Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss.

BACKGROUND: Aspirin and heparin are widely used as preventive strategy to reduce the high risk of recurrent pregnancy loss in women with antiphospholipid antibodies (aPL). This review supersedes a previous, out-of-date review that evaluated all potential therapies for preventing recurrent pregnancy loss in women with aPL. The current review focusses on a narrower scope because current clinical practice is restricted to using aspirin or heparins, or both for women with aPL in an attempt to reduce pregnancy complications. OBJECTIVES: To assess the effects of aspirin or heparin, or both for improving pregnancy outcomes in women with persistent (on two separate occasions) aPL, either lupus anticoagulant (LAC), anticardiolipin (aCL) or aß2-glycoprotein-I antibodies (aß2GPI) or a combination, and recurrent pregnancy loss (two or more, which do not have to be consecutive). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 June 2019), and reference lists of retrieved studies. Where necessary, we attempted to contact trial authors. SELECTION CRITERIA: Randomised, cluster-randomised and quasi-randomised controlled trials that assess the effects of aspirin, heparin (either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH]), or a combination of aspirin and heparin compared with no treatment, placebo or another, on pregnancy outcomes in women with persistent aPL and recurrent pregnancy loss were eligible. All treatment regimens were considered. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion criteria and risk of bias. Two review authors independently extracted data and checked them for accuracy and the certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: Eleven studies (1672 women) met the inclusion criteria; nine randomised controlled trials and two quasi-RCTs. The studies were conducted in the USA, Canada, UK, China, New Zealand, Iraq and Egypt. One included trial involved 1015 women, all other included trials had considerably lower numbers of participants (i.e. 141 women or fewer). Some studies had high risk of selection and attrition bias, and many did not include sufficient information to judge the risk of reporting bias. Overall, the certainty of evidence is low to very low due to the small numbers of women in the studies and to the risk of bias. The dose and type of heparin and aspirin varied among studies. One study compared aspirin alone with placebo; no studies compared heparin alone with placebo and there were no trials that had a no treatment comparator arm during pregnancy; five studies explored the efficacy of heparin (either UFH or LMWH) combined with aspirin compared with aspirin alone; one trial compared LMWH with aspirin; two trials compared the combination of LMWH plus aspirin with the combination of UFH plus aspirin; two studies evaluated the combination of different doses of heparin combined with aspirin. All trials used aspirin at a low dose. Aspirin versus placebo We are very uncertain if aspirin has any effect on live birth compared to placebo (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.71 to 1.25, 1 trial, 40 women, very low-certainty evidence). We are very uncertain if aspirin has any effect on the risk of pre-eclampsia, pregnancy loss, preterm delivery of a live infant, intrauterine growth restriction or adverse events in the child, compared to placebo. We are very uncertain if aspirin has any effect on adverse events (bleeding) in the mother compared with placebo (RR 1.29, 95% CI 0.60 to 2.77, 1 study, 40 women). The certainty of evidence for these outcomes is very low because of imprecision, due to the low numbers of women involved and the wide 95% CIs, and also because of risk of bias. Venous thromboembolism and arterial thromboembolism were not reported in the included studies. Heparin plus aspirin versus aspirin alone Heparin plus aspirin may increase the number of live births (RR 1.27, 95% CI 1.09 to 1.49, 5 studies, 1295 women, low-certainty evidence). We are uncertain if heparin plus aspirin has any effect on the risk of pre-eclampsia, preterm delivery of a live infant, or intrauterine growth restriction, compared with aspirin alone because of risk of bias and imprecision due to the low numbers of women involved and the wide 95% CIs. We are very uncertain if heparin plus aspirin has any effect on adverse events (bleeding) in the mother compared with aspirin alone (RR 1.65, 95% CI 0.19 to 14.03, 1 study, 31 women). No women in either the heparin plus aspirin group or the aspirin alone group had heparin-induced thrombocytopenia, allergic reactions, or venous or arterial thromboembolism. Similarly, no infants had congenital malformations. Heparin plus aspirin may reduce the risk of pregnancy loss (RR 0.48, 95% CI 0.32 to 0.71, 5 studies, 1295 women, low-certainty evidence). When comparing LMWH plus aspirin versus aspirin alone the pooled RR for live birth was 1.20 (95% CI 1.04 to 1.38, 3 trials, 1155 women). In the comparison of UFH plus aspirin versus aspirin alone, the RR for live birth was 1.74 (95% CI 1.28 to 2.35, 2 trials, 140 women). AUTHORS' CONCLUSIONS: The combination of heparin (UFH or LMWH) plus aspirin during the course of pregnancy may increase live birth rate in women with persistent aPL when compared with aspirin treatment alone. The observed beneficial effect of heparin was driven by one large study in which LMWH plus aspirin was compared with aspirin alone. Adverse events were frequently not, or not uniformly, reported in the included studies. More research is needed in this area in order to further evaluate potential risks and benefits of this treatment strategy, especially among women with aPL and recurrent pregnancy loss, to gain consensus on the ideal prevention for recurrent pregnancy loss, based on a risk profile.

