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Fetal and Maternal Medicine Review 2011; 22:4 265–286 C Cambridge University Press 2011doi:10.1017/S0965539511000131 First published online 3 November 2011OBSTETRIC ANTIPHOSPHOLIPID SYNDROME - A REVIEWK SCHREIBER, O ATEKA-BARRUTIA, MA KHAMASHTA AND GRV HUGHESSt Thomas Hospital Lupus Research Unit, The Rayne Institute, King’s College London School of Medicine,London, United Kingdom.INTRODUCTIONThe Antiphospholipid syndrome (APS) is one of the current hot topics embracingrheumatology and obstetrics. The ﬁrst clinical description of APS was in 1983.1 Venous or arterial thrombosis,abortion and cerebral manifestations along with circulating antibodies were the ﬁrstdescribed hallmarks of the syndrome. In the following years other clinical features,which include pregnancy complications, such as recurrent miscarriages (RM), pre-eclampsia or severe placental insufﬁciency were described. The ﬁrst classiﬁcation criteria of APS were not deﬁned until 1998. Apartfrom laboratory criteria they included pregnancy morbidity, such as one or moreunexplained deaths of a morphologically normal fetus at or beyond 10 weeks gestation,one or more premature births before 34 weeks of gestation due to severe pre-eclampsia,eclampsia, placental insufﬁciency or recurrent early miscarriages. In 2006 the criteriawere updated including changes of the laboratory criteria, while the obstetric clinicalcriteria remained unchanged.2 (Table 1) Due to its preponderance for women in their reproductive age (3.5:1 in primary APSand 7:1 in secondary APS) and the pregnancy morbidity, pregnancy management playsa central role and is of enormous importance in this syndrome.3 Untreated womenare likely to develop adverse pregnancy outcomes, such as pre-eclampsia, and the livebirth rate without intervention may be as low as 10%.4,5 Successful pregnancy management of APS patients combines pre-conceptioncounselling, monitoring during pregnancy, consequent education of the patient andsubsequently a post partum follow-up, ideally in a multidisciplinary set-up. Animprovement in monitoring and treating these patients allows more than 70% ofwomen with APS to deliver a viable live infant.6 In our review we aim to focus on the obstetric antiphospholipid syndrome (OAPS),the pathogenesis, its clinical manifestations and complications. In order to keep ourreview as clinically useful as possible, the entity of OAPS is divided by its serologicalMunther A Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas Hospital, London SE1 7EH,UK. E-mail address: email@example.com
266 K Schreiber et al. Table 1 Adapted from the revised classiﬁcation criteria (Sapporo Criteria) for antiphospholipid syndrome. • Vascular thrombosis: ≥ 1 clinical episode of arterial, venous or small vessel thrombosis. Thrombosis must be objectively conﬁrmed. For histopathological conﬁrmation, thrombosis must be present without inﬂammation of the vessel wall. • Pregnancy morbidity: • ≥ 1 unexplained deaths of a morphologically normal fetus ≥ 10 weeks of gestation. • ≥ 1 premature delivery of a morphologically normal fetus < 34 weeks gestation because of: (i) severe pre-eclampsia or eclampsia deﬁned according to standard deﬁnitions. (ii) recognised features of placental insufﬁciency. • Laboratory criteria: • The presence of antiphospholipid antibodies (aPL), on two or more occasions at least 12 weeks apart and no more than ﬁve years prior to clinical manifestations, as demonstrated by ≥ 1 of the following. • Presence of lupus anticoagulant in plasma • Medium to high-titre anticardiolipin antibodies (> 40GPL or MPL, or > 99th percentile) of IgG or IgM isoforms • anti-β2 glycoprotein-I antibody (anti- β2GP I) of IgG or IgM present in plasma. APS classiﬁcation criteria. Classiﬁcation criteria for APS have recently been updated in 2006 in Sydney, but were ﬁrst proposed in 1998 (Sapporo, Japan). At least one clinical manifestation such as vascular thrombosis or pregnancy morbidity, together with positive laboratory tests, currently including LA, anticardiolipin (aCL) and anti-β2-glycoprotein I antibodies (anti-β2GPI), detected at least twice12 weeks apart, are necessary to fulﬁl the classiﬁcation criteria.and clinical phenotypes. For each subgroup we will address the current treatmentrecommendations.PATHOGENESISIn the last century, APS was mainly considered as an antibody induced thrombophilia,while 21st century view of the syndrome is wider as other important pathogenicmechanisms, such as inﬂammation, have been revealed. Antiphospholipid antibodies (aPL) represent a heterogeneous group of antibodiesdirected against negatively charged phospholipids and/or phospholipid bindingproteins, with direct or indirect pro-thrombotic effects. Amongst the variety ofthese antibodies, current classiﬁcation criteria include anti-cardiolipin (aCL) andanti-beta2GP1 (a␤2GP1), along with the lupus anticoagulant (LA) phenomenon incoagulation tests. (Table 1) APL have the ability to interact with the coagulation cascade at several stagesby directly binding to thrombin, activated Protein C, plasmin and activated factorX and thereby promote coagulation7–10 . Other target antigens include prothrombinor annexin V.11 Anti-annexin V promotes indirect procoagulant activity, as AnnexinV inhibits the activation of prothrombin and has also been shown to be of clinicalrelevance in patients with early pregnancy loss.12,13 Taking into account that thrombophilia alone does not explain all obstetriccomplications, research in recent years highlights inﬂammation as an important
