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Can LMWH cause negative pregnancy result?

Pregnancy complications in the placenta, including preeclampsia, placental abruption, inhibition of intrauterine / sub-age development of p...

Can LMWH cause negative pregnancy result?

Pregnancy complications in the placenta, including preeclampsia, placental abruption, inhibition of intrauterine / sub-age development of pregnancy and recurrent or premature loss, affect more than 5% of pregnancies and can lead to significant maternal and perinatal mortality and death. These problems have been suggested that at least in part arise from placental abnormalities, possibly due to improper coagulation function. This association has led to the notion that anticoagulant treatment, such as low-dose heparin, may reduce their incidence. The following review will attempt to summarize the in-depth research conducted so far to examine this theory and provide guidance on the current and future role of low heparin molecular weight for women at risk of moderate to severe pregnancy complications. There will be a case of skepticism about the widely accepted practice of determining low heparin cell counts for women with pre-existing pregnancy complications and suggesting potential areas for future research.


Pregnancy complications in the placenta represent a complex group of adverse pregnancy outcomes including preeclampsia (PET) placental abruption (PA), intrauterine growth retardation (IUGR) / minimal pregnancy years (SGA) and miscarriage. PET is defined as systolic blood pressure ≥140 mm Hg and / or diastolic blood pressure ≥90 mm Hg associated with proteinuria or adverse events that occur after 20 weeks of gestation and no pre-hypertensive disease (Magee et al, 2014 ; American College of Obstetricians and Committee of Gynecologists (ACOG) Practice Bulletins, 2002). PET is classified as critical if systolic blood pressure is mm160 mm Hg and / or diastolic blood pressure ≥110 mm Hg or the presence of severe complications (Magee et al, 2014) and early onset of PET is defined as okuqala34 of pregnancy weeks (von Dadelszen et al, 2003; Huppertz, 2011). Early onset of PET is not very common, involving 5-20% of cases, but it is thought that there is a strong interaction with the placenta, as well as the causes of many diseases and deaths associated with PET (Huppertz, 2011). PA is defined as premature separation of the placenta and is clinically diagnosed with antepartum bleeding and evidence of retroplacental thrombus (Oyelese & Ananth, 2006). SGA is defined as the fetal <10th percentile weight in ultrasound (Lausman et al, 2013), with a strong SGA defined as the <5th percentile. The term IUGR refers specifically to the SGA fetus caused by a disease process and not just the fetus that has grown normally at the lower end of the normal range (Huppertz, 2011; Lausman et al, 2012). SGA, as measured in population growth charts, is widely used as the IUGR surrogate; however, experimental studies have suggested that customized growth charts for adjustments such as maternal height, weight, unity and national group are better predictors of adverse outcomes for newborns (Clausson et al, 2001; Carberry et al, 2014).

Clinically, these adverse events are common, affecting more than 5% of pregnancies (Kujovich, 2004). They are also the leading causes of critical maternal and prenatal illness and are linked to the future consequences of mother and child. Women who develop PET are at risk for fainting, strokes, pulmonary edema and hepatic dysfunction, and an increased lifelong risk of developing heart disease (Huppertz, 2011). Placental disorders are associated with an increased risk of maternal mortality and childbirth (Ananth et al, 1999; Oyelese & Ananth, 2006; Tikkanen, 2011; Tikkanen et al, 2013). IUGR is the second leading cause of death by birth (Huppertz, 2011). IUGR infants face more problems compared to non-IUFR infants born at the same time of pregnancy including sudden intrauterine sudden death, respiratory depression, diarrhea and late sequelae such as mental retardation and behavioral problems (Pallotto and Kilbride, -2006; Lausman et al, 2012). Pregnancy loss is devastating for affected families and is associated with chronic stress (Christiansen et al, 2013). Although each of these problems can be the result of many and varied causes, there is good evidence to link them to the common pathophysiology of reactivation of the coagulation method (Clark et al, 1999; Greer et al, 2014). Supporting this common approach is the fact that women suffering from a single-risk pregnancy problem are at greater risk of developing complications in subsequent pregnancies. Women suffering from early PET in early pregnancy were found to have increased incidence of PET (25%), PA (3%), SGA baby (10%) and perinatal mortality (1 · 7%) in subsequent pregnancies (van Rijn et al. , 2006). Similarly, women with PA in the first pregnancy had increased incidence of PET (15%), PA (2 · 8%) and SGA baby (15%) (Ananth et al, 2007).