A less-intensive anticoagulation protocol of therapeutic unfractionated heparin administration for pregnant patients.

Heparin anticoagulant therapy for thromboembolic disorders during pregnancy is problematic due to unexpected adverse bleeding. To avoid bleeding, we have used a less-intensive anticoagulation protocol of unfractionated heparin (UFH). The protocol had a therapeutic activated partial thromboplastin time (APTT) ratio of 1.5-2.0 with the control value, a UFH dose of ≤ 30,000 U/day, and an antithrombin (AT) activity target of ≥ 70%. In the present study, we evaluated this protocol using an anti-Xa assay. We collected UFH-treated plasma samples from ten consecutive pregnant Japanese patients with current or previous thromboembolic disorders. Seven patients remained in the therapeutic APTT ratio range (heparin-sensitive [HS] group). The other three patients had difficulty remaining within the therapeutic range (heparin-resistant [HR] group). In the HR group, two had AT deficiency and one had congenital absence of the inferior vena cava. Of the HS and HR samples, 73% and 31%, respectively, were within the therapeutic anti-Xa activity range 0.3-0.7 U/mL, indicating difficulty for the HR group to remain within the therapeutic range. Neither major bleeding nor symptomatic thromboembolic episodes occurred in either group. These findings suggest that the less-intensive anticoagulation protocol is permissive and may be beneficial in the HS group.

Maternal leukocytosis after antenatal corticosteroid administration: a systematic review and meta-analysis.

Although it is known that corticosteroid administration causes leukocytosis, the magnitude and length of time this leukocytosis persists is unknown during pregnancy. This study aimed to establish the expected range of maternal leukocytosis in healthy pregnant women at risk for preterm delivery after antenatal corticosteroid administration. PubMed, Embase and ClinicalTrials.gov were searched to identify the studies in healthy women at risk for preterm delivery without signs of clinical infection that reported white blood cell values preceding and after antenatal corticosteroid administration. The inverse variance weighting technique was used to calculate the weighted means and the standard deviation from the mean for each time period. Six studies met inclusion criteria and included 524 patients and 1406 observations. Mean ± standard deviation maternal white blood cell count values prior to antenatal corticosteroid administration and up to 24, 48, 72 and 96 hours after corticosteroid administration were 10.4 ± 2.4, 13.6 ± 3.6, 12.1 ± 3.0, 11.5 ± 2.9 and 11.1 ± 2.5 × 109/L, respectively. Leukocytosis in healthy, non-infected women is expected to peak 24 hours after antenatal corticosteroid administration and the magnitude of increase is small. Impact statement What is already known on this subject: While it is well known that administration of antenatal corticosteroids causes leukocytosis, it is currently unknown the magnitude and length of time the leukocytosis persists. What the results of this study add: This study establishes the expected range and the temporal progression and regression with antenatal corticosteroid administration in healthy pregnant women at risk for preterm delivery without clinical signs of infection. What the implications are of these findings for clinical practice and/or further research: Clinicians may wish to consider further investigation into the clinical cause, whether infectious or non-infectious, for absolute values and changes outside this range.

Heparin-induced thrombocytopenia in pregnancy: an interdisciplinary challenge-a case report and literature review.

Heparin-induced thrombocytopenia is a serious adverse event of anticoagulation with a high risk of thromboembolic complications. As a consequence, anticoagulants other than heparins must be administered. These may be unavailable, contraindicated during pregnancy, off-label, impractical due to short half-lives and, most importantly, may be unfamiliar to many anesthesiologists. Impaired coagulation bears the risk of adverse events following neuraxial procedures and of peripartum hemorrhage. We describe the case of heparin-induced thrombocytopenia in a 29-year-old pregnant woman at 27weeks of gestation with severe valvular heart disease.