Obstetric antiphospholipid syndrome - a review 267Figure 1 Pathogenesis of thrombosis in the antiphospholipid syndrome.additional mechanism. There is evidence that aPL are able to activate cells playing arole in inﬂammation, such as platelets, monocytes and endothelial cells. Activated platelets increase the expression of Glycoprotein IIb/IIIa andsubsequently the synthesis of thromboxane A2, which among other functionsfacilitates the aggregation of thrombocytes and hence plays a key-role in thrombosis. APL with a␤2GP1 activity generates activation of monocytes and endothelial cells.Endothelial cells and monocytes in turn express adhesion molecules and upregulatethe production of tissue factor, which in turn initiates the activation of the coagulationcascade.14,15 (Figure 1) Additionally, aPL complexes formed by ␤2GPI/anti-␤2GPI are able to activate theclassical and alternative pathway of the complement system. This mechanism seemsimportant and its pathogenic role in pregnancy is a ﬁeld of growing interest. It isshown that complement deﬁciency or direct inhibition of the complement systemis protective against thrombosis and pregnancy loss.16 Therapeutic agents, such as
268 K Schreiber et al.heparin, which inhibit the complement system and hence show anti-inﬂammatorycapacity in combination with an anti-thrombotic effect, may well have more than onerole in APS.17–21CLASSIFICATION/CLINICAL MANIFESTATIONSAPS is widely considered as a systemic autoimmune disease and the main acquiredthrombophilia. The syndrome is considered as ’primary antiphospholipid syndrome’(PAPS) if there is no accompanying connective disease, in particular SLE, and as‘secondary antiphospholipid syndrome’ (SAPS) if there is evidence for such. Due tothe fact that occasional patients with PAPS develop features of SLE, clinical andserological monitoring on a regular basis in these patients has been suggested.22The syndrome contains a variety of clinical manifestations, which include deep veinthrombosis and pulmonary embolism as the most frequent features.23 In contrast toother thrombophilia disorders, which mainly affect the venous vascular bed, APS alsocauses thrombosis in arterial vessels and is hence responsible for different neurologicalmanifestations such as stroke or transient ischaemic attacks. Other neurologicalfeatures include migraine headaches, memory loss and epilepsy.24 Thrombocytopenia and livedo reticularis are the most important haematologicaland dermatological characteristics, respectively, and can be found in over 20% of APSpatients. The former is usually not associated with haemorrhagic events but ratherwith thrombosis, while livedo reticularis has been associated with occlusive arterialevents.23,25–27 Pregnancy morbidity, such unexplained fetal death, premature birth before 34weeks of gestation due to severe pre-eclampsia, eclampsia or placental insufﬁciencyor recurrent early miscarriages are common features of the syndrome. Pre-eclampsia,premature birth or fetal loss are the most common manifestations and are seen in10–20% of the APS cases.23 In women suffering from RM, aPL are found in up to 20%. APS has also been associated with a broad range of cardiac manifestations, whichhowever are less common, but still can be found in 10–20% of APS patients. Theyinclude valvular disease, such as verrucus endocarditis and valvular thickening orinsufﬁciency. A similar percentage suffer occlusive arterial heart disease and aPL havebeen implicated in premature coronary artery bypass graft occlusion.28 They havebeen described as a signiﬁcant and independent risk factor for myocardial infarctionor cardiac death in young age.29,30 The more unusual clinical manifestations found in less than 10% include retinalartery or vein thrombosis, amaurosis fugax, renal thrombotic microangiopahty,pulmonary hypertension and vascular dementia. Adrenal haemorrhage, avascularnecrosis, pathological bone fractures, transverse myelitis or Budd-Chiari Syndromeare rare conditions, as they are present in less than 1% of the patients, but deserve tobe mentioned. A rare but lifethreatening condition is the catastrophic APS which canbe found in less than 1% of patients and has a mortality of over 50%.31,32 Frequentmanifestations of APS are illustrated in Table 2.33