This review will attempt to summarize the evidence for coagulation pathway abnormalities in placental abruption complications and provide a critical study of a growing research body examining the use of low-molecular weight heparin (LMWH) to prevent placental abruption complications. 

Placental development and intermediate pregnancy complications

In healthy pregnancies, implants include trophoblast invasion of approximately 100 subsequent uterine arterioles resulting in low blood circulation system without maternal vasomotor control (Dekker, 2005; Hossain & Paidas, 2007; Kingdom and Drewlo, 2011). The emerging low-circulatory system of the utero-placental circulation allows large-scale blood flow to the placenta and fetus. The key to placental placement is controlled by the activation of the haemostatic system. This process of activating haemostasis is thought to mimic the process of trophoblast invasion and protect against hemorrhage (Greer et al, 2014). Key measures include tissue breakdown and plasminogen activator inhibitor 1 and complex interactions between mother and parent cycles (Greer et al, 2014). Placental vascular problems arise when normal body changes fail, resulting in prostate dysfunction associated with endothelial cell deficiency, continued coagulation stiffness, fibrin / fibrin degradation production and utero-placental thrombosis (Hossain & Paidas, 2007) .

Placental pathology is thought to result from impaired placental development in two stages: (i) trophoblast invasion failure, followed by (ii) systemic endothelial dysfunction (Hossain & Paidas, 2007). In complex pregnancies by PET and IUGR, shallow trophoblast attacks are observed, leading to high vascular resistance, decreased placental abruption and placental ischemia (Dekker, 2005; Hossain & Paidas, 2007; Norwitz, 2007; Huppertz, 2011; Huppertz, 2011; ; Khong & Brosens, 2011). Examination of body tissues from PET-induced pregnancy reveals one-third to one-half of the arterial arteries that do not receive this remodeling (Khong & Brosens, 2011). The second stage of placental pathology occurs as the inactive placenta secretes vasoactive substances, such as soluble fms such as tyrosine kinase 1 and soluble endoglin (Hossain and Paidas, 2007). These factors are thought to contribute directly to the clinical features of PET, such as high blood pressure (altering matotal endothelial vascular tone), proteinuria (increased glomerular vascular permeability), liver dysfunction (hepatic ischaemia) and hepatitis coagulopathy (increased prolonged maternal expression of procoagulants). Normal body failure is associated with severe atherosis in approximately 50% of placentas tested in PET and IUGR and vessel formation in thrombosis, aneurysmal formation and decreased oral blood flow (Khong & Brosens, 2011). Finally, regeneration of malformed fertile arteries and acute atherosis can lead to placental abruption with decreased placental blood flow (Khong & Brosens, 2011).

Abnormal vascular remodeling was demonstrated in a retrospective analysis of 1534 consecutive singleton pregnancies tested for placental histology and clinical manifestations (Avagliano et al, 2011). Common physiological changes include the open artery light, the missing muscle wall, the alteration of the vascular layer by fibrinoid material and the penetration of the arterial wall by trophoblasts. Abnormal vascular modification (ASAM) has been defined as incomplete vascular remodeling with incomplete and / or incomplete body changes in at least 70% of vascular segments. ASAM has been detected in 3 · 3% of common miscarriages, 6 · 6% of pregnancies with maternal and / or fetal complications and 30 · 2% of pregnancies end in intrauterine fetal death (IUFD). Pregnancy where ASAM is diagnosed is more likely to be complicated by hypothyroidism (P <0 · 05), PET (P <0 · 05), oligohydramnios (P <0 · 05), PA (P <0 · 05), rupture premature membranes (P <0 · 05) and IUFD (P <0 · 001). Acute vascular remodeling is a common complication of disease associated with many birth defects including: premature and premature loss of birth, prenatal birth, PA, PET and IUGR (Romero et al, 2011). Evidence of the unusual effectiveness of coagulation has been demonstrated by a team of NĂ®mes Obstetricians and Haematologists. In a prospective case-control study, factor XII deficiency and hypofibrinolysis were found in women with ≥3 other unexplained congenital malformations prior to 16 weeks of gestation (Gris et al, 1997). In a separate study conducted by the same group, a study of placenta pathology of women with ≥1 uterine lateness after 22 weeks of pregnancy showed higher evidence of placental abruption (Gris et al, 1999).

