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Low-molecular-weight heparins (LMWH) are widely used in patients in whom anticoagulant therapy is indicated. Side-effects include bleeding, heparin-induced thrombocytopenia, and hypersensitivity reactions [1]. Skin complications due to LMWH use are considered to be rare, but their incidence is likely to be underreported [2]. They vary from an urticarial rash (type I immediate hypersensitivity reaction), to erythematous lesions (delayed type IV hypersensitivity reaction) and, exceptionally, skin necrosis.

LMWH are considered safe and effective in pregnant and lactating women [3]. In systematic reviews of LMWH use during pregnancy or the postpartum period, the reported incidences of generalized skin reactions were low, i.e. 0.3%−0.6% [3,4]. We report here a remarkably higher rate of skin complications.

The efficacy and safety of treatment with LMWH during pregnancy and the postpartum period in consecutive women is evaluated in an ongoing prospective, observational study in two university hospitals. Indications included thromboprophylaxis in women with an increased risk of pregnancy-related VTE, treatment of VTE, and prophylaxis in women with mechanic heart valves. During scheduled follow-up visits, data on pregnancy and drug-related complications were collected. All patients were instructed to contact the study center in case of complications. LMWH were prescribed in body weight adjusted therapeutic dosages (75 anti-Xa IU kg−1 day−1) or in prophylactic dosages (less than 75 anti-Xa IU kg−1 day−1), depending on the indication. Laboratory measurements included among others platelet counts and anti-Xa levels. For calculating the incidence of complications only the first episode was counted and subsequent episodes were censored.

Until the present interim analysis 66 pregnant or postpartum women were treated with LMWH. Thirty-nine women received LMWH during the entire pregnancy and postpartum period, 13 during pregnancy only, and 14 in the postpartum period only. None of the women had a history of allergy to unfractionated heparin or LMWH. Besides folic acid, women were not using other drugs. Skin complications occurred in 19 [29%] of the 66 women during LMWH use (Table 1), all except one during pregnancy. These consisted of itching (n = 13, 20%), local redness (n = 15, 23%), subcutaneous infiltrates localized at the injection sites (n = 7, 11%) and pain during injection (n = 2, 3%). Two women (3%) developed a generalized erythematous rash with well circumscribed lesions of various size at the injection areas, elbows, thighs and armpits. No other side-effects of LMWH, especially no bleeding, thrombocytopenia, skin necrosis, angiedema or anaphylaxis were reported. There were also no signs of cholestasis.

Table 1.  Types of LMWH used as first, second and third choice and skin complications
 LMWH of first choiceAny skin complication to LMWH of first choiceFirst switch to another LMWHSecond choiceAny skin complication to LMWH of second choiceThird choice LMWH
  • *

    In one of these women using Danaparoid as third LMWH symptoms persisted (see text).

Nadroparin2411 (46%)7 (29%)21
19.000 anti-Xa IU mL−1 (all given in therapeutic dosages)
Nadroparin396 (15%)6 (15%)21
9.500 anti-Xa IU mL−1 (77% was given as therapeutic dosage)
Enoxaparin11 (100%)1 (100%)51
10.000 anti-Xa IU mL−1 (all given in therapeutic dosages)
Dalteparin141
25.000 anti-Xa IU mL−1 (all given in therapeutic dosages)
Tinzaparin11 (100%)1 (100%)21
14.000 anti-Xa IU mL−1 (all given in therapeutic dosages)
Danaparoid4*
750 anti-Xa IU mL−1 (all given in therapeutic dosages)
Total6619 (29%)15 (23%)155 (33%)4

Skin complications began 7–95 (median 26) days after start of LMWH, and disappeared spontaneously or after switch to another LMWH after 1–59 (median 10) days. Although therapy had to be changed in 15 women (23%), it was not necessary in four women because of the mild course of symptoms.