Obstetric antiphospholipid syndrome - a review 269Table 2 Frequent clinical manifestations of APS• Venous and/or arterial thrombosis: VTE, PE, stroke, TIA, coronary artery disease, retinal artery or vein thrombosis• Obstetric: RM, stillbirth, pre-eclampsia, eclampsia, premature birth, FGR, HELLP, abruptio placentae• Thrombocytopenia• Livedo reticularis• Thrombotic microangiopathy: nephropathy, leg ulcers• Other: Heart valve disease, epilepsy, pulmonary hypertension, osteonecrosisMANAGEMENT OF DIFFERENT PHENOTYPES IN APSAsymptomatic aPL carriersAPL can be detected in 1–5% the background population, and there is an existingoverlap in a signiﬁcant number of the patients with SLE and APS; aPL are found inapproximately 30–40% of patients with SLE.23,25 APL carriers have an increased risk of developing pre-eclampsia during pregnancy.Although speciﬁc data of other poor pregnancy outcomes are currently lacking,antiplatelet therapy for the prevention of pre-eclampsia is suggested in these patients,based on observational study results.34—40Early miscarriages (<10) and recurrent early miscarriagesIn Europe the most widely used deﬁnition for early miscarriage is pregnancy losswithin the ﬁrst 12 completed weeks of pregnancy. Ten to 15% of all clinicallyrecognised pregnancies end in miscarriage.41 The fact that there is no standardised deﬁnition of early miscarriage resultsin a certain controversy regarding the frequency of APS in early RM. The lackof alignment includes among others the deﬁnition of intrauterine pregnancy, thediagnosis of intrauterine pregnancy (ultrasound or biochemical), the exclusion ofother causes of RM and the number of miscarriages required. However, most authorsin Europe consider three consecutive miscarriages before 12 gestational weeks asRM. The theoretical estimated risk of three consecutive miscarriages is 0.34%, butRM affects approximately 1% of all women and is hence greater than expected.42The most common reasons for early miscarriage and RM are genetic abnormalities,anatomic variations, cervical weakness, endocrine factors and immune factors, suchas thyroid factors, infective agents i.e. TORCH (Toxoplasmosis, Other, Rubella,Cytomegalovirus, Herpes simplex virus) and aPL.43 Among all possible causes, APS could be responsible for 2–50% of RM whereasaPL could be identiﬁed in 5–20% of RM women.44—48 Maternal age and previous
270 K Schreiber et al.number of miscarriage are two independent risk factors for further miscarriage.41,49The prevalence of aPL in women with a low risk obstetric history is less than 2%.35,50 Regarding complications, differences between the study designs hamper thecomparison and combination of the data. In a multicenter prospective cohort study of1,000 APS patients, the most frequent fetal complication was miscarriage, followed byfetal loss and premature birth, while the most common maternal manifestations werepre-eclampsia, followed by eclampsia and abruptio placentae.25,51 Of the different aPLthat have been investigated thus far, LA is shown to have the strongest associationwith early (and late) miscarriages. RM is the only area of APS for which treatment is based on several trials,including three randomised trials. Two trials, including one randomized trial, did notshow improvement in pregnancy outcome by using LDA and low molecular weightheparin (LMWH)52,53 while two randomized trials showed improvement of pregnancyoutcome by combining LDA with unfractionated heparin (UFH).54,55 The newer trialsfailed to show any beneﬁt of additional heparin treatment, but a non-consistence inAPS classiﬁcation criteria and the use of different heparin agents (LMWH and UFH)limits the direct comparison of these studies. Additionally, a meta-analysis showeda signiﬁcant reduction in pregnancy complications in women at high risk for pre-eclampsia treated with antiplatelet agents. Some observational studies also showedhigh pregnancy success rates on aspirin alone.56–58 Interestingly, Girardi et al19 were able to identify the inﬂammatory aspect of APSand showed that UFH and LMWH, which are heparins with known anti-inﬂammatoryeffects, were able to prevent aPL induced pregnancy loss. This could not be provenfor agents such as Fondaparinux or Hirudin, which do not have anti-inﬂammatoryabilities. It is important to note that this has only been proven in a murine model.19Heparin has been shown to affect aPL binding to trophoblast cells and restores normaltrophoblast invasiveness and differentiation, which is an important mechanism inpreventing pre-eclampsia.59—61 Despite obvious controversies raised by the above-mentioned trials, a Cochranesystematic review34 recommends that women with RM and APS should be treatedwith LDA and heparin, which is consistent with some expert recommendations.62However, a recent international task force group was not able to deﬁne a treatmentfor this group due to discrepancies in the literature.63 Summarising, some centres use the combination of LDA and heparin as ﬁrst linetherapy, while others prefer to start mono-therapy with LDA and add LMWH in caseof failure. Some authors using LDA and LMWH suggest discontinuing LWMH at 20weeks of gestation provided the uterine artery Doppler is normal.Late pregnancy lossLate pregnancy loss or fetal death is deﬁned as pregnancy loss after 10 weeks ofgestation, while the term stillbirth indicates a loss after 20 weeks gestation.
