Antiphospholipid syndrome in pregnancy

Figures & data

Table 1. Summary of recommended tests for women with antiphospholipid syndrome prior to and during pregnancy.

Indications	Recommended tests	Ref.
For SLE disease activity	ANAs, anti-dsDNA, ENAs (especially Ro and La antibodies), complement levels SLEDAI or any other scoring system the hospital uses for determining SLE activity (usually performed by a rheumatologist)	[70,73,77,81,82]
For those with current/previous nephritis	Urine should be dipsticked for proteinuria at each visit Urine PCR and a 24-h quantification for proteinuria should be performed at baseline Check full blood count, liver and renal function at baseline	[83,84]
Early dating scan and scans for congenital abnormalities and markers of chromosomal abnormalities	Accurate dating scans essential to determine dates from an early stage as risk of FGR Check for fetal malformations, especially if the woman is on multiple medications that are potentially teratogenic such as warfarin, mycophonolate mofetil, and so on	[85–87]
For pregnancy-induced hypertension or preeclampsia	At each antenatal visit, women should be screened for symptoms of preeclampsia, have their BP checked and urine dipsticked for proteinuria Clinicians should have a low threshold for initiating investigations for presumed preeclampsia/HELLP syndrome Flares of SLE may be difficult to distinguish from preeclampsia, but low complement and elevated anti-dsDNA suggest SLE flare	[56,83,88]
For FGR	Uterine artery waveforms at 20–22 weeks gestation. Those with notched waveforms will require closer surveillance for FGR Doppler flow of the umbilical artery (for those with FGR): absent or reversal of end-diastolic flow is indicative of poor fetal outcomes Serial measurement of fetal growth, weight and amniotic fluid measurements Fetal biophysical profile	[75,78,89–91]

ANA: Antinuclear antibody; BP: Blood pressure; ENA: Extractable nuclear antigen; FGR: Fetal growth restriction; HELLP: Hemolysis, elevated liver enzymes and low platelets; SLE: Systemic lupus erythematosus; SLEDAI: SLE disease activity index.

Table 2. Brief overview of the drugs and other therapies used in antiphospholipid syndrome pregnancy.

Drug	Use	Evidence	Safety in pregnancy	Safety in breastfeeding
Aspirin 75–100 mg daily from conception until ∼36 weeks gestation	Antiplatelet effect Reduction of fetal loss Prevention of preeclampsia	No controlled trials of aspirin for the prevention of VTE. However, there is evidence for aspirin use in improving pregnancy outcomes, particularly in the prevention of preeclampsia [32,33,74,75,92]	Will cross the placenta, but low doses have not been shown to cause fetal harm	Very low doses excreted in breast milk, and at low doses should be safe
Warfarin to be discontinued as soon as pregnancy is confirmed	Its use is not recommended in pregnancy unless risk of thrombosis is exceptionally high, such as in recurrent cerebral thrombotic events [53,93] Can be used postpartum as thromboprophylaxis	Teratogenic between 6 and 12 weeks of gestation Recommended that this is changed to LMWH at confirmation of intrauterine pregnancy	Teratogenic In general, fetal effects are dose dependent, and doses >5 mg daily are associated with increased risk [94] However, the genetic makeup of the mother and fetus can affect dose response, hence warfarin is best avoided if possible [95]	Does not enter breast milk
UH	Similar to that of LMWH May be used when therapeutic doses of anticoagulation are required in massive pulmonary embolism, or rapid reversal of anticoagulation may be needed peripartum or during operative procedures	Most of the studies using UH have since been superseded by studies using LMWH (as discussed in the next row)	Safe in pregnancy as it does not cross the placenta	Does not enter breast milk
LMWH can be started at confirmation of pregnancy	The drug of choice for women established on warfarin, or women who have had thrombosis during pregnancy or previous arterial thrombosis, women with previous late pregnancy complications, women who are immobile in hospital, and women who require thromboprophylaxis	Evidence for its role in preventing first-trimester fetal loss is controversial [31,93,96]	Does not cross the placenta	Has a high molecular weight, thereby reducing risk of excretion in breast milk. If consumed, will be broken down in the infant’s GI tract
Glucocorticoids (e.g., prednisone)	Little evidence for therapeutic benefit in APS However, it is used in immune thrombocytopenia associated with APS or coexistent active SLE	Little evidence of therapeutic benefit in obstetric APS [30,37,42,92,97,98] Any benefit is outweighed by its adverse effects (e.g., development of gestational diabetes, preeclampsia, increased risk of infections and preterm deliveries)	Low serum concentrations in the fetus Adverse events have been reported when massive doses used. Cleft palate has been reported in first-trimester use	Found in low concentrations in breast milk with no adverse events reported
HCQ	Most often used when woman has concurrent SLE It has a mild anti-thrombotic effect [99,100] Used in women with Ro and La antibodies	Cessation of HCQ may trigger flares of SLE in women [101,102] Anti-thrombotic effects are mild and do not replace conventional anticoagulation in women who need it [103–105] Case-controlled studies show reduced incidence of congenital heart block in women on HCQ [106]	No reports of fetal toxicity Benefits of disease control (particularly for SLE) outweigh any potential risks [107]	Considered safe despite excretion in breast milk [108]
Intravenous immunoglobulins	Used in a small number of women with APS as salvage therapy for refractory disease Also used to treat idiopathic thrombocytopenic purpura related to APS	No evidence of additional benefit when added to conventional therapy with aspirin and heparin [109,110] When added to conventional therapy (aspirin and heparin) in women with FGR after late second trimester, there is a temporary improvement of uteroplacental Doppler waveforms [111]	Will cross the placenta after 30 weeks of gestation	Excretion in breast milk is unknown
Plasmapheresis	Usually reserved for the treatment of catastrophic APS Able to rapidly remove clotting factors, cytokines and other pathogenic products	Evidence is limited to case reports [112,113]	Rarely used in pregnancy, small literature base limited to case reports [114–117]	Probably safe

