Low-molecular-weight heparin and preeclampsia — does the sword cut both ways? Three case reports and review of literature

Table 1 Summary of the literature review findings for low-molecular-weight heparin application in pregnancy

Ref.	Year	Included population	Number of studies included	Comparison	Efficacy	Safety: Bleeding risk
Areia et al[15]	2016	Women with hereditary thrombophilia	4 studies; 222 participants	LMWH + LDA vs LDA	No difference was found with regard to live births rate in LMWH + LDA group versus LDA group	Not reported
Bettiol et al[16]	2021	Pregnant women at high risk of FGR, defined as those with at least one of the follow: history of FGR in the previous pregnancies, history of late pregnancy loss or recurrent early pregnancy loss, hypertensive disorders, inherited or acquired thrombophilia	30 studies; 4326 participants	LMWH/UFH/LDA/other antiplatelet agents vs control	Low molecular weight heparin (LMWH), alone or associated with low-dose aspirin (LDA), appeared more efficacious than controls in preventing FGR	No treatment was associated with an increased risk of bleeding
Cruz-Lemini et al[6]	2022	Patients who had any known risk factors for developing PE, and medical history including thrombophilia, autoimmune diseases, and chronic hypertension	15 studies; 2795 participants	LMWH ± LDA vs control; LMWH vs LDA	In high-risk women, LMWH was associated with a reduction in the development of PE, SGA and perinatal death	No statistically significant difference in bleeding was found between LMWH and control, regardless of whether or not LMWH was combined with aspirin
Dias et al[17]	2021	Women with a history of recurrent abortion without an identified cause	7 studies 1855 participants	LMWH vs control	The LMWH group had a higher incidence of continuous pregnancy after the 20th week of gestation	There was no statistically significant difference between the groups on hemorrhagic events
Guerby et al[18]	2021	Pregnant women with APS	13 studies; 1916 participants	LMWH/UFH ± LDA vs LDA/IVIG	Heparin and LMWH, associated or not to aspirin, significantly increased the rate of live birth and decreased the rate of preeclampsia	Treatment with heparin and LMWH was associated with a significant increase in minor bleeding (bruises, epistaxis) (RR 2.58, 95%CI 1.03-6.43)
Hamulyák et al[19]	2020	Women with persistent (on two separate occasions) aPL, either lupus anticoagulant (LAC), anticardiolipin (aCL) or aβ(2)-glycoprotein-I antibodies [aβ(2)GPI] or a combination, and recurrent pregnancy loss	11 studies; 1672 participants	LMWH/UFH ± LDA vs LDA; LMWH/UFH ± LDA vs control	Heparin plus aspirin may increase the number of live births. Heparin plus aspirin may reduce the risk of pregnancy loss. We are uncertain if heparin plus aspirin has any effect on the risk of pre-eclampsia, preterm delivery or intrauterine growth restriction, compared with aspirin alone	We are very uncertain if heparin plus aspirin has any effect on bleeding in the mother compared with aspirin alone
Intzes et al[20]	2021	Women with or without hereditary thrombophilia and recurrent pregnancy loss	12 studies; 2298 participants	LMWH vs control	LMWH on live birth rates is not significant in women with or without thrombophilia	Not reported
Jacobson et al[21]	2020	Pregnant women receiving enoxaparin	24 studies	Enoxaparin vs control	In patients with a history of recurrent pregnancy loss, the rates of pregnancy loss were significantly lower for enoxaparin compared to untreated controls	Bleeding events were non-significantly compared between enoxaparin with untreated controls or aspirin
Jiang et al[9]	2021	Pregnant women with recurrent pregnancy loss	8 studies; 1854 participants	LMWH vs control	LMWH had significantly improved live births rates and reduced miscarriage rates	Receiving LMWHs had no substantial impact on bleeding episodes
Liu et al[8]	2021	Patients with recurrent pregnant loss	6 studies; 1034 participants	Enoxaparin vs control	Enoxaparin has no obvious impact on live births, abortion rate, birth weight, preterm delivery and preeclampsia	Enoxaparin has no obvious impact on postpartum hemorrhage
Liu et al[22]	2020	Naturally pregnant women aged 18 or older with a diagnosis of recurrent pregnancy loss and APS	12 studies; 1910 participants	LMWH/UFH + LDA vs control	LMWH plus aspirin had a higher live birth rate than aspirin alone, UFH plus aspirin showed a higher live birth rate than aspirin alone	Not reported