Consumption of arsenic-contaminated drinking water and anemia among pregnant and non-pregnant women in northwestern Romania.

Anemia is a global health problem. To evaluate the impact of low-moderate water arsenic exposure (mostly <10 µg/L) on anemia, we conducted a cross-sectional study of 217 Romanian women. The adjusted prevalences for 'any' anemia (prevalence proportion ratio (PPR)=1.71, 95% CI 0.75-3.88) and pregnancy anemia (PPR=2.87, 95% CI 0.62-13.26) were higher among drinking water arsenic exposed women than among unexposed women. These preliminary data underscore the need for a more definitive study in this area.

Does smoke from biomass fuel contribute to anemia in pregnant women in Nagpur, India? A cross-sectional study.

BACKGROUND: Anemia affects upwards of 50% of pregnant women in developing countries and is associated with adverse outcomes for mother and child. We hypothesized that exposure to smoke from biomass fuel--which is widely used for household energy needs in resource-limited settings--could exacerbate anemia in pregnancy, possibly as a result of systemic inflammation. OBJECTIVE: To evaluate whether exposure to smoke from biomass fuel (wood, straw, crop residues, or dung) as opposed to clean fuel (electricity, liquefied petroleum gas, natural gas, or biogas) is an independent risk factor for anemia in pregnancy, classified by severity. METHODS: A secondary analysis was performed using data collected from a rural pregnancy cohort (N = 12,782) in Nagpur, India in 2011-2013 as part of the NIH-funded Maternal and Newborn Health Registry Study. Multinomial logistic regression was used to estimate the effect of biomass fuel vs. clean fuel use on anemia in pregnancy, controlling for maternal age, body mass index, education level, exposure to household tobacco smoke, parity, trimester when hemoglobin was measured, and receipt of prenatal iron and folate supplements. RESULTS: The prevalence of any anemia (hemoglobin < 11 g/dl) was 93% in biomass fuel users and 88% in clean fuel users. Moderate-to-severe anemia (hemoglobin < 10 g/dl) occurred in 53% and 40% of the women, respectively. Multinomial logistic regression showed higher relative risks of mild anemia in pregnancy (hemoglobin 10-11 g/dl; RRR = 1.38, 95% CI = 1.19-1.61) and of moderate-to-severe anemia in pregnancy (RRR = 1.79, 95% CI = 1.53-2.09) in biomass fuel vs. clean fuel users, after adjusting for covariates. CONCLUSION: In our study population, exposure to biomass smoke was associated with higher risks of mild and moderate-to-severe anemia in pregnancy, independent of covariates. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01073475.

Tinzaparin safety and efficacy in pregnancy.

BACKGROUND: Unfractionated heparin has largely been replaced by low molecular weight heparin in the treatment and prevention of thrombosis and recurrent miscarriage in pregnancy. There is little information, however, about the efficacy and safety of tinzaparin, which has the advantage of being administered as a single daily dose. AIMS: To evaluate the safety and efficacy of tinzaparin use in pregnancy. METHODS: We retrospectively reviewed the medical records of women who were prescribed tinzaparin during pregnancy and the puerperium in our hospitals from January 2000 to December 2008. Tinzaparin was given as a single daily prophylactic dose for women with a history of venous thromboembolism (VTE) or recurrent miscarriage and as a single daily therapeutic dose for women diagnosed with VTE. The primary outcomes recorded were thrombosis, bleeding, allergy and thrombocytopenia. RESULTS: One hundred and forty-nine women aged between 17 and 44 years received tinzaparin in pregnancy and the puerperium over the study period. The dose administered was therapeutic in 21 (14 %) cases and prophylactic in all others. VTE recurred in three women who had a history of VTE (3.6 %). Antepartum and postpartum haemorrhage occurred in 9.7 and 5 % of cases, respectively and two women developed thrombocytopenia but their platelets remained above 100,000/ml. Fifty-seven women (38 %) had regional anaesthesia without complication. CONCLUSION: Our study demonstrates a safety profile for tinzaparin in pregnancy that is equivalent to other low molecular weight heparins with the advantage of single daily dosing.

Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic agent used to prevent fetal thrombocytopenia in those pregnancies identified to be at risk for fetal and neonatal alloimmune thrombocytopenia. Although generally considered a safe medication, hemolytic anemia is a known side effect of IVIG treatment that may result in maternal medical complications. CASES: We present three cases of IVIG-induced maternal anemia from separate institutions that occurred during treatment for fetal and neonatal alloimmune thrombocytopenia and resolved after discontinuation or alteration of therapy. None of the treated fetuses had thrombocytopenia at birth. CONCLUSION: There is a potential for hemolysis when prescribing IVIG. We recommend laboratory monitoring for hemolytic anemia and suggest options for management including drug modification or cessation of therapy.

Severe thrombocytopenia after contrast infusion in pregnancy.

BACKGROUND: Intravenous contrast-induced thrombocytopenia is a rare but potentially life-threatening complication in pregnancy. CASE: A 22-year-old woman, gravida 2 para 1, at 33 2/7 weeks of gestation presented with chest pain, shortness of breath, and tachycardia. A computed tomography angiogram was pursued to evaluate for pulmonary embolus. During contrast infusion the woman experienced facial flushing, throat tightening, and worsening dyspnea. Her platelet count was noted to decrease precipitously to 4,000/microliter several hours after the imaging study. With medical management and observation, the woman's platelet count steadily recovered without further exacerbation of thrombocytopenia during gestation. CONCLUSION: Prompt recognition and therapy for intravenous contrast-induced thrombocytopenia during pregnancy are essential to optimize maternal-fetal outcome.

Abnormal inflammation leads to maternal coagulopathies associated with placental haemostatic alterations in a rat model of foetal loss.

Spontaneous pregnancy loss is often associated with aberrant maternal inflammation and systemic coagulopathies. However, the role of inflammation in the development of obstetric coagulopathies is poorly understood. Further, questions remain as to whether systemic coagulopathies are linked to placental haemostatic alterations, and whether these local alterations contribute to a negative foetal outcome. Using a model of spontaneous foetal loss in which pregnant rats are given a single injection of bacterial lipopolysaccharide (LPS), we characterised the systemic maternal coagulation status following LPS administration using thromboelastography (TEG), a global haemostatic assay that measures the kinetics of clot formation. Systemic maternal coagulopathy was evident in 82% of LPS-treated rats. Specifically, we observed stage-I, -II, and -III disseminated intravascular coagulation (DIC) and hypercoagulability. Modulation of inflammation through inhibition of tumour necrosis factor α with etanercept resulted in a 62% reduction in the proportion of rats exhibiting coagulopathy. Moreover, inflammation-induced systemic coagulopathies were associated with placental haemostatic alterations, which included increased intravascular, decidual, and labyrinth fibrin deposition in cases of DIC-I and hypercoagulability, and an almost complete absence of fibrin deposition in cases of DIC-III. Furthermore, systemic and placental haemostatic alterations were associated with impaired utero-placental haemodynamics, and inhibition of these haemostatic alterations by etanercept was associated with maintenance of utero-placental haemodynamics. These findings indicate that modulation of maternal inflammation may be useful in the prevention of coagulopathies associated with complications of pregnancy.

Reason for clozapine cessation.

OBJECTIVE: Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation. METHOD: The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy. RESULTS: The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia. CONCLUSION: Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.

Clopidogrel use throughout pregnancy in a patient with a drug-eluting coronary stent.

BACKGROUND: Little information regarding the potential implications of drug-eluting stents and clopidogrel on pregnancy exists. CASE: We report a case of a 27-year-old woman who received a drug-eluting coronary stent for an acute myocardial infarction and was started on clopidogrel as treatment. She was on clopidogrel when she conceived and delivered a child by cesarean. Her postpartum course was complicated by postoperative bleeding requiring transfusion. CONCLUSION: This case highlights the perinatal and peripartum concerns of these interventions in women of childbearing age. It suggests that cesarean delivery is associated with an elevated risk of perioperative bleeding and may best be approached like other surgical procedures, with the optimal timing of surgery, when feasible, being 5 or more days after the discontinuation of clopidogrel.

Thrombophilic-type placental pathologies and skeletal growth delay following maternal administration of angiostatin4.5 in mice.