APS: Antiphospholipid syndrome; FGR: Fetal growth restriction; HCQ: Hydroxychloroquine; LMWH: Low-molecular-weight heparin; SLE: Systemic lupus erythematosus; UH: Unfractionated heparin; VTE: Venous thromboembolism.

Table 3. Summary of various therapeutic interventions involving women with recurrent early pregnancy losses and antiphospholipid antibodies.

Study (year)	Intervention	Additional comments	Women (n)	ASA (n received ASA only)	UH (n)	LMWH (n)	Other (n)	LB (%)		Conclusions or comments	Ref.
								ASA alone	ASA + UH/LMWH
Cowchock et al. (1992)	ASA + UH vs ASA + prednisone 40 mg/day		20	Yes ^†All received ASA	Yes (12)		Yes Prednisone (8)	ASA + prednisone 75	75	Those on prednisone had higher rates of complications	[30]
Kutteh (1996)	ASA vs ASA + UH	Those with LA were excluded	50	Yes (25)	Yes (25)			44	80		[34]
Rai et al. (1997)	ASA vs ASA + UH	aCL-positive if IgG >5 GPL or IgM >3 MPL or LA-positive based on RVVT	90	Yes (45)	Yes (45)			42	71		[31]
Pattison et al. (2000)	ASA vs placebo	Only placebo-controlled trial. aCL-positive if IgG ≥5 GPL, IgM ≥5 MPL	40	Yes (20)				80	Placebo LB rate was 85	Addition of ASA is the same as best supportive care	[32]
Farquharson et al. (2002)	ASA vs ASA + LMWH	aCL positive IgG >9 GPL, IgM >5 MPL	98	Yes (47)		Yes (51)		72	78	High LB achieved with ASA alone	[33]
Franklin et al. (2002)	ASA vs ASA + UH	Complex definition of positive aPL^†. Both groups (group 1 and 2) received ASA + UH and group 3 received only ASA	79	Yes (26)	Yes (53)	–		46	ASA + UH – Group 1: 76; Group 2: 64	Study concluded that other aPLs may be associated with pregnancy loss	[129]
Stephenson et al. (2004)	ASA + LMWH vs ASA + UH	All medications were started preconceptually	26	Yes ^†All received ASA	Yes (13)	Yes (13)			ASA + LMWH 69 ASA + UH 31	Pilot study comparing UH with LMWH	[35]
Noble et al. (2005)	ASA + LMWH vs ASA + UH		50	Yes ^†All received ASA	Yes (25)	Yes (25)			ASA + LMWH 84 ASA + UH 80	No statistically different LB rates between both arms	[36]
Goel et al. (2006)	ASA vs ASA + UH	Only women with APS and high-positive IgG aCL were included in this study	72	Yes (39)	Yes (33)			61.5	84.8	Birthweight with UH was 3.21 ± 0.33 kg vs only 2.77 ± 0.14 kg	[128]
Laskin et al. (2009)	ASA vs ASA + LMWH	Study included women with RPL and either one of the following: aPL, an inherited thrombophilia or ANA. aPL was present in 47.7% of women in each group	88	Yes (43)		Yes (45)		79.1	77.8	Addition of LMWH to ASA may not confer additional benefit	[100]

