lesions. Laboratory tests revealed elevated bile acids with no other altered findings and a diagnosis of intra-hepatic cholestasis of pregnancy was made. Labor induction occurred at 37 weeks. Caesarean delivery was performed due to nonreassuring fetal cardiotography. A live male new-born weighing 2870 g was delivered, with APGAR scores 9/10/10. She was discharged on dalteparin 12500 UI per day with oral prednisolone 20 mg, until six weeks postpartum. The puerperal period was uneventful.

At six weeks postpartum, testing for inherited and acquired thrombophilic disorders was negative.

Discussion

According to the Najaro Scale, this case is likely to be an adverse reaction to LMWH, ⁸ not only enoxaparin, but also tinzaparin and dalteparin. Among the risk factors described for the development of DTHR to heparins, this case report has two risk factors, namely female sex and pregnancy status.^9,10 A prospective study cohort demonstrated an incidence of 19.8% of skin lesions caused by DTHR in pregnant women. ¹¹ The appearance of erythematous plaques occurs at the injection sites after a latency period of 2 days to 3 weeks as shown in this case. ¹²

The major challenge in the diagnosis of heparin-induced skin lesions is the distinction between lesions caused by HIT from cutaneous DTHR. HIT can lead to fatal thromboembolism, whereas DHTR is not life-threatening. ¹³ In this case, HIT was less likely than DTHR because of normal platelet count (252 000 platelets). To confirm the diagnosis of a DTHR, a skin biopsy could have been performed; however it is not routinely required for diagnosis since it can be made based on the history and clinical manifestations. ¹⁴

In the literature, the risk of a cross-reaction between LMWH is documented, thereby switching between LMWH agents should be avoided.^3,12,15 Therapeutic alternatives are UFH and fondaparinux. ¹⁵ UFH has an unpredictable and highly variable individual responses and it typically requires monitoring by the activated partial thromboplastin time. ⁷ Furthermore, it has been reported to have cross-reactivity in 50% of the cases. ³ LMWH does not need monitoring, has more predictable plasma levels and it was considered have a better safety profile than UFH. ¹⁶ On the other hand, the effectiveness of fondaparinux has been reported during pregnancies in which cutaneous allergic reactions to heparins or HIT occurred. However, data is based on case reports or case series and larger prospective studies are needed to establish its safety profile in pregnancy. ¹⁷ Given the difficulty of using UFH and fondaparinux to ensure an appropriate treatment in outpatient setting, the concomitant use of LMWH with corticosteroids can be a therapeutic alternative.

This case report reminds obstetricians to be aware of the adverse reactions of administration of LMWH, and how important the multidisciplinary surveillance of anticoagulated pregnant women is. In our case adding prednisolone was successful in achieving tolerance to LMWH. To the best of our knowledge, there are no described cases using this approach. In cases of DTHR to LMWH during pregnancy, when the therapeutic options are reduced, our case suggests that switching LMWH with adjuvant administration of prednisolone can be an option. More evidence is needed to validate this approach.