Obstetric antiphospholipid syndrome - a review 271 In unselected pregnancies fetal death in the 2nd or 3rd trimester of pregnancyoccurs in up to 5%. Although correlation between this condition and aPL is widelyaccepted64–66 no population-based studies have proven APS to be a cause of fetal death.However, promising data regarding this association will soon be available from theNIH founded Stillbirth Collaborative Research Network population-based study. An ideal treatment during pregnancy for women with previous fetal death has notbeen deﬁned by randomised trials yet, most experts recommend LDA and prophylacticheparin from the beginning of pregnancy. This regime has shown to result in goodpregnancy outcomes.6,34,62,63,67 Indeed, LMWH appears to reduce the recurrence ofplacental-mediated complications.67Pre-eclampsia and other pregnancy complicationsPre-eclampsia and/or placental insufﬁciency can present as fetal growth restriction(FGR) and occurs in about 5–10% of all pregnancies68 , while severe pre-eclampsia andeclampsia is found in 0.5% of pregnancies in developed countries.69 The association between aPL and these complications has not been elucidated yet70 ,although most prospective observational studies support this association.35,36,71–74A recent systematic meta-analysis showed that moderate to high levels aCL areassociated with pre-eclampsia.75 Several prospective25,76–78 and retrospective79 studies have shown that women withhigh levels of aPL and/or more than one positive aPL detected, have a higher risk ofFGR and preterm deliveries; 10–50% of them may develop pre-eclampsia, and about10% of them will present with FGR. Data from case-control studies have shown thatamong patients who previously have suffered pre-eclampsia or have delivered a FGRchild, aPL could be found in around 11–29%, compared to 7% or less in healthypregnant women.78 The association between aPL carriers and severe pre-eclampsia and placentalinsufﬁciency is still an area of controversy, mainly based on negative results of severalcase-control studies.80–82 However, patients with a diagnosis of APS have a higher riskof developing these complications in future pregnancies and the past obstetric historyis the best predictor of pregnancy outcome in these patients.78 Regarding treatment, a meta-analysis of 31 randomized trials showed that, amonghigh risk patients, LDA treatment reduced the risk of pre-eclampsia, prematurity (<34weeks) and serious adverse pregnancy outcome to 10%.83 Furthermore, in pregnanciesprogressing beyond 20 weeks’ gestation, maternal and fetal-neonatal outcomes wereclose to those found in the general population. Randomised trials do not clearly deﬁne the treatment for patients with a historyof prematurity (<34 weeks) or fetal death (>10 weeks) due to severe pre-eclampsia orplacental insufﬁciency. Nonetheless, a retrospective study shows that treatment withLDA and LMWH signiﬁcantly decreased the risk of HELLP in future pregnancies.84Taking into account that most of the studies show good pregnancy outcomes with
272 K Schreiber et al.heparin initiated in early ﬁrst trimester of pregnancy, most experts recommend LDAand LMWH as the standard treatment for these patients.6,34,62PRIMARY THROMBOPROPHYLAXISThe risk of thrombosis for asymptomatic aPL carriers is uncertain, although it seemsto be less than 2% and related to traditional vascular risk factors.85,86 According toretrospective studies, the risk of developing a thrombotic event among SLE patientswith aPL is around 3–4% per year. Likewise, between 1% and 7% of women withstrictly OAPS will develop thrombosis per year.87–90 The protective effect of LDA in patients with SLE with positive aPL, as well asin patients with OAPS has been shown in several observational studies.30,87,91—94In contrast, the authors of a prospective randomized trial concluded that LDA isineffective in preventing thrombosis in aPL asymptomatic carriers.95 However, thestudy included only 98 patients and 6 thrombotic events. Short follow-up, good controlof vascular risk factors and non-reliable patients’ immunological proﬁle are limitingfactors in this study. Taking into account the low