Thromboprophylaxis for PlacentalComplications: Perspectives in 2015

Nadine Sauvé, MDCanadian Society of Internal MedicineOctober 2015

No conflict of interest to declare

Objectives• After the conference, the participant will be able to:

• Use appropriate thrombophilia work-up for women at risk of placental complications.

• Identify women that could benefit from thromboprophylaxis to prevent placental complications.

Synopsis• Pathophysiology

• Thrombophilia screening

• Pre-eclampsia, late intrauterine fetal death, intrauterine growth restriction/small for gestational age, placental abruption• Role for LMWH? Role for ASA?

• Early recurrent pregnancy loss• Role for LMWH? Role for ASA?

• Conclusion: • Guidelines• What I am doing at present…

Pathophysiology

Pathophysiology• ASA and LMWH: antithrombotics, mitigation of

trophoblastic apoptosis.• LMWH: complement inhibitors.

• Before initiating these mesures, we must eliminate all other causes:• Maternal anatomy• Chromosomal• Fetal malformation • Infection in utero• Fetomaternal hemorrhage• Platelet alloimmunisation, erythroblastosis fetalis (Rh-negative)• Metabolic disorders (diabetes, thyroid dysfunction, etc.)• Other

Thrombophilias

Screening for thrombophilia• Prospective and retrospective studies: ACCP 2012

Screening for thrombophilia• Prospective studies only

Thrombophilia Earlyrecurrent fetal loss

Late intrauterine fetal death

Pre-eclampsia Placental abruption

IUGR

FVL heterozygous+ ? - - - -

Prothrombin mutation heterozygous - - - - -

Antithrombin III deficiencyNA - - - NA

Protein C deficiency NA - - - NA

Protein S deficiency NA + ? - - NA

APL + + ? + +? +?

Legend: NA, non applicable; +, association; ?+, weak association; -, no association.

Adapted from Mahone, Sauvé. CJGIM 2014.

ACCP 2012 GuidelinesComplications APL APL: my opinion Hereditary TP

≥3 early fetal loss(<10 weeks)

YES (1-B) YES NO (2-C)

Late intrauterine fetal death

? YES (> 20 weeks) NO (2-C)

Preeclampsia ? YES (< 340 weeks) NO (2-C)

Spontaneous placentalabruption

? YES (< 340 weeks or if causing IUFD)

NO (2-C)

Small for gestational age

? YES (< 5th percentile) NO (2-C)

Placental complications

Placental complications (excluding recurrent early fetal loss)

• Pre-eclampsia (PE)• Late intrauterine fetal death (IUFD)• Placental abruption• Intrauterine growth restriction (IUGR) or Small for

gestational age (SGA)

• Prevalence: 1/6 pregnancies

Placental complications (excluding recurrent early fetal loss)

• Risk of recurrence:• Severe pre-eclampsia: 25-65%• Placental abruption: 3%• Small for gestational age < 10th percentile: 10%

• Risk of combined outcomes or different placental complication in a next pregnancy

Rodger MA. Blood 2014; 123(6):822-828)

Approved preventive treatments• PE: ASA (1-A)

• PARIS1: ↓ PE 10%, ↓ births < 34 weeks 10%, ↓ serious complications 10%

• Roberge2: • ASA <16 weeks: ↓ RR PE 53%, severe PE 82%,

perinatal mortality 59%, prematurity 65%, IUGR 54%

• ASA >16 weeks: ↓ PE 22%, ↓ prematurity 10%

• PE: Calcium 1g / d if daily intake is insufficient (<600 mg/j) (1-A)

1. Askie et al. Lancet 2007;369(9575):1791-1798.2. Roberge et al. Ultras Obstet Gynecol 2013;41:491-499.

Cochrane 2012

• 10 studies (n=1139) of which 9 compared heparin (alone, with ASA or with dipyridamole) to placebo

• Quality: average to good

• Very heterogeneous; those not included in Rodger: • Patients with nephropathy (Kincaid-Smith)• Patients with ongoing IUGR or PE (Yu x2)• Biomarkers/placental morphology/abnormal Doppler < 24 weeks

(Kingdom)

Cochrane 2012Clinical outcome

Number of studies

N Relative risk 95% CI

Perinatal mortality

6 653 0.40 0.20-0.78

Prematurity < 34 weeks

3 494 0.46 0.29-0.73

Prematurity< 37 weeks

5 621 0.72 0.58-0.90

Small for gestational age < 10th

percentile

7 710 0.41 0.27-0.61

Apgar < 7 at 6 minutes

3 260 0.42 0.29-0.60

Rodger MA.Blood 2014;123(6): 822-828

• 6 randomized controlled trials (RCT) n=854• Does not include TIPPS

• More than 40% come from a single centre (Gris, Nîmes).• Inclusion criteria:

• Pre-eclampsia: 70% (68% of these severe or early, so 32% non-severe).

