Severe maternal morbidity in women with high BMI in IVF and unassisted singleton pregnancies.

STUDY QUESTION: Is there a synergistic risk of severe maternal morbidity (SMM) in overweight/obese women who conceived by IVF compared to normal-weight women without IVF? SUMMARY ANSWER: SMM was more common in IVF pregnancies, and among overweight/obese women, but we did not detect a synergistic effect of both factors. WHAT IS KNOWN ALREADY: While much is known about the impact of overweight and obesity on success rates after IVF, there is less data on maternal health outcomes. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study of 114 409 singleton pregnancies with conceptions dating from 11 January 2013 until 10 January 2014 in Ontario, Canada. The data source was the Canadian Assisted Reproductive Technologies Register (CARTR Plus) linked with the Ontario birth registry (BORN Information System). PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women who delivered at ≥20 weeks gestation, and excluded those younger than 18 years or with twin pregnancies. Women were classified according to the mode of conception (IVF or unassisted) and according to pre-pregnancy BMI (high BMI (≥25 kg/m2) or low-normal BMI (<25 kg/m2)). The main outcome was SMM, a composite of serious complications using International Classification of Diseases, 10th revision (ICD-10) codes. Secondary outcomes were gestational hypertension, pre-eclampsia, gestational diabetes and cesarean delivery. Adjusted risk ratios (aRR) with 95% CI were estimated using log binomial regression, adjusted for maternal age, parity, education, income and baseline maternal comorbidity. MAIN RESULTS AND THE ROLE OF CHANCE: Of 114 409 pregnancies, 1596 (1.4%) were IVF conceptions. Overall, 41.2% of the sample had high BMI, which was similar in IVF and non-IVF groups. We observed 674 SMM events (rate: 5.9 per 1000 deliveries). IVF was associated with an increased risk of SMM (rate 11.3/1000; aRR 1.89, 95% CI: 1.06-3.39). High BMI was modestly associated with SMM (rate 7.0/1000; aRR 1.23, 95% CI: 1.04-1.45) There was no interaction between the two factors (P = 0.22). We noted supra-additive effects of high BMI and IVF on the risk of pre-eclampsia and gestational diabetes, but not gestational hypertension or cesarean delivery. LIMITATIONS, REASONS FOR CAUTION: We were unable to assess outcomes according to reason for treatment. Type II error (beta ~25%) may affect our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results support previous data indicating a greater risk of SMM in IVF pregnancies, and among women with high BMI. However, these factors do not interact. Overweight and obese women who seek treatment with IVF should be counseled about pregnancy risks. The decision to proceed with IVF should be based on clinical judgment after considering an individual's chance of success and risk of complications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Research Institute of the McGill University Health Centre (grant 6291) and also supported by the Trio Fertility (formerly Lifequest) Research Fund. The authors report no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

The transfer of pravastatin in the dually perfused human placenta.

HMG-CoA reductase inhibitors (statins) are contraindicated during pregnancy. However, it has been suggested that the hydrophilic property of pravastatin prevents its placental transfer to the fetus, explaining neutral effects observed in controlled studies. Using the ex-vivo placental perfusion model, placental transfer of pravastatin (50 ng/ml) was determined. The mean maximum fetal concentration was 4.4 ng/ml. The transfer of pravastatin's across the placenta appears to be limited and slow. Combined with its rapid elimination half-life of 2 h and 50% protein binding, the transfer of pravastatin from maternal to fetal compartments is substantially more limited than observed in the perfusion experiments.

Ultrasound diagnosis of severe thrombotic placental damage in the second trimester: an observational study.