^†Positive aPL defined as either positive to aCL, phosphatidyl serine ± or LA (group 1), or positive to phosphatidyl inositol, phosphatidyl glycerol ± phosphatidyl ethanolamine (Group 2).

aCL: Anticardiolipin antibody; ANA: Antinuclear antibody; aPL: Antiphosphloipid antibody; APS: Antiphospholipid syndrome; ASA: Aspirin; LB: Live birth; LMWH: Low-molecular-weight heparin; RPL: Recurrent pregnancy loss; UH: Unfractionated heparin.

Table 4. Summary of potential clinical scenarios, and suggested management guidelines and supporting evidence.

Clinical scenario	Therapeutic options in pregnancy (and the evidence)		Need for postpartum thromboprophylaxis/anticoagulation
	Aspirin	Heparin or LMWH
Women with aPL but no clinical features of APS	Yes^†	No ^†Only antenatal surveillance is required	Yes – for 1 week only of thromboprophylaxis, unless additional risk factors present [201]
Women with recurrent early pregnancy losses but no VTE (obstetric APS)	Yes [31,33,34]^†	No [33,32,96] More recent publications appear to indicate that LMWH was of little benefit when added to aspirin. Hence, LMWH should not be routinely started in this group. If it is used it should be stopped at 12 weeks or at 20 weeks if the uterine artery Doppler scan is normal Evidence to support the use of LMWH is based on older studies [31,34]	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present [126,201]
Women with adverse obstetric outcomes (late pregnancy losses, early-onset preeclampsia, HELLP syndrome, previous FGR, preterm delivery <34 weeks) but no VTE (obstetric APS)	Yes	Yes [93,130] Prophylactic doses of LMWH suggested based on expert opinion and nonrandomized studies. LMWH appears to reduce the recurrence of placental-mediated complications. Specific randomized control trial data are not available	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present
Women with thrombotic APS and on long-term anticoagulation with warfarin	Yes	Yes Swap from warfarin to LMWH immediately on confirmation of intrauterine pregnancy Intensity of anticoagulation debated, with some groups advocating the use of high-dose prophylactic regimen and others suggesting full therapeutic doses of LMWH [93,53,131]. Two studies have attempted to risk stratify VTE risks in pregnancy and set up guidelines for intensity of anticoagulation treatment. Studies were not specific to women with APS alone [132,133]	Yes. They can be swapped back to warfarin after delivery
Women with thrombotic APS who are experiencing recurrent thrombosis in pregnancy, despite high-dose prophylactic LMWH	Yes	Yes Swap to therapeutic doses of LMWH on confirmation of intrauterine pregnancy If high-risk women such as those with arterial thrombosis, cerebral thrombotic events, and so on, warfarin could be cautiously restarted after the first trimester [93]	Yes. Warfarin to be restarted
Women with thrombotic APS but not anticoagulated prepregnancy	Yes	Yes High-dose prophylactic LMWH suggested [201]	Need for anticoagulation should be reviewed postpartum and long-term anticoagulation should be considered
Women with aPLs and RPL (<three), but who do not fulfill the criteria for APS	No	No Evidence for the use of aspirin and heparin in this group is extrapolated from studies on women with APS and RPL [31,34], although two very recently published randomized controlled trials have not demonstrated any benefit over placebo [122,123]	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present (see guideline on obstetric APS) [201]
Women with aPL undergoing IVF	Yes [136]	No [137] However, if the woman is admitted with complications of IVF (e.g., ovarian hyperstimulation syndrome, and so on) and is bed bound, then prophylactic doses of LMWH should be given	Yes Only 1 week of thromboprophylaxis, unless additional risk factors present [201]