Five of the 15 women (33%) in whom the initial LMWH had been discontinued developed new skin complications or had persistent complaints while receiving a different LMWH as second choice (Table 1). In three of these five women, signs and complaints resolved after replacement of the second LMWH by danaparoid; in one woman (receiving Tinzaparin and Nadroparin (9.500 anti-Xa IU mL−1) as first and second choice, respectively) symptoms persisted during danaparoid and labor was induced in the 37th week of gestation for this reason; the remaining patient (receiving Nadroparin (19.000 anti-Xa IU mL−1) and Nadroparin (9.500 anti-Xa IU mL−1) as first and second choice, respectively) switched to vitamin K antagonists from the 16th to 36th weeks of gestation and subsequently tolerated an alternative LMWH (Tinzaparin) during the rest of her pregnancy.

Risk factors for development of skin complications were a history of former use of LMWH (RR 3.5, 95%CI 1.1–11.1) and inherited protein C deficiency (RR 3.3, 95%CI 1.8–6.1).

We preferentially prescribed Nadroparin which makes it difficult to extrapolate our results to all LMWH. However, given the known and observed cross-reactivity we conclude that skin complications occur far more frequently during long-term use of LMWH in pregnant women than previously reported for short-term use in non-pregnant individuals or other series of pregnant women.

Skin complications were a reason for alteration of therapy in almost one-quarter of the pregnant women using LMWH for prophylaxis or treatment of thrombosis. Because of the characteristic time relation between start of LMWH and onset of skin complications, and the absence of signs of skin necrosis, our patients are most likely to have moderate delayed type IV skin reactions.

The clinical course was self-limiting in most of the women after switching to another LMWH or a vitamin K antagonist, and no antihistaminics or corticosteroids were necessary. However, about one-third of the women who had switched also had skin complications on another LMWH, indicating cross-reactivity between preparations.

An alternative explanation for our observations could be pruritic urticarial papules and plaques of pregnancy (PUPPP) [5,6]. However, this common feature usually occurs during the last weeks of pregnancy, and eruptions often become manifest within striae, which was different from the clinical picture in our patients.

Although subcutaneous tests are considered to be the gold standard in case of delayed hypersensitivity type IV skin reactions, there is no consensus about the optimal diagnostic strategy, and we preferred a pragmatic approach in the management of skin complications [2].

It is of interest to note that pregnant women on the once-a-day injection formulation of nadroparin (19.000 anti-Xa IU mL−1) appeared to have an increased risk of skin complications when compared to those using the lower concentration of the same preparation twice daily (observed difference: 30.4%, 95%CI, 7.5–53.4). Since these formulations contain the same substances, this observation cannot yet be understood.

In the absence of alternative and safe anticoagulants during pregnancy, LMWH remain the treatment of choice, but physicians should be aware of skin complications, and should instruct patients properly. A pragmatic approach to switch to another LMWH when skin complications occur seems appropriate, since the majority of the patients will tolerate the other LMWH.

References

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  2. References
  • 1
    Dukes MNG, Aronson JK. eds. Meyer's Side Effects of Drugs, 14th edn. Drugs affecting blood clotting, fibrinolysis, and hemostasis, Amsterdam: Elsevier; 2000, 35, p. 1171–207.
  • 2
    Wutschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins. Drug Safety 1999; 20: 51525.
  • 3
    Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 66872.
  • 4
    Ensom MH, Stephenson MD. Low-molecular-weight heparins in pregnancy. Pharmacotherapy 1999; 19: 101325.
  • 5
    Aronson IK, Bond S, Fiedler VC, Vomvouras S, Gruber D, Ruiz C. Pruritic urticarial papules and plaques of pregnancy: clinical and immunopathologic observations in 57 patients. J Am Acad Dermatol 1998; 39: 9339.
  • 6
    Lawley TJ, Hertz KC, Wade TR, Ackerman AB, Katz SI. Pruritic urticarial papules and plaques of pregnancy. JAMA 1979; 241: 16969.