The mechanism by which LMWH may alter pregnancy problems in the placenta remains unclear, but it is thought to extend beyond its anticoagulant action. Early effects may occur at the cellular level by reducing trophoblast apoptosis and an increase in protease involvement in the trophoblast attack of the maternal endometrium (D'Ippolito et al, 2011; Greer et al, 2014). Additional mechanisms of action include antiinfigueatory and anticomplement, and LMWH reduces the growing inflammatory response known to be associated with conditions such as PET (D'Ippolito et al, 2011; Kingdom & Drewlo, 2011). Heparin has been shown to counteract cytokines, such as interferon gamma, to reduce inflammatory damage to the trophoblast and maternal endothelium (Rai & Regan, 2006). These nonmicoagulation mechanisms of LMWH are also suggested by histological evidence that there is no change in placental vasculopathic findings (infarction, fibrin necrosis of fixed vessels, PA and perivilious fibrin deposition) among heparin-treated and untreated patients. noted in some patients (State et al, 2011; Kupferminc et al, 2011). However, at least these are the concepts and evidence of clinical trials needed to show the benefits of the provision of these drugs to prevent pregnancy .

 LMWH and recurrent previous pregnancy losses

Early miscarriage or total miscarriage is estimated to occur in 12-15% of known clinical pregnancies (Regan & Rai, 2000; Rai & Regan, 2006). Recurrent losses, defined as three or more consecutive losses, occur in 1% of women (Regan & Rai, 2000; Rai & Regan, 2006). This rate of increase increases to 3-5% when defined as two or more losses (Regan & Rai, 2000; Rai & Regan, 2006). The underlying causes of recurrent early pregnancy loss include infectious, physiological, chromosomal, uterine abnormalities and endocrine factors (Regan & Rai, 2000; Rai & Regan, 2006), however 50-60% of women have no definite cause. (Jaslow et al, 2010). Even after suffering three or more consecutive pregnancy losses, however, experimental studies have shown live birth rates in subsequent 70-75% pregnancies with supportive care only (Clifford et al, 1997; Brigham et al, 1999). Several interventions are considered to improve the following live birth rates for women with recurrent miscarriage. Consideration of the thrombotic origin of recurrent losses arises from initial observational studies showing both hereditary associations (APS) thrombophilia (Rai & Regan, 2006). These combination studies lead to the use of LMWH and / or aspirin as much as possible treatment to prevent recurrence. To date, there have been many randomized controlled trials testing this hypothesis, although significant heterogeneity was present among the trials (Table 3). All studies required that patients undergo a preliminary investigation into the possible causes of recurrent miscarriage and exclude women who had lost recurrence with a clear, non-thrombotic aetiology. Repeated pregnancy losses in these studies were defined as two or three unexplained pregnancy losses and gestational age deficits of premature miscarriage varied significantly between studies (from 12 weeks to <32 weeks) (Table 3). Given that there may be differences in the causal pathway between these different patients and recurrent miscarriage losses, comparisons between trials should be made with caution. The trials were different with respect to the inclusion of patients with known or acquired or acquired thrombophilia and aspirin use. One study (Laskin et al, 2009) included only patients with hereditary thrombophilia (PC, PS, APCR, F5 G1691A, F2 G20210A), methylene-tetra-folate-reductase receptor mutation (MTHFR C677T), APLA (LAC or ACL) or positive ANA, and all other studies do not include patients with APLA, and four studies (Dolitzky et al, 2006; Badawy et al, 2008; Fawzy et al, 2008; Clark et al, 2010) and do not exclude patients with any inherited thrombophilia. Visser et al (2011) excluded thrombophilia ‘at high risk’ (combined error, AT or homozygous F5 G1691A) and Kaandorp et al (2010) excluded patients with or without hereditary thrombophilia. Of these seven randomized trials, all but one (Fawzy et al, 2008) did not show a clear LMWH benefit in improving live birth rates (Table 3). In another study (Kaandorp et al, 2010), there was a tendency to increase live birth rates in patients with hereditary thrombophilia, but the small number of patients in that small group prevented sufficient capacity to make these comparisons. The case used a reduced prophylactic dosage of nadroparin (2850 U.c. once a day), which may not have been sufficient in terms of total LMWH kidney transplant during pregnancy.