OBJECTIVES: To screen women with uteroplacental insufficiency between 18 and 26 weeks' gestation for sonographic evidence of destructive placental lesions, to observe the effect of low molecular-weight heparin (LMWH) in these cases, and to compare the outcome with similar but untreated controls. METHODS: We screened 180 women at high risk for placental damage using 16-week maternal serum screening (alpha-fetoprotein and human chorionic gonadotropin), placental shape and texture, and uterine artery Doppler waveforms at the 18-20-week level II examination. Serial gray-scale examinations of placental texture were performed at 22, 24 and 26 weeks. LMWH was offered to women with ultrasound evidence of destructive placental lesions in the absence of intrauterine growth restriction and/or pre-eclampsia. RESULTS: We prospectively identified six women (3.3%) with abnormal maternal serum screening and uterine artery Doppler in whom abnormal placental texture (echogenic cystic lesions) suggestive of destructive lesions in the placental parenchyma was found either at the 18-20-week ultrasound examination (n = 4), or by 26 weeks of gestation (n = 2). All six received LMWH and had live births (gestational age at delivery, 33-37 weeks; birth weight, 1000-3200 g). A further 14 women were referred with similar multiparameter evidence of placental damage at or after 26 weeks, outside the screening study. All had significant fetal growth restriction and were therefore not offered heparin. In 9/14 cases there was a perinatal death. Ischemic and/or thrombotic placental pathology was confirmed in each case, but no maternal thrombophilia disorders were identified in the 20 women. CONCLUSIONS: Integrated biochemical and ultrasound testing of placental function at 16-20 weeks of gestation, followed by serial placental gray-scale ultrasound, may be an effective method of identifying a subset of pregnancies at high risk of adverse pregnancy outcome due to destructive lesions in the placental parenchyma. This strategy of identifying thrombo-occlusive placental lesions before the development of pregnancy complications may prove useful in the design of trials to study the effectiveness of LMWH in the prevention of clinical complications resulting from thrombo-occlusive placental disease.

Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases.

Chronic use of chloroquine and hydroxychloroquine inthe treatment of rheumatic disease carries a small risk of sight-threatening pigmentary retinopathy. To obtain safety data for its use in pregnancy, we did ophthalmic examinations in 21 children born to women who took these drugsduring pregnancy. Average daily maternal doses of the two drugs were 317 mg hydroxychloroquine and 332 mg chloroquine. The mean duration of gestational exposure was 7.2 months. No ophthalmic abnormality was detected in these children. Therapeutic use of these drugs during pregnancy may not pose a significant risk of ocular toxicity to offspring.

Prevalence of antibodies to beta2-glycoprotein I in systemic lupus erythematosus and their association with antiphospholipid antibody syndrome criteria: a single center study and literature review.

OBJECTIVE: To determine the prevalence of anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) in patients with systemic lupus erythematosus (SLE), and to assess their association with and predictive value for the clinical classification criteria of the antiphospholipid antibody syndrome (APS). METHODS: One hundred thirty-three consecutive patients with SLE were recruited from 2 lupus clinics in the University of Toronto. Serum and plasma samples were tested for IgG anticardiolipin antibodies (aCL), prolonged partial thromboplastin time (PTT), a panel of lupus anticoagulant (LAC) assays, and anti-beta2-GPI (IgG, IgM, IgA). Normal ranges for the assays were established using 129 healthy controls. A literature review from 1992 to 2000 was performed using beta2-GPI, SLE, APS, thrombosis, and recurrent pregnancy loss as key search words. RESULTS: The distribution of anti-beta2-GPI antibodies (of any isotype) in each group were as follows: all patients with SLE, 36.8%; SLE with clinical features of APS, 40.4%; SLE without clinical features of APS, 34.9%; and healthy controls, 3%. The positive predictive values of prolonged PTT, IgG aCL, and anti-beta2-GPI for at least one clinical feature of APS in SLE were 59.3, 50.0, and 38.8%, respectively. There were 27 patients with SLE who had antibodies to beta2-GPI but a normal PTT and negative aCL and LAC. Six (20.7%) of these had a history of thrombosis and/or recurrent pregnancy loss. Twelve studies (including ours) were identified in which patient groups were similar and the same antibody isotype was measured. No agreement was apparent after reviewing the literature regarding an association of anti-beta2-GPI IgG and clinical features of APS in patients with SLE. CONCLUSION: Antibodies to beta2-GPI were frequently seen (35%) in our SLE population. The prevalence of anti-beta2-GPI was similar in those with (19/47) and without (39/86) APS. Anti-beta2-GPI did, however, identify 6 patients with clinical features of APS who were negative for aCL and prolonged PTT. Our results indicate that anti-beta2-GPI may provide additional information for the diagnosis of APS in SLE, but do not supercede other established assays. However, when we attempted to place our results in the context of other reports, the literature review revealed that secondary diagnoses of patient groups and assay techniques are too variable among different investigators to allow useful comparison. Thus, no conclusions could be drawn regarding anti-beta3-GPI and clinical features of secondary APS in SLE.