• Placental abruption: 45%• Small for gestational age < 10th percentile: 37%• Intrauterine fetal death > 12 weeks: 27%

• 25% with thrombophilia• With ASA: 52%

StudiesCentre/ quality

# Inclusion criteria Thrombo-philias

Interventions Outcomes NNT

Mello et al. 2005 16

Single/ Poor

80 PE and ACE genotype GG

Excluded Dalteparin 5000 U vs. no Dalteparin

PE, SGA < 10th perc.7.3% vs. 28.2 %

5

Rey et al. 2009

+/-Multi/ average

116 Severe PE < 34 6 weeks (52%), SGA < 5th perc.

(18%), placentalabruption (14%), IUFD >

12 weeks (15%)

Excluded Dalteparin 5000 U +/- ASA vs. +/-

ASA(ASA used >80%)

PE, SGA <5th perc., placental abruption ,

stillbirth5.5% vs. 23.6%

5

NOH-AP2010

Single/ average

160 Placental abruption (44% with PE)

Allowed (16% +)

Enoxaparin 40 mg +/- ASA (19%) vs.

+/- ASA (41%)

PE, SGA <5th perc., placental abruption,

stillbirth12% vs. 31.3%

5

NOH-PE 2011

Single/ average

224 Severe PE60% > 34 weeks 40% < 34 weeks

17% HELLP

Allowed (14% +)

Enoxaparin 40 mg + ASA vs. ASA

PE, SGA <5th perc., placental abruption,

stillbirth8.9% vs. 25 %

7

FRUIT-RCT 2012

Multi/ good

139 Before 340 weeks:Severe PE (77%) and/or SGA< 10th perc. (68%)

Inclusion criteria

Dalteparin 5000 U + ASA vs. ASA

PE 18.6% vs. 21.7%

PE < 34 weeks0% vs. 8.7% 12

HAPPY2012

Multi/ very good

135 IUFD > 15 weeks (36%), PE (30%), SGA < 10th

perc. (21%), placentalabruption (4%)

Allowed(10% +)

Nadroparine 3800 IU vs. no

Nadroparine

PE, LBW <10th perc., placental abruption,

IUFD >15 weeks21% vs. 18%

Halted early for

futility

Rodger MA et al. Blood 2014;123(6):822-828)

StudyCentre/ quality

# Inclusion criteria Thrombo-philias

Interventions Outcomes

TIPPS2014

Multi/ Good

292 Placental complications or risk of thromboembolism

Inclusion criteria

Dalteparin 5000 die 5000 BID

vs. no Daltep.

All negative

Rodger. Lancet 2014;384(8): 1673-1683.

AN EXTRA WORD ON LATE INTRAUTERINE FETAL DEATH…

Late intrauterine fetal death > 10 weeks

• Theory: • At around 10 weeks, the placenta takes over from the yolk sac to ensure embryonic infusion.

• If pathophysiology is placental inflammation/thrombosis, it will occur > 10 weeks.

Late IUFD > 10 weeks• 1 RCT: Gris, Blood 2004; 103:3695-3699.

• NOH: Nîmes Obstetricians and Haematologists studies• N=160 (184 eligibles:174 accepted, 12 spontaneous abortions T1)• Heterozygous Factor V Leiden or prothrombin gene mutation or

protein S deficiency• 1 intrauterine fetal death > 10 weeks

• N=96 60% (10-16 weeks)• N= 50 31% (16-22 weeks)• N= 14 9% (> 22 weeks)

• Exclusion: any etiology (infection, congenital defect or maternal anatomic anomaly, APL, chromosomal anomaly, PE, trauma, diabetes, thyroid, ITP, platelet alloimmunisation, etc.)

• ASA 100 mg vs. Enoxaparine 40 mg s/c from 8 weeks

Live births: 23 (29%) vs. 69 (86%) ↓ small for gestational age in Enoxaparine group (3043g vs. 2742g)

Gris et al. Blood 2004; 103:3695-99.