To summarize these findings, a recent Cochrane review, which includes patients with at least twice the pre-pregnancy loss <24 weeks of pregnancy (de Jong et al, 2014) has been published. Patients with or without thrombophilia are included. This systematic review and meta-analysis showed no benefit of LMWH without the combination of aspirin or compared with aspirin or placebo (LMWH versus placebo RR 1 · 16, 95% CI 0 · 93-1 · 45, LMWH compared to aspirin RR 1 · 23, 95% CI 0 · 84–1 · 81, LMWH and aspirin compared to placebo RR 1 · 01, 95% CI 0 · 87–1 · 16, LMWH and aspirin compared and aspirin RR 1 · 11, 95% CI 0 · 94– 1 · 30). These findings remained consistent when analysis was limited to high-level studies. There were insufficient data to perform a small cohort analysis based on the status of thrombophilia. In summary, there is strong strong evidence that LMWH does not improve live birth rates in women with recurrent previous pregnancy loss in the absence of thrombophilia. Given the lack of data, further research may be needed in women with thrombophilia and recurrent miscarriage.

LMWH and preeclampsia

PET is estimated to occur in 5-8% of pregnancies and is a multisystem disorder associated with major maternal and infant problems (ACOG Committee on Practice Bulletins, 2002). A related disease, HELLP syndrome, can occur in the absence of high blood pressure. Pediatric malnutrition as a result of PET indicates a serious and common problem (Rodger, 2011). While the pathophysiology may be multifaceted, the proposed placenta process is frequently suggested (ACOG Committee on Practice Bulletins, 2002).

There is currently a general agreement on the use of aspirin in patients at risk for PET, with Cochrane reviews and meta-analyzes - indicating that aspirin is associated with reduced risk of PET (17% risk reduction risk), preterm birth (8%), infant mortality / newborn (14%) and SGA (10%) (Duley et al, 2007). In addition, there are three randomized controlled trials that have increased LMWH benefits especially for women with a previous history of PET (Mello et al, 2005; Gris et al, 2011; de Vries et al, 2012). A small, single, open-label, randomized controlled trial enrolled women with previous PET (in any pregnancy) and angiotensin-converting enzyme (ACE) DD geneotype (Mello et al, 2005). This study does not include women with inherited or acquired thrombophilia. Eight women were randomly assigned to receive LMWH, dalteparin 5000 units sc // compared to treatment. Treatment was started during the first positive pregnancy test and continued throughout pregnancy. LMWH treatment is associated with a reduction in any recurrent PET (3/41, 7 · 3%, LMWH compared to 11/39, 28 · 2%, control arm, OR 4 · 88, 95% CI 1 · 31- 23 · 5). Preliminary onset of PET before 34 weeks of pregnancy was also reduced (1/41, 2 · 4%, LMWH compared to 8/39, 20 · 5%, control arm, OR 10 · 07, 95% CI 1 · 50 -236 · 1), as in the case of IUGR (4/41, 9 · 8%, LMWH compared to 17/39, 43 · 6%, control arm, OR 6 · 96, 95% CI 2 · 17- 26 · 87). The case, however, was not registered and there was no information provided about permit prices, loss of compliance or random discharge. Moreover, the main effect of the study was not previously described. One small, randomized controlled trial of pilot trials included patients who suffered before PET (defined as pregnancy caused by high blood pressure, diastolic blood pressure ≥90 mm Hg and proteininuria and one additional risk factor: diastolic pressure ≥110 mm Hg or systolic pressure ≥160 mm Hg, fainting, pulmonary edema, proteinuria ≥5 g / 24 h, renal insufficiency, elevated liver transaminase with abdominal pain or platelets <100 × 109 / l) during pregnancy first (Gris et al, 2011). Prior to IUFD patients with good APLA were not included. Patients were recruited in a preliminary study group study, and 224 women were randomly assigned to receive LMWH, enoxaparin 4000 iu sc daily injection in addition to aspirin 100 mg / d, or aspirin therapy alone. Treatment was started as soon as a confirmation blood test confirmed the pregnancy and treatment continued throughout the pregnancy until the onset of labor. The primary combination effect of PET, SGA <5th percentile, PA, or IUFD after 20 weeks of pregnancy, was reduced by LMWH (10/112, 8 · 9%, of LMWH compared to 28/12 , 25% control arm, OR 6 · 97, 95% CI 2 · 17-26 · 87). The secondary effects of any PET and strong PET were also significantly reduced in the LMWH-treated arm but there was no significant decrease in other secondary outcomes of PA, SGA, or IUFD after 20 weeks of gestation. The case was not registered as a priori. Finally, the FRUIT (FRactionated heparin trial for pregnant women with a history of Utero-placental Insufficiency and Thrombophilia) was a multi-label, open label, randomized controlled trial that tested whether LMWH (dalteparin 5000 units / d) was administered aspirin, started before 12 weeks of gestation, has reduced the frequency of high-risk pregnancies in patients with hereditary thrombophilia (de Vries et al, 2012). The case involved women with a history of pre-pregnancy hypertensive disease (PET, defined as a hypertension caused by proteinuira, HELLP syndrome or SGA baby <10th percentile) and thrombophilia (heterozygous inherited). F5 G1691A, F2 G20210A, APCR, PC or PS). Eighty-nine women were randomly assigned to receive a prophylactic dose of LMWH, dalteparin 5000 sc units once a day and aspirin 80 mg / d or aspirin 80 mg / d only. This case showed a reduction in the secondary outcome of high blood pressure recurrences prior to 34 weeks of pregnancy (0% vs. 8 · 7%, total risk difference 8 · 7%, 95% CI 1 · 9-15 · 5%, P = 0 · 012), but there is no difference in the main outcome: the risk of recurrent PET regardless of age of pregnancy (18 · 6% in LMWH compared to 21 · 7% in aspirin, P = 0 · 642). There were no noticeable differences in second child mortality outcomes> 16 weeks, PA or SGA between the two study groups. The study was a high-quality, registered multicenter trial. The original sample size was revised after a systematic time analysis and was switched to a one-sided test depending on the expected increase in PET or SGA and a new sample size was obtained. Taken together, it seems likely that LMWH may play a role in the second inhibition of recurrent PET and in particular, complex or primary PET. The effectiveness of these studies precludes complete recommendations for this high-risk patient.