Spontaneous blastomere fusion after freezing and thawing of early human embryos leads to polyploidy and chromosomal mosaicism.

The incidence of blastomere fusion after cryopreservation of early human embryos (day 2 and day 3) was investigated using the standard propanediol technique. The process of fusion was observed in all developmental stages (from 2 to 10 cells) and the frequency of this event was 4.6% in day 2 (41/889) and 1.5% in day 3 (10/646) embryos that survived the thawing (embryos with 50-100% intact cells). Fusion of two, and occasionally of several, blastomeres resulted in the formation of multinucleated hybrid cells, which clearly indicated that the ploidy of these newly created cells had been altered. This event, depending on the number of fused cells per embryo, transformed the embryos into either entirely polyploid embryos (complete fusion at 2- or 3-cell stage) or into mosaics being a mixture of polyploid and normal cells. Chromosomal preparations of embryos affected by blastomere fusion indicated the presence of tetraploid mitotic plates. Also, fluorescence in-situ hybridization (FISH) analysis using DNA probes targeting unique sequences on chromosomes 9, 15, 17 and 22 indicated the existence of tetraploid and diploid fluorescence signals in the interphase nuclei within mosaics. Therefore, observations on live and fixed embryos suggested that tetraploid (4n) or hexaploid (6n) and tetraploid-diploid or more complex aberrations of ploidy might be formed as a consequence of blastomere fusion. Furthermore, this demonstrates that freezing and thawing may induce numerical chromosomal changes in human embryos.

Pharmacokinetic profile of a low-molecular weight heparin (reviparin) in pregnant patients. A prospective cohort study.

Anticoagulant therapy during pregnancy is problematic. Patients are frequently treated with long-term low-molecular weight heparin despite a lack of evidence for its effectiveness, and in the absence of validated dosing recommendations. The objectives of this investigation were to characterize the safety and pharmacokinetic behavior of a low-molecular weight heparin (reviparin) administered throughout pregnancy. Forty-two patients followed in a tertiary-care rheumatology clinic who received prophylactic doses of reviparin (4900 anti-Xa units subcutaneously once daily) were enrolled in this investigation. Anti-Xa heparin levels, weights, and gestational ages of the patients were obtained on up to four occasions distributed throughout their pregnancy. The achieved anti-Xa heparin levels were highly correlated with the patient's weight, irrespective of the gestational age. No toxicity other than injection site hematomas was observed. The achieved intensity of anticoagulation with reviparin varies during pregnancy in direct proportion to the patient's weight. This variability may mandate dose adjustment in response to changes in a patient's weight during pregnancy, particularly if low-molecular weight heparin is administered at therapeutic doses.

The effects of low-intensity warfarin on coagulation activation in patients with antiphospholipid antibodies and systemic lupus erythematosus.

The optimal intensity of oral anticoagulant therapy for the prevention of thromboembolism in patients with antiphospholipid antibodies (APLA) and systemic lupus erythematosus is controversial. Retrospective studies have suggested that patients with APLA are resistant to oral anticoagulant therapy, with a targeted International Normalization Ratio (INR) of 2.0 to 3.0, and that a higher intensity of anticoagulation (INR: 2.6 to 4.5) is required to prevent recurrent thromboembolism. To investigate if patients with APLA are resistant to the anticoagulant effect of low intensities of warfarin therapy, we performed a randomized trial in which 21 patients with APLA and systemic lupus erythematosus were allocated to receive one of three intensities of warfarin (INR: 1.1 to 1.4, 1.5 to 1.9 or 2.0 to 2.5) or placebo for four months. The main outcome was the effect of each intensity of warfarin therapy on prothrombin fragment 1+2 level (F1+2), that was used as a marker of coagulation activation. When F1+2 levels in patients allocated to the three warfarin intensities were compared to F1+2 levels in the placebo group, there was a statistically significant decrease (p<0.05) in the patient group receiving warfarin with a targeted INR of 2.0 to 2.5 at two, three and four months, and in the patient group with a targeted of INR 1.5 to 1.9 at three months. We conclude that in patients with APLA and systemic lupus erythematosus, warfarin therapy, with a targeted INR of 2.0 to 2.5, is effective in suppressing coagulation activation, and therefore, might be effective in preventing thromboembolism.

Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review.