incidence of side effects and recent data suggestingbeneﬁt in women96 , many experts agree that long term LDA should be considered asprimary thromboprophylaxis in OAPS patients63 . Consequently the same approachshould be considered in SLE patients with aPL antibodies, in combination withantimalarial agents, such as hydroxychloroquine (HCQ). Regarding asymptomatic aPL carriers prophylactic treatment should be individuallytailored. Treatment of patients with LA and/or positivity of different aPL isrecommended, as these patients are at highest risk of developing a thromboticevent.90,97–101 Classic vascular risk factors, such as smoking, hypertension, hyper-cholesterolaemia, diabetes mellitus, Body Mass Index > 30, should be conscientiouslycontrolled in all patients with aPL. Oestrogen containing oral contraceptives orhormone replacement therapy should be avoided in these patients.102 According to two recent prospective studies85,86 primary thromboprophylaxis (withheparin) in patients with aPL should be limited to high-risk situations, such as surgery,immobilisation and the puerperium.SECONDARY THROMBOPROPHYLAXISEven though inﬂammation plays an important role in APS, the current treatment forAPS patients with a previous thrombotic event is long-term anticoagulation ratherthan immunosuppression. In the case of ﬁrst venous thrombosis, secondary thromboprophylaxis with oralVitamin K antagonists (VKA), to a target INR of 2.0–3.0 is indicated. According to
Obstetric antiphospholipid syndrome - a review 273expert recommendations, patients with APS and arterial thrombosis should receiveeither VKA targeting an INR >3.0, or standard anticoagulation (INR 2.0–3.0) combinedwith antiplatelet agents. With regards to the treatment of recurrent thrombotic eventsthere is a lack of consensus21 , although intensiﬁcation of treatment, use of LMWH,HCQ and/or statins are suggested.101 Although pregnant APS patients with a previous thrombotic event (thromboticAPS) have not been included in most of the studies, LDA and therapeutic dose heparin(preferably LMWH) throughout pregnancy is recommended.62 Oral VKA should be avoided between the 6th and 10th week of gestationdue to the risk of fetal malformations during organogenesis, hence women whoreceive this treatment should switch to heparin (preferably LMWH) as soon aspregnancy is conﬁrmed. The use of VKA during pregnancy from 10–12 weeks ofgestation should be restricted to special situations (e.g. mechanic heart valve, heparinallergy/intolerance).103,104 Table 4 summarises treatment recommendations (Table 4)PREGNANCY COUNSELLING AND CONTRAINDICATIONSPreconception counselling represents the ideal scenario where patient’s previoushistory can be summarised and important issues regarding a planned pregnancy, suchas risks, visits and treatment highlighted. Patients with a suspicious obstetric history, such as RM, fetal death, pre-eclampsia,eclampsia, HELLP, prematurity or FGR, previous thrombosis, or previously diagnosedSLE, should be tested for aPL. Patients with a previous diagnosis of APS should beretested for aPL prior to pregnancy.105 All patients should be encouraged to stop smoking and to reduce/cease their alcoholintake. In certain circumstances it might be indicated to assess a haemoglobinopathyproﬁle. Patients with severe pulmonary hypertension should be advised against pregnancy,because of the high risk of deterioration of such and the risk of maternal death. Patientswith a recent thrombotic event in the last 6 months, especially arterial events, oruncontrolled hypertension should be encouraged to postpone further pregnancies.106 Ideally, prior to conception, or early in pregnancy, all women should be assessedregarding risk factors for venous thromboembolism. (Table 3). Recently, the BritishRoyal College of Obstetricians and Gynaecologists (RCOG) has published an updatedguideline for thromboprophylaxis assessment and management during pregnancy andpostpartum for the general population (Figure 2).107GENERAL MANAGEMENTLDA and heparin treatment have improved the live birth rate and reduced the riskof obstetric complications; however, these pregnancies still remain at high risk.