Conclusion: late intrauterine fetal death

Author Gestational age

% TP Number of patients

Outcomes specific to sub-group

Rey > 12 weeks 0 % 17 Unknown

Martinelli(HAPPY)

> 15 weeks 10% 49 Unknown

Gris 2004 > 10 weeks 100% 160 Questionable

Various studies: recurrent fetal loss

> 10 weeks Majority without

thrombophilia

? Unknown

Conclusion: placental complicationsOutcomes Relative risk CI 95%

Severe composite 0.37 0.25-0.55

Non-severe composite 0.80 0.44-1.46

Severe PE 0.16 0.07-0.36

Non-severe PE 0.46 0.28-0.75

Delivery <34 weeks 0.45 0.30-0.69

Delivery <37 weeks 0.77 0.62-0.96

Fetal death > 20 weeks 0.41 0.17-1.02

Fetal death < 20 weeks 0.89 0.50-1.6

Rodger MA. Blood 2014 et Lancet 2014.

Conclusions: placental complications• HAPPY (Martinelli) negative because …

• Majority (36%) included in fetal deaths > 15 weeks?• Inclusion of non-severe PE? (severity unknown in 38% of PE, early

onset not in inclusion criteria) • Stopped early?• 37% previous normal pregnancies?

• TIPPS (Rodger) negative because…• Inclusion criteria large/heterogeneous and often low risk

Recurrent early fetal loss

Prevalence

• 1 early fetal loss: 15%• 2 early fetal loss: 3-5%• 3 early fetal loss: 1-2%

Study summaryStudy Inclusion n Intervention Control Thrombo-

philiaResults Comment

Dolitsky, 2006

T1 ≥ 3T2 ≥ 2

107 Enoxaparine40 sc die

ASA 100 mg die

- 18.5% vs. 16%RR 1.16 (0.5-2.7)

Good quality

Badawy2008

T1 ≥ 3 350 Enoxaparine20 mg sc die

- - 5.3% vs. 11.2%RR 0.47 (0.22-1.02)

Many methodo-logical biases

Fawzy2008

≥ 3 fetalloss < 24 weeks

109 Enoxaparine20 mg sc die

Placebo - 19.3% vs. 52%RR 0.37(0.21-0.67)

Many methodo-logical biases

HepASA2009

≥ 2 fetalloss < 32 weeks(75% < 14weeks)

88 Dalteparine5000 UI sc die + ASA 81 mg die

ASA 81 mg die

+ (hered. APL or ANA)47.7% APL

77.8% vs. 79.1%P=0.71

Halted early for futility

Zolghadri2010

≥ 3 consecu-tive fetal

100 Dalteparine5000 BID + ASA 75 die

- RR 1.52 (1.14-2.02)

Many methodo-logical

Study Inclusion n Intervention Control Thrombo-philia

Results Comment

Kaandorp,ALIFE 2010

≥ 2 FD before 20 weeks (60% ≥3) (30% late*)

299 Nadroparin 2850 mg s/c die + ASA 80mg

ASA 80 mg (n=99) or placebo (n=103)

+/-*12% -17% TP hereditairy

* No difference

LMWH 27.8% vs. ASA 37.4% vs. Placebo 30.1% RR 0.92 (0.60-1.43)

Good quality.Halted for futility.

Clark, SPIN 2010

≥ 2 FD before 24 weeks (43% ≥3)

294 Enoxaparin 40 mg sc die + ASA 75mg

- -3.5% hered. TP, 2.4% APL

22.4% vs. 20.7% RR 1.08 (0.69-1.69)

Good quality.

HABENOX 2011

≥ 3 FD T1≥ 2 FD T2≥ 1 FD T3 + 1 FD T1

207 Enoxaparine 40 mg sc die +/-ASA 80 mg die

ASA 80 mg die

+/-(25% APL)

65% vs. 71% vs. 61%P= 0.45

Good quality.Halted early.

Giancotti2012

≥ 2 FD < 12 weeks

124 Enoxaparine 40 mg sc die ORASA ad 32 weeks and Enox.40 die

ASA 100 mg die (63%)

+/-(35% with TP)

RR Enox1.39 (1.08-1.78)RR ASA/ Enox 1.54 (1.23-1.94)

High risk of bias.

TIPPS2014

≥ 3 FD <10≥ 2 FD10-16≥ 1 FD >16

129 Dalteparine 5000 die->BID

- + Nonsignificanttotal andsubgroup

Very hetero-geneousinclusion.

Conclusion

• Still very heterogeneous inclusion criteria• Early and late• With and without TP• Antiphopholipid antibody syndrome and hereditary thrombophilias

• It doesn’t look good…

Secondary effects

Secondary effects?• FRUIT:

• Cutaneous allergy, pruritis pain, edema: 11.4%• Need to change LMWH type: 2.9%• Hematoma: 1.4%• Major bleeding, thrombocytopenia, osteoporotic fracture: n=0

• TIPPS:• Major bleeding : 2.1% vs. 1.4% p=1.0• Minor bleeding : 19.6% vs. 9.2%• No heparin-induced thrombocytopenia, change in bone density or

fracture.• Does not cross the placenta• May interfere with neuraxial analgesia • Cost (patient/society)• Inconvenient for patient (daily injections)

Guidelines

ACCP 2012 guidelinesAPLS Hereditary TP Without

hereditary TP≥ 3 early fetalloss< 10 weeks

ASA + UH or LMWH (1-B)

NO (2-C) ?