Placental infarction or abruption, recurrent pregnancy loss and pre-eclampsia are thought to arise due to defects within the placental vascular bed. Deficiencies of vitamin B12 and folate, or other abnormalities within the methionine-homocyst(e)ine pathway have been implicated in the development of such placental diseases. We conducted a systematic literature review to quantify the risk of placental disease in the presence of these metabolic defects. Studies were identified through OVID Medline between 1966 and February 1999. Terms relating to the measurement of vitamin B12, folic acid, methylenetetrahydrofolate reductase or homocyst(e)ine were combined with those of pre-eclampsia, placental abruption/infarction or spontaneous and habitual abortion. Human studies comprising both cases and controls and published in the English language were accepted. Their references were explored for other publications. Data were abstracted on the matching of cases with controls, the mean levels of folate, B12 or homocyst(e)ine in each group or the frequency of the homozygous state for the thermolabile variant of methylenetetrahydrofolate reductase. The definition of 'abnormal' for each exposure was noted and the presence or absence of the exposure of interest for each outcome was calculated as an absolute rate with a 95 per cent confidence interval. The crude odds ratios were calculated for each study and then pooled using a random effects model. Eighteen studies were finally included. Eight studies examined the risk of placental abruption/infarction in the presence of vitamin B12 or folate deficiency, or hyperhomocyst(e)inaemia. Folate deficiency was a prominent risk factor for placental abruption/infarction among four studies, though not statistically significant (pooled odds ratio 25.9, 95 per cent CI 0.9-736.3). Hyperhomocyst(e)inaemia was also associated with placental abruption/infarction both without (pooled odds ratio 5.3, 95 per cent CI 1.8-15.9) and with methionine loading (pooled odds ratio 4.2, 95 per cent CI 1.2-15.0), as was the homozygous state for methylenetetrahydrofolate reductase (pooled odds ratio 2.3, 95 per cent CI 1.1-4.9). Vitamin B12 deficiency was not a demonstrable risk factor. Eight studies examined blood levels among women with spontaneous abortion or recurrent pregnancy loss. The pooled odds ratios were 3.4 (95 per cent CI 1.2-9.9) for folate deficiency, 3.7 (95 per cent CI 0.96-16.5) for hyperhomocyst(e)inaemia following methionine challenge, and 3.3 (95 per cent CI 1.2-9.2) for the methylenetetrahydrofolate reductase mutation. Five case-control studies examined the relationship between pre-eclampsia and abnormal levels of vitamin B12, folate, homocyst(e)ine or methylenetetrahydrofolate reductase. Folate deficiency was not an associated risk factor (odds ratio 1.2, 95 per cent CI 0.5-2.7), but hyper-homocyst(e)inaemia was (pooled odds ratio 20.9, 95 per cent CI 3.6-121.6). Similarly, homozygosity for the methylenetetrahydrofolate reductase thermolabile variant was associated with a moderate risk of preeclampsia (odds ratio 2.6, 95 per cent CI 1.4-5.1). Some pooled data were associated with significant statistical heterogeneity, however. There is a general agreement among several observational studies that folate deficiency, hyperhomocyst(e)inaemia and homozygosity for the methylenetetrahydrofolate reductase thermolabile variant are probable risk factors for placenta-mediated diseases, such as pre-eclampsia, spontaneous abortion and placental abruption. Vitamin B12 deficiency is less well defined as an important risk factor. Due to the limited quality of these data, including insufficient matching of cases with controls, and possible laboratory measurement bias relating to pregnancy, prospective studies are needed to confirm these findings and guide future preventative and therapeutic research.

Umbilical artery blood flow velocity in pregnancies complicated by systemic lupus erythematosus.

PURPOSE: We evaluated the role of umbilical artery Doppler velocimetry in the surveillance of pregnancies complicated by systemic lupus erythematosus (SLE). METHODS: We retrospectively studied 56 women with SLE whose pregnancies were managed at our perinatal center between 1988 and 1995. RESULTS: Absent or reversed end-diastolic flow velocity was detected in 6 (11%) of 56 patients. This sub-group of patients had an increased risk of pre-eclampsia, intrauterine growth restriction, cesarean section, and preterm delivery. CONCLUSIONS: A high incidence (11%) of abnormal umbilical artery waveforms was detected. This finding was associated with an increased risk of maternal and fetal complications.

Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.

BACKGROUND: Recurrent fetal loss has been well described in women with antiphospholipid antibodies. Such women also often have other autoantibodies commonly found in patients with systemic lupus erythematosus. Treating them with prednisone and aspirin may reduce the risk of fetal loss. METHODS: We screened 773 nonpregnant women who had the unexplained loss of at least two fetuses for antinuclear, anti-DNA, antilymphocyte, and anticardiolipin antibodies and for the lupus anticoagulant. Of 385 women with at least one autoantibody, 202 who later became pregnant were randomly assigned in equal numbers to receive either prednisone (0.5 to 0.8 mg per kilogram of body weight per day) and aspirin (100 mg per day) or placebo for the duration of the pregnancy. The women were stratified according to age (18 to 34 years or 35 to 39 years) and the week of gestation at which the previous fetal losses had occurred (< or = 12 or > 12 weeks). The primary outcome measure was a successful pregnancy. RESULTS: Live infants were born to 66 women in the treatment group (65 percent) and 57 women in the placebo group (56 percent, P=0.19). More infants were born prematurely in the treatment group than in the placebo group (62 percent vs. 12 percent, P<0.001). The major side effects of therapy in the mothers were hypertension (treatment group, 13 percent; placebo group, 5 percent; P=0.05) and diabetes mellitus (15 percent and 5 percent, P=0.02). CONCLUSIONS: Treating women who have autoantibodies and recurrent fetal loss with prednisone and aspirin is not effective in promoting live birth, and it increases the risk of prematurity.

Increased liking for salty foods in adolescents exposed during infancy to a chloride-deficient feeding formula.

In a model selected for its similarity to the hormonal consequences of sodium deficiency, food choices of 169 adolescents exposed during infancy to a chloride-deficient feeding formula were compared to those of their closest-aged siblings. Questionnaires completed by parents were used to assess food likes and dislikes. When a salty food was mentioned by parents as one craved by either child, exposed children were more likely than siblings to crave that food (p = 0.005). Frequencies of two of four salt-related dietary behaviors [adding salt to food before tasting (p = 0.03) and to atypical foods (p = 0.05)] were higher in exposed adolescents than in siblings, while frequencies of parallel sugar-related behaviors did not differ between the groups. Foods classified as being lower in saltiness were disliked by exposed children relative to siblings (p = 0.003), although ratings of foods higher in saltiness did not differ. Finally, when asked to rank eight foods in order of preference, ranks assigned by exposed children to salty foods tended (p = 0.07) to be higher than those of siblings. The data suggest a persistent effect of early experience on human salt preference. Additional studies are needed to determine whether salt intake is increased in this and other populations that suffer electrolyte depletion during early development.

Sera from habitual aborters induce monocyte procoagulant activity: a lymphocyte-dependent event.

Placental thrombosis is a prominent feature in patients with unexplained recurrent fetal loss. To determine whether induction of monocyte procoagulant activity might be a relevant mechanism for unexplained recurrent fetal loss, peripheral blood mononuclear cells isolated from normal healthy controls were cocultured with (a) sera from normal healthy controls (n = 16), (b) sera from habitual aborters (n = 41), and (c) lipopolysaccharide as a positive control. Sera from three patients were fractionated on Sephracryl S-300 and the inducing molecule(s) characterized. Sera from normal healthy controls failed to induce procoagulant activity above basal levels of 21 +/- 4.6 mU/10(5) peripheral blood mononuclear cells. Of the sera from 41 habitual aborters examined 26 (63%) induced procoagulant to a mean value of 410 +/- 48 mU/10(5) peripheral blood mononuclear cells (P < 0.01). Sera from 15 patients failed to augment procoagulant activity. The induction of procoagulant activity was maximal after 6 hr of incubation and was lymphocyte dependent. Fractionation of serum from the three patients on Sepharcryl S300 revealed the procoagulant activity (PCA)-inducing factor(s) to have a molecular weight of between 300,000 and 800,000 Da. The serum factor was found to be heat, alkaline, and acid sensitive. Both anti-IgM and anti-IgA immunoabsorbents reduced the PCA-inducing factor. We conclude that IgM and IgA from some patients with unexplained recurrent fetal loss are capable of inducing procoagulant activity and could contribute to the development of placental microthrombi and infarction, prominent features of this syndrome.