Lu et al[23]	2019	Women with APS and recurrent spontaneous abortion	19 studies; 1251 participants	LMWH/UFH ± LDA vs LDA; LMWH/UFH ± LDA vs control	With respect to live birth, it was remarkably improved in aspirin plus heparin or heparin alone group compared with aspirin alone group. Low-dose aspirin plus heparin therapy was significant reduce the risk of preeclampsia	Aspirin plus heparin therapy did not significantly increase minor bleeding risk
Mastrolia et al[24]	2016	Pregnant women at risk for developing preeclampsia, IUGR, placental abruption, spontaneous preterm delivery and fetal death	5 studies; 403 participants	LMWH vs control	The overall use of LMWH was associated with a risk reduction for preeclampsia and IUGR	Minor bleeding complication in two patients in LMWH group
Middleton et al[25]	2021	Women who were pregnant or had given birth in the previous six weeks, at increased risk of VTE, were included. Women at increased risk were those having/following a caesarean section, with an acquired or inherited thrombophilia, and/or other risk factors for VTE	29 studies; 3839 participants	LMWH/UFH vs control; LMWH vs UFH	Evidence was very uncertain for antenatal (± postnatal) prophylaxis for prevent thromboembolic event (PE and DVT)	Evidence was very uncertain on adverse effects sufficient to stop treatment caused by bleeding. Only one study reported adverse effects sufficient to stop treatment caused by bleeding during LMWH treatment (3 patients with placenta previa)
Roberge et al[26]	2016	Women with previous history of PE	8 studies; 885 participants	LMWH/UFH ± LDA vs LDA	In women with previous history of PE, treatment with LMWH and aspirin, compared to aspirin alone, was associated with a significant reduction in PE and birth of SGA neonates	Not reported
Rodger et al[27]	2016	Women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate, pregnancy loss after 16 wk’ gestation, or two losses after 12 wk’ gestation	8 studies; 963 participants	LMWH vs control	LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications. In subgroup analyses, LMWH in multicenter trials reduced the placenta-mediated pregnancy complications in women with previous abruption	In the antepartum period, there is no significant difference in risk for major bleeding. In the peripartum and postpartum periods, the incidence of major bleeding did not differ between the treatment and control groups
Sirico et al[28]	2019	Women who underwent thromboprophylaxis with LMWH during the third trimester of pregnancy	8 studies; 22162 participants	LMWH vs control	Not reported	Women treated with LMWH had an higher risk of PPH (RR 1.45, 95%CI 1.02 to 2.05) compared to controls. There was no difference in mean of blood loss at delivery and in risk of blood transfusion at delivery
Urban et al[7]	2021	Patients affected by obstetric APS, with or without thrombotic APS	8 studies; 395 participants	UFH/LMWH + LDA vs LDA; LMWH + LDA vs UFH + LDA; LDA + UFH + IVIg vs LDA + UFH	No difference among treatments emerged in terms of FGR prevention, but estimates were largely imprecise	No treatment was associated with an increased risk of bleeding
Wang et al[29]	2020	Women with subsequent pregnancies who previously had early onset or severe PE	7 studies; 1035 participants	LMWH vs LDA; LMWH vs control	There were risk reductions on PE rate, small-for-gestational-age neonate rate. LMWH led to an increase in gestational length and neonatal weight	Not reported
Yan et al[30]	2022	Patients with unexplained recurrent miscarriage with negative antiphospholipid antibodies	7 studies; 1849 participants	LMWH ± LDA vs control	No substantial influence on miscarriage rate and the occurrence rate of pre-eclampsia	Not reported
Yang et al[31]	2018	Women undergoing IVF/ICSI	5 studies; 935 participants	LMWH vs control	No significant differences for live birth rate, clinical pregnancy rate and miscarriage rate were found between the low-molecular-weight heparin and control groups	One study reported five cases of minor vaginal bleeding in women receiving LMWH treatment, but not serious enough to stop the use of LMWH

For the above studies, patients in the control group received no treatments or placebo. APS: Anti-phospholipid syndrome; aPL: Antiphospholipid antibodies; DVT: Deep vein thrombosis; IUGR: Intrauterine growth restriction; IVIG: Intravenous immune globulin; LDA: Low dose aspirin; LMWH: Low molecular weight heparin; PE: Preeclampsia; SGA: Small for gestational age; UFH: Unfractionated heparin.