274 K Schreiber et al.Figure 2 Obstetric thromboprophylaxis risk assessment and management.
Obstetric antiphospholipid syndrome - a review 275Table 3 Risk factors for venous thromboembolism in pregnancyTimeframe FactorsPre-existing Previous venous thromboembolism Thrombophilia: Heritable: Antithrombin deﬁciency Protein C deﬁciency Protein S deﬁciency Factor V Leiden Prothrombin gene G20210A Acquired (antiphospholipid syndrome): Persistent lupus anticoagulant Persistent moderate/high-titre anticardiolipin antibodies or β2 glycoprotein 1 antibodies Medical comorbidities (e.g. heart or lung disease, SLE, cancer, inﬂammatory conditions (inﬂammatory bowel disease or inﬂammatory polyarthropathy), nephrotic syndrome (proteinuria > 3 g/day), sickle cell disease,36 intravenous drug user Age > 35 years Obesity (BMI > 30 kg/m2 ) either prepregnancy or in early pregnancy Parity ≥ 3 Smoking Gross varicose veins (symptomatic or above knee or with associated phlebitis, oedema/skin changes) ParaplegiaObstetric Multiple pregnancy, assisted reproductive therapy Pre-eclampsia Caesarean section Prolonged labour, mid-cavity rotational operative delivery PPH (> 1 litre) requiring transfusionNew-onset transient Surgical procedure in pregnancy or puerperium (e.g. ERPC, appendicectomy, postpartum sterilisation)Potentially reversiblea Hyperemesis, dehydration Ovarian hyperstimulation syndrome Admission or immobility (≥ 3 days’ bed rest) e.g. symphysis pubis dysfunction restricting mobility Systemic infection (requiring antibiotics or admission to hospital) e.g. pneumonia, pyelonephritis, postpartum wound infection Long-distance travel (> 4 hours)BMI = body mass index; ERPC = evacuated PPH = postpartum haemorrhage; evacuation of retainedproducts of conception; SLE = systemic lupus erythematosusa May develop at later stages in gestation than the initial risk assessment or may resolve and thereforecontinuing individual risk assessment is importantHence, APS pregnant women need close antenatal surveillance and should generallybe monitored in a multidisciplinary set-up with experience in the management of thiscondition. Early recognition of signs related to APS’ complications (either thromboticand/or obstetric) is essential to improve both maternal and fetal-neonatal outcomes.
276 K Schreiber et al. Table 4 Summary of treatment recommendations Scenario Treatment • Women with aPL but no clinical features of • Pregnancy: LDA APS, or women with aPL and recurrent early • Puerperium: prophylactic LMWH for 7 days. miscarriages (RM) (<3) • Patients with ≥ 3 consecutive RM (< 10 • Pregnancy: LDA +/- prophylactic LMWH (if so, weeks) but no thrombotic events stop at 20w if uterine artery Doppler normal) • Puerperium: prophylactic LMWH for 7 days. • Women with adverse obstetric outcomes • Pregnancy: LDA + prophylactic LMWH (late pregnancy losses, early onset • Puerperium: prophylactic LMWH for 7 days. pre-eclampsia, HELLP, previous FGR, preterm delivery) and no thrombotic event • Women with thrombotic APS and treated with • Pregnancy: LDA + therapeutic LMWH long-term VKA • Puerperium: switch to VKA • Women with APS and acute thrombotic event • Pregnancy: LDA + high therapeutic LMWH during pregnancy • Puerperium: switch to VKA Standard of care includes early contact with a midwife and with the medicaland obstetric team who will monitor the patient throughout pregnancy and thepuerperium. The frequency of antenatal visits should be dependent on the past historyand the progress of the current pregnancy; consequently complicated medical orobstetric background will imply more frequent visits. As a guide, from 16 weeks to 32weeks of gestation women should usually be reviewed every 4 weeks, and fortnightlyfrom 32–36 weeks of gestation. Every visit should include maternal assessment, withspecial attention to proteinuria, maternal hypertension and other features of pre-eclampsia, as well as obstetric ultrasound assessment, in order to rule out impairmentof fetal growth/development and/or other signs of placental insufﬁciency. Uterine and umbilical artery Doppler scans after 20 weeks of gestation are standardof care in these patients, due to their high negative predictive value and theirability to assess the risk of poor obstetric outcome (pre-eclampsia, FGR and placentalinsufﬁciency)108 . If the uterine artery Doppler around the 20th week of gestation isabnormal, it should be conﬁrmed around the 24th week, and subsequent umbilicalartery Doppler should be carried out with each growth scan.POSTPARTUMAs mentioned above, all women with aPL should receive thromboprophylaxis duringthe postpartum period62,63 , although its duration is still an area of controversy. TheBritish RCOG suggest in their recent guidelines prophylactic LMWH for 7 days for aPLhealthy carriers as well as for OAPS patients, in the absence of other risk factors.107Previous American guidelines recommend prolonging prophylactic treatment for 4–8weeks after delivery.62