1-2 early fetal loss

? ? NO (1-B)

Pre-eclampsia ? NO (2-C) ?

IUFD > 10 weeks ? NO (2-C) ?

Abruptio placentae

? NO (2-C) ?

SGA < 10th

percentile? NO (2-C) ?

UH: Unfractionated heparin

Guidelines• SOGJ 2014 for high-risk patients:

• 1. The following are recommended for prevention of preeclampsia: low-dose aspirin (I-A; High/Strong) and calcium supplementation (of at least 1 g/d) for women with low calcium intake (I-A; High/Strong).

• 2. Aspirin should be: taken in a low dose (75–162 mg/d) (III-B; Very low/Strong), administered at bedtime (I-B; Moderate/Strong), initiated after diagnosis of pregnancy but before 16 weeks’ gestation (I-B; Low/Weak), and considered for continuation until delivery (I-C; Very low/Weak).

• 3. Prophylactic doses of LMWH may be discussed in women with previous placental complications (including preeclampsia) to prevent the recurrence of ‘severe’ or early-onset preeclampsia, preterm delivery, and/or SGA infants (I-B; Moderate/Weak).

Guidelines• ACOG 2014:

• ASA 60-80 mg daily beginning at the end of first trimester for women having had:• Early-onset PE with delivery < 34 weeks• or• PE in more than one pregnancy

• No mention of LMWH, calcium

What I do…

Conclusion

• I do not look for hereditary TP with any placental complication• Recurrent early fetal loss WITH thrombophilia: I wait for proof

(consequences on insurance, familial screening)

• I look for APLA in all cases; ASA + LMWH antepartum + 6 weeks post-partum (expert recommendation…)

ConclusionPlacentalcomplication

n Do I recommend ASA + LMWH?

Comments

Preeclampsia < 340

weeksN=310Rey + FRUIT

YES, with some confidence

Between 340 and 346 weeks: only if other arguments (severe IUGR, IUFD, abruption)

Severe late onset preeclampsia

NOH-PE: n=134HAPPY: n? But negativeTIPPS: n?

NO No proof and different pathophysiology

Late onset/postpartumeclampsia

0 NO No proof and different pathophysiology

ConclusionPlacentalcomplication

n Do I recommend ASA + LMWH?

Comments

Placental abruption > 20 weeks with IUFD or delivery < 34 weeks

181 Discussion, less data: tendency to treat

Placental pathology can help decide.

SGA < 5 percentile, unexplained, without PE

134 Discussion, less data.Rare reason of consultation in Obstetric Medicine.

Placental pathology can help.

ConclusionPlacentalcomplication

n Do I recommend ASA + LMWH?

Comments

Unexplained IUFD > 20 weeks

N unknown in Rey and HAPPY

Discussion, tendency to treat especially if placental pathology compatible.

No specific data for this subgroup

1-2 IUFD 10-20 weeks

N unknown in Rey, HAPPY, multiples studies on recurrent fetal loss

Mostly NO, but case by case

No specific data for this subgroup

3 early fetal loss < 10 weeks without TP or TP status unknown

N unknown NO, with confidence

3 early fetal loss with hereditary TP

N unknown Mostly NO Higher consideration according to thromboembolic risk

Conclusion• If we can prevent something, it is mostly PE, regardless of

index placental complication

• Prevention of PE +/- important: prevention of complications more important (prematurity, maternal and fetal/neonatal complications) • Rodger’s meta-analysis shows reduction of severe outcomes when

severe index complications• Cochrane shows that we also diminish some of these outcomes

including perinatal mortality, prematurity, IUGR, Apgar ↓

QUESTIONS?

Early recurrent fetal loss• Middeldorp S. Thrombosis Research 2011;127

Supp.3:S105-109.

APL Screening

HereditaryTP

screening

ASA LMWH

≥ 3 fetaldeaths <10 weeks

YES NO YES NO

PE <34 0-6/7 YES NO YES YES

Late PE NO NO YES NO

Late eclampsia

NO NO YES NO

Fetal death > 12-20 weeks

YES? NO Mostly NO

Fetal death > 20 weeks

YES NO Mostly YES

Abruptio placentae

YES NO

LBW <5th OUI NON