^†There is no evidence to support the use of aspirin for VTE prevention in pregnant women. Its use in improving obstetric outcomes in women with APS is controversial. However, there is good evidence to support its use in the prevention of preeclampsia [74]. For this reason, the Royal College of Obstetricians and Gynaecologists recommends that all women with APS be started on aspirin [201].

aPL: Antiphospholipid antibody; APS: Antiphospholipid syndrome; FGR: Fetal growth restriction; HELLP: Hemolysis, elevated liver enzymes and low platelets; LMWH: Low-molecular-weight heparin; RPL: Recurrent pregnancy loss; VTE: Venous thromboembolism.

Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J. Am. Coll. Cardiol.33(6), 1637–1641 (1999).

 PubMed Web of Science ®Google Scholar

Sadler L, McCowan L, White H, Stewart A, Bracken M, North R. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG107(2), 245–253 (2000).

 PubMed Web of Science ®Google Scholar

Izmirly PM, Kim MY, Llanos C et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann. Rheum. Dis.69(10), 1827–1830 (2010).

 PubMed Web of Science ®Google Scholar

Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr. Rheumatol. Online J.7, 9 (2009).

 PubMed Web of Science ®Google Scholar

Motta M, Tincani A, Faden D et al. Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J. Perinatol.25(2), 86–89 (2005).

 PubMedGoogle Scholar

Somerset DA, Raine-Fenning N, Gordon C, Weaver JB, Kilby MD. Intravenous immunoglobulin therapy in compromised pregnancies associated with antiphospholipid antibodies and systemic lupus erythematosus. Eur. J. Obstet. Gynecol. Reprod. Biol.79(2), 227–229 (1998).

 PubMed Web of Science ®Google Scholar

Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol.166(5), 1318–1323 (1992).

 PubMed Web of Science ®Google Scholar

Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am. J. Obstet. Gynecol.174(5), 1584–1589 (1996).

 PubMed Web of Science ®Google Scholar

Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br. Med. J.314(7076), 253–257 (1997).

 PubMed Web of Science ®Google Scholar

Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am. J. Obstet. Gynecol.183(4), 1008–1012 (2000).

 PubMed Web of Science ®Google Scholar

Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet. Gynecol.100(3), 408–413 (2002).

 PubMed Web of Science ®Google Scholar

Franklin RD, Kutteh WH. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population. Hum. Reprod.17(11), 2981–2985 (2002).

 PubMed Web of Science ®Google Scholar

Stephenson MD, Ballem PJ, Tsang P et al. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J. Obstet. Gynaecol. Can.26(8), 729–734 (2004).

 PubMedGoogle Scholar

Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin. Fertil. Steril.83(3), 684–690 (2005).

 PubMed Web of Science ®Google Scholar

Goel N, Tuli A, Choudhry R. The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies. Med. Sci. Monit.12(3), CR132–CR136 (2006).

 PubMed Web of Science ®Google Scholar

Espinola RG, Pierangeli SS, Gharavi AE, Harris EN. Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb. Haemost.87(3), 518–522 (2002).

 PubMed Web of Science ®Google Scholar

RCOG. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-Top Guidelines No. 37, 1–35 (2009) www.rcog.org.uk/womens-health/clinical-guidance/reducing-risk-of-thrombosis-greentop37

 Google Scholar

Stone S, Hunt BJ, Khamashta MA, Bewley SJ, Nelson-Piercy C. Primary antiphospholipid syndrome in pregnancy: an analysis of outcome in a cohort of 33 women treated with a rigorous protocol. J. Thromb. Haemost.3(2), 243–245 (2005).

 Google Scholar

Erkhan D, Patel S, Nuzzo M et al. Management of the controversial aspects of antiphospholipid syndrome pregnancies: a guide for clinicians and researchers. Rheumatology (Oxford)47, iii23–iii27 (2008).

 Google Scholar

Stern C, Chamley L, Norris H, Hale L, Baker HW. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil. Steril.80(2), 376–383 (2003).

 PubMed Web of Science ®Google Scholar

Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst. Rev.2, CD004659 (2007).

 PubMed Web of Science ®Google Scholar