Obstetric antiphospholipid syndrome - a review 277 Women with previous thrombosis should receive long-term anticoagulation, andshould be switched to VKA when the risk of haemorrhages is low (usually 5–7 daysafter delivery). VKA and heparin are safe in breastfeeding.103 Additional obstetricthromboprophylaxis risk assessment postpartum is implicit (Figure 2).‘REFRACTORY’ OAPSThe best approach to OAPS patients who have failed to have a successful pregnancy onLDA and heparin (‘refractory OAPS’) is still uncertain. Although further assessment isneeded, recent data suggest that the additional treatment with low dose prednisoloneduring the ﬁrst trimester109,110 and/or with HCQ111 might be beneﬁcial. Additionaltreatment with high doses of steroids increases the risk of maternal morbidity (e.g.diabetes, hypertension, infections, preterm delivery) without any further beneﬁt topregnancy outcomes.112 The role of anti-TNF-␣ drugs in these cases is still not known. Recent data from anAPS murine model have indicated the key importance of TNF-␣ in fetal loss, togetherwith complement activation.113 Safety-wise, a recent systematic review suggests thatsome anti-TNF-␣ are safe in pregnancy114 although it remains as a class B drug in FDAclassiﬁcation. IVIG was proposed as a possible rescue treatment by some authors, butdata from 3 trials have shown no beneﬁt in obstetric or fetal-neonatal outcomes.115–117OTHER IMPORTANT ISSUESWomen receiving therapeutic doses of LMWH should discontinue it or swapto prophylactic doses 24 hours prior to the planned delivery. Women onprophylactic doses of LMWH should not continue LMWH once labour is established.Reestablishment of LMWH should be postponed until the placenta is delivered. Epidural anaesthesia can be safely used 24 hours after the last dose of LMWH(therapeutic dose), or 12 hours after the last dose of LMWH in prophylactic doses.LMWH can be restarted 2 hours after the epidural catheter has been removed.118,119 LDA should be continued throughout pregnancy. There is no evidence todiscontinue LDA treatment before labour or due to planned epidural anaesthesia,as LDA does not signiﬁcantly increase the risk for spinal haematoma. However, manyanaesthesiologists would recommend withdrawal of LDA 3–7 days prior to labour.118 Albeit data are scarce, 1st and 2nd trimesters of pregnancy and lactation areconsidered as high bone resorption periods and hence calcium demands areincreased.120,121 Nevertheless, clinically signiﬁcant bone mass loss is infrequent, andusually related to classical risk factors such as genetic background, smoking, lack ofregular exercise, BMI<19, low calcium diet and/or vitamin D deﬁciency. The association between bone mass loss during pregnancy and LMWH isuncertain, and no controlled trials have addressed this question yet. The incidence ofunfractionated heparin induced osteoporosis in pregnancy is around 2.2–5%.122,123However, a recent systematic review suggests that LMWH does not have a
278 K Schreiber et al.negative impact on bone mineral density compared to physiological pregnancy boneresorption.124 Surprisingly, LMWH-induced osteoporosis has only been evaluated inpregnancy, which hampers the comparison to non-pregnant situations. Taking into account the beneﬁcial effects of LMWH in APS patients, its usein APS is more than justiﬁed when indicated. Concomitant prophylactic calciumsupplements (with or without Vitamin D) in order to prevent LMWH’s theoreticalosteoporotic effect is a logical and generalized practice. Bearing in mind that a recent meta-analysis of 13 randomized trials comparing theintake of at least 1g of calcium daily versus placebo during pregnancy showed a >50%reduction in the risk of preeclampsia and a 25% reduction in the risk of pretermdelivery, calcium supplementation becomes a cornerstone of management in thesepatients.FUTURE PERSPECTIVE AND FUTURE THERAPIESSince the ﬁrst description of the disease extensive interest and research has improvedthe basic understanding, diagnosis and treatment of patients with APS. Futureresearch needs to focus on the investigation of new therapies, the re-deﬁnition ofthe classiﬁcation criteria, novel pregnancy outcome markers or research in patientscurrently labeled as seronegative APS. New therapeutic agents for the