LMWH and placental abruption

Placental disorders occur in about 1% of births and involve bleeding in the placental connective tissue, leading to placental abruption (Ananth et al, 1999; Oyelese & Ananth, 2006). This results in a child’s compromise with reduced gas and nutrient exchange, as well as maternal morbidity through the spread of intravascular coagulopathy and bleeding (Oyelese & Ananth, 2006). Although various risk factors have been described for PA, such as trauma, smoking and cocaine use, most PAs are thought to represent a chronic disease process (Oyelese & Ananth, 2006). Central to its pathophysiology is decidua ischemia leading to necrosis, vascular disorders and bleeding (Romero et al, 2011). There has been one small, single, randomized trial to evaluate the use of LMWH to prevent adverse effects of pregnancy only in patients with previous PA (Gris et al, 2010). In the design of the same trial with the PET trial described above (Gris et al, 2011), patients were selected from previous study group participants during their first pregnancy. Those women who developed PA during early pregnancy, defined by clinical signs and symptoms and confirmed by histopathology, were eligible to participate, however, prior to IUFD and the presence of APLA were excluded methods. Six hundred and sixty women were randomly assigned to receive prophylactic doses of LMWH, enoxaparin 4000 iu sc / d, with or without medication, starting within 2 d of positive pregnancy blood tests and continuing until delivery. Aspirin 100 mg / d was prescribed at the discretion of the treating physician. The primary combined effect of PET, IUGR -5th percentile, PA or IUFD after 20 weeks of pregnancy was significantly reduced in the LMWH group (10/80, 12 · 5%, LMWH compared to 25 / 80, 31 · 3%, no treatment, OR 3 · 16, 95% CI 1 · 42-7 · 42). The reduction in PA itself did not achieve statistical calculation, but there was a significant decrease in any PET and PET intensity. 

It is difficult to conclusions based on this one study. The placental abruption was included as part of the combined outcome of placenta-related pregnancy complications in many additional studies to be discussed in the next section.

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