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............................................................................................................................................................................. Different sources of evidence can be used for the risk classification of drugs applied during pregnancy.

12.1.2 Drug classes in pregnancy 12.1.2.1 Anticoagulants VKA and LMWH have advantages and disadvantages during pregnancy, which are also discussed in the sections related to specific indications. However, comparison between studies is hampered by reporting differences, and conclusions concerning the safety of low-dose VKA (warfarin <5 mg daily) in the current literature are controversial.5,196,217,219,223,227 VKAs cross the placenta and their use in the first trimester can result in embryopathy (limb defects and nasal hypoplasia) in 0.6–10% of cases.216,218,219,228 Substitution of a VKA with UFH or LMWH in weeks 6–12 almost eliminates the risk of embryopathy. There is evidence that the embryopathy risk with VKA is also dosedependent. The risk was 0.45–0.9% in pregnancies with low-dose warfarin according to two recent systematic reviews.217,219 In addition to the risk of embryopathy that is limited to the first trimester, there is a 0.7–2% risk of foetopathy (e.g. ocular and central nervous system abnormalities and intracranial haemorrhage) when VKAs are used in the second and third trimesters.216,219,223,228–230 Foetopathy has also been described with UFH but not with LMWH throughout pregnancy.219,223 Vaginal delivery while the mother is on VKAs is contraindicated because of the risk of foetal intracranial bleeding.228 Haemorrhagic complications in the mother occur with all regimens.219 The efficacy and safety of several LMWH preparations was shown in a reviewof2777pregnantwomentreatedforDVTorPE.Theriskofrecurrent VTE with therapeutic doses of LMWH was 1.15%. The observed rate of major bleeding was 1.98%. Heparin-induced thrombocytopenia is markedlylowerwithLMWHthanwithUFH,asisheparin-inducedosteoporosis (0.04%).13 In clinically suspected DVT or PE, therapeutic LMWH shouldbegivenuntilthediagnosisisexcludedbyobjectivetesting. Monitoring is essential in patients treated with LMWH with mechanical valves (see section 6), but the evidence is less clear in patients with VTE. Given the need for dose increase as pregnancy progresses to maintain a certain therapeutic anti-Xa level (peak: 0.7–1.2 U/mL),224,421 it seems reasonable to also determine anti-Xa peak levels during pregnancy in patients with VTE. This appears particularly justified in view of the fact that PE occurred in women receiving prophylactic doses of LMWH.396 As with the use of LMWH in women with mechanical valves, using trough levels and adjusting the dosage frequency may be necessary to achieve adequate anticoagulation.225 UFH does not cross the placenta either, but is associated with more thrombocytopenia (platelet levels should be measured every 2–3 days), osteoporosis, and more frequent dosing when given subcutaneously compared with LMWH. Typically, UFH is used in the acute treatment of massive pulmonary emboli. It is also used around the time of delivery if the maintenance of anticoagulation is critical and when the ability to reverse anticoagulation urgently using protamine is advantageous. In this circumstance, LMWH should be switched to i.v. UFH at least 36 h before the induction of labour or caesarean delivery is planned. UFH should be discontinued 4–6 h before anticipated delivery and restarted 6 h after delivery if there are no bleeding complications.

12.1.2.2 Thrombolytics Thrombolytics are considered to be relatively contraindicated during pregnancy and peripartum, and should only be used in high-risk patients with severe hypotension or shock.405 The risk of haemorrhage, mostly from the genital tract, is around 8%.422 There are more than 200 reported patients in whom streptokinase was mostly used and, more recently, recombinant tissue plasminogen activator (alteplase). Neither of these thrombolytics crosses the placenta in significant amounts. Foetal loss in 6% and pre-term delivery in 6% of cases were reported.414 When thrombolysis is given, the loading dose of UFH should be omitted and an infusion started at a rate of 18 U/kg/h, and carefully adjusted according to the aPTT level. After stabilization of the patient, UFH can be switched to LMWH.

12.1.2.3 Factor Xa and thrombin inhibitors No adequate, well-controlled studies in pregnant women are available. Fondaparinux indirectly inhibits factor Xa activity via ATIII binding. There are a few observational studies on the use of fondaparinux in pregnancy, with the largest reporting good outcomes for 65 pregnancies managed with fondaparinux.423 Its use can be considered if there is an allergy or adverse response to LMWH. One study showed minor transplacental passage of fondaparinux,424 and more work is required to assess the risk of congenital malformations. Rivaroxaban, a direct factor Xa inhibitor, crosses the placental barrier and therefore is not recommended in pregnancy. A systematic review of 137 pregnancies with pregnancy outcome data revealed a miscarriage rate of 23% (n = 31), elective terminations in 29% (n = 39) of cases, and possible embryopathy in 2.2% (n = 3) of cases.425 Most cases were on rivaroxaban, and in most pregnancies the duration of use was limited to the first trimester. Rivaroxaban is currently not recommended in pregnant patients. Other direct factor Xa inhibitors—such as apixaban, edoxaban, and the direct oral thrombin inhibitor dabigatran—should not be used in pregnant patients.

12.1.2.4 Beta-adrenergic blocking agents Beta-adrenergic blocking agents are generally safe in pregnancy, but may be associated with increased rates of foetal growth restriction and also hypoglycaemia. Beta-1-selective drugs are preferred,426 except in TdP (see section 9), as they are less likely to affect uterine contraction and peripheral vasodilation, and they have exhibited lower rates of foetal growth retardation.427 Examples are metoprolol and bisoprolol. Unselective beta-blockers such as atenolol have been associated with higher rates of foetal growth retardation.427,428 Among the alpha/beta-blockers, labetalol is a drug of choice for hypertension in pregnancy380,381, and carvedilol used for HF therapy did not show any association with foetal growth retardation in a recently published small study with 13 patients receiving this drug.427

12.1.2.5 Renin–angiotensin–aldosterone system inhibitors: ACE inhibitors, ARBs, ARNIs, and aldosterone antagonists ACE inhibitors and ARBs are teratogenic and contraindicated during pregnancy.36 Renal or tubular dysplasia, renal failure, oligohydramnios, growth retardation, ossification disorders of the skull, lung hypoplasia, contractures, large joints, anaemia, and intrauterine foetal death have been described. In a systematic review, 48% of 118 foetuses exposed to ACE inhibitors and 87% of foetuses exposed to ARBs had complications related to the use of these medications.36 These recommendations and data also apply to ARNIs (sacubitril/valsartan), since they contain ARBs. Downloaded from academic.oup.com/eurheartj/article/39/34/3165/5078465 by guest on 07 October 2026