treatment of APS are widely discussed. Aspreviously discussed antiplatelet agents, mostly aspirin, different heparin types orcoumadin derivates are used for the treatment of obstetric complications or assecondary thromboprophylaxis. Other anti-aggregation agents such as dipyridamoleor clopidogrel in combination with aspirin are widely used in patients suffering artrialﬁbrillation or stroke. The combination of these agents has been shown to be moreefﬁcient than mono-therapeutic aspirin in selected patient groups126–127 , and could bean alternative for patients with contraindications for VKA. Though, at present, thereis only limited evidence for the use of antiplatelet agents other than aspirin in patientssuffering APS. Novel agents such as rivaroxaban or dabigatran are currently licensed for primarythromboprophylaxis. Dabigatran, an oral direct thrombin inhibitor, administeredat a dose of 150 mg has been shown to be more effective than warfarin in theprevention of stroke and systemic thrombotic events, while the incidence rate ofmajor haemorrhages was similar. The study was conducted on patients with atrialﬁbrillation.128 Its efﬁcacy in the secondary prevention of thromboembolism is similarto warfarin when administered at a dose 150 mg twice daily.129 These drugs display anenormous advantage compared to warfarin treatment, not only regarding warfarin’sslow onset of action, its very narrow therapeutic window and its numerous dietary anddrug interactions, but also its socio-economic impact and/or resource implications.However, due to insufﬁcient experience this new generation of anticoagulants willnot be licensed for the use in pregnancy and/or lactation immediately.
Obstetric antiphospholipid syndrome - a review 279 Of particular interest is the antimalarial agent HCQ, which has been used in SLEfor many years. HCQ displays a broad spectrum of beneﬁcial effects and is henceconsidered as a cornerstone in the treatment of SLE. Given its safety proﬁle, HCQis given to most SLE patients and should be continued during pregnancy.130 Studiessuggest a positive effect of HCQ in APS.91,131 However, randomised clinical trials areneeded to conﬁrm this beneﬁt. The anti-inﬂammatory effect of statins, is the logical reasoning why theseagents are discussed as adjuvant treatment. Fluvastatin for example has anti-thrombogenic and anti-inﬂammatory properties132 and has recently been shownto reduce vascular endothelial growth factor, serum tissue factor and TNF-␣signiﬁcantly.133 Additionally, different types of statins have been shown to havepositive effects on serum activity of markers involved in pre-eclampsia in a murinemodel134,135 . The current StAmp trial will hopefully prove the role of statins duringpregnancy and determine effects on pregnancy outcomes. Rituximab is a monoclonal antibody targeting CD-20 positive B-lymphocytes.Speculations about the role of Rituximab in APS is a consequence of the fact thatB-cells are involved in the pathogenesis of the syndrome136,137 . The RITAPS study isunderway to elucidate the drug’s safety and effectiveness in persistently aPL positivepatients. Other agents, such as anti-TNF-␣ therapy, have been suggested, as it hasbeen hypothesised that TNF-alpha plays a role in the pathophysiology of APS inducedthromboses.138 However, a possible clinical usefulness has still to be proved and asfar as safety is concerned, the lack of experience in the use of biological agents duringpregnancy is a major limiting factor.139 In parallel with current research that focuses on the achievement of a bettermechanistic understanding regarding the patho-mechanism of APS, future therapiesmight be targeted on anti-inﬂammatory and/or immunomodulatory aspects. Thismight amongst others include targets such as the complement system, tissue factoractivation or the inhibition of speciﬁc platelet glycoproteins.140 ACKNOWLEDGEMENTKaren Schreiber has been supported by ESF BIOLUPUS - European ScienceFoundation.REFERENCES 1 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, et al. Anticardiolipin antibodies: detection by radioimmuneoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 26: 1211–214. 2 Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update to the classiﬁcation criteria for deﬁnite antiphospholipid syndrome. J Thromb Haemost 2006; 4: 295–306. 3 Cervera R, Abarca-Costalago M, Abramovicz D, Allegri F, Annunziata P, Aydintug AO et al; Lessons from the ’Euro-Lupus Cohort’. Ann Med Interne (Paris) 2002; 153: 530–36. 4 Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010; 376: 631–44.
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