During placentation, the concentration of fibrinous deposits on the surfaces of maternal vasculature plays a role in villous development and has been strongly implicated in the pathophysiology of human fetal growth restriction (FGR). Fibrinous deposits are conspicuous sites of platelet aggregation where there is local activation of the hemostatic cascade. During activation of the hemostatic cascade, a number of pro- and antiangiogenic agents may be generated at the cell surface, and an imbalance in these factors may contribute to the placental pathology characteristic of FGR. We tested the hypothesis that angiostatin(4.5) (AS(4.5)), a cleavage fragment of plasminogen liberated at the cell surface, is capable of causing FGR in mice. Increased maternal levels of AS(4.5) in vivo result in reproducible placental pathology, including an altered vascular compartment (both in decidual and labyrinthine layers) and increased apoptosis throughout the placenta. In addition, there is significant skeletal growth delay and conspicuous edema in fetuses from mothers that received AS(4.5). Maternally generated AS(4.5), therefore, can access maternal placental vasculature and have a severe effect on placental architecture and inhibit fetal development in vivo. These findings strongly support the hypothesis that maternal AS(4.5) levels can influence placental development, possibly by directly influencing trophoblast turnover in the placenta, and contribute to fetal growth delay in mice.

Protective effects of selenium on methimazole-induced anemia and oxidative stress in adult rats and their offspring.

The present study investigates the potential ability of selenium, considered as an antioxidant with pharmacological property to alleviate oxidative stress and hematological parameter disorders induced by methimazole, an antithyroid drug. Pregnant Wistar rats were randomly divided into four groups of six each: group I served as negative control and received a standard diet; group II received 250 mg/L of methimazole in drinking water and a standard diet; group III received both methimazole (250 mg/L, orally) and selenium (0.5 mg/kg of diet) supplemented to the standard diet; group IV served as positive control and received a supplement of selenium in the diet (0.5 mg/kg of diet) as sodium selenite (Na(2)SeO(3)). Treatment was started from the 14th day of pregnancy until day 14 after delivery. Methimazole reduced the number of red blood cells, hemoglobin concentration and hematocrit in mothers and their pups. Besides, plasma iron, vitamins B(9), B(12), C and E levels were reduced. Lipid peroxidation increased, objectified by high malondialdehyde levels and lactate dehydrogenase activity in plasma, while glutathione, glutathione peroxidase, superoxide dismutase and catalase activities showed a significant decline. Co-administration of selenium through diet improved all the parameters cited above. It can be concluded that the administration of selenium alleviates methimazole-induced toxicity, thus demonstrating its antioxidant efficacy.

Diphenylhydantoin-induced severe yet reversible anemia during pregnancy.

Diphenylhydantoin (DPH) therapy, often used in treating epileptic seizures, can cause anemia in some patients. A 26-year-old female suffered from convulsions due to encephalitis and was placed on DPH therapy. About two months after the initiation of DPH therapy, her hemoglobin level was 3.8 g/dL. Her anemia improved after the discontinuation of DPH, confirming that the anemia was caused by DPH. Pure red-cell aplasia (PRCA) combined with hemolytic anemia was indicated by results such as erythroid aplasia, an increased LDH level, and a decreased haptoglobin level. PRCA complicated by hemolytic anemia could be responsible for anemia associated with DPH.

Association between anemia and aflatoxin B1 biomarker levels among pregnant women in Kumasi, Ghana.

Aflatoxins are fungal metabolites that contaminate staple food crops in many developing countries. Up to 40% of women attending a prenatal clinic in Africa may be anemic. In a cross-sectional study of 755 pregnant women, Aflatoxin B(1)-lysine adducts (AF-ALB) levels were determined by high-performance liquid chromatography. Participants were divided into quartiles "low," "moderate," "high," and "very high." Anemia was defined as hemoglobin levels < 11 g/dL. Logistic regression was used to examine the association of anemia with AF-ALB. The mean AF-ALB level was 10.9 pg/mg (range = 0.44-268.73 pg/mg); 30.3% of participants were anemic. The odds of being anemic increased 21% (odds ratio [OR], 1.21, P = 0.01) with each quartile of AF-ALB reaching an 85% increased odds in the "very high" compared with the "low" category (OR, 1.85; confidence interval [CI], 1.16-2.95). This association was stronger among women with malaria and findings were robust when women with evidence of iron deficiency anemia were excluded. This study found a strong, consistent association between anemia in pregnancy and aflatoxins.