Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial.

BACKGROUND: Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. METHODS: In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. FINDINGS: Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4-24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8-26·3%]; risk difference -1·8% [95% CI -10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI -6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3-18·4; p=0·01). INTERPRETATION: Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.

The pregnant heart: cardiac emergencies during pregnancy.

BACKGROUND: Cardiovascular emergencies in pregnant patients are often considered a rare event; however, heart disease as a cause of maternal mortality is steadily increasing. DISCUSSION: In this article, we review 3 common cardiovascular emergencies and the important subtle differences in their treatment in the pregnant patient: peripartum/postpartum cardiomyopathy, acute myocardial infarction, and cardiac resuscitation. CONCLUSION: Managing these conditions in the emergency department setting requires a high index of suspicion, knowledge of anatomical and physiologic changes associated with pregnancy, and updated management strategies related to optimizing maternal and fetal health.

Pulmonary embolism in pregnancy.

Pulmonary embolism (PE) is the leading cause of maternal mortality in the developed world. Mortality from PE in pregnancy might be related to challenges in targeting the right population for prevention, ensuring that diagnosis is suspected and adequately investigated, and initiating timely and best possible treatment of this disease. Pregnancy is an example of Virchow's triad: hypercoagulability, venous stasis, and vascular damage; together these factors lead to an increased incidence of venous thromboembolism. This disorder is often suspected in pregnant women because some of the physiological changes of pregnancy mimic its signs and symptoms. Despite concerns for fetal teratogenicity and oncogenicity associated with diagnostic testing, and potential adverse effects of pharmacological treatment, an accurate diagnosis of PE and a timely therapeutic intervention are crucial. Appropriate prophylaxis should be weighed against the risk of complications and offered according to risk stratification.

Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample.

OBJECTIVE: Evaluate the association of OSA with birth outcomes including the risk of congenital anomalies and the need for a higher level of clinical care at delivery. METHODS: Population-based study that linked newborn records with maternal records. Data from 95 perinatal centers across all geographic census divisions of the U.S. of women with a delivery diagnosis from 2010 to 2014 whose records could be linked to the corresponding newborn record. An International Classification of Diseases, ninth Revision (ICD-9) code for sleep apnea was used to identify exposure and outcome variables. Univariate and multivariate logistic regression analyses were performed with a model that included substance use, obesity, diabetes, maternal co-morbidities, and pregnancy complications. RESULTS: In this study, 1,423,099 maternal records were linked to live newborn records. OSA was associated with a higher risk for congenital anomalies in offspring (aOR 1.26, 1.11 to 1.43), with the highest risk being that of musculoskeletal anomalies (aOR 1.89, 1.16 to 3.07) after adjusting for comorbidities and potential teratogens. Neonates born to mothers with OSA were more likely to be admitted to the intensive care unit (25.3% vs. 8.1%, p < 0.001), require resuscitation (aOR 2.76, 1.35 to 5.64) and have a longer hospital stay (aOR 2.25, 1.85 to 2.65). CONCLUSIONS: Although our study does not establish causation, it is the first to demonstrate a higher risk of congenital anomalies and resuscitation at birth in neonates of mothers with OSA, emphasizing the importance of identifying OSA in pregnant women and women of reproductive age.

The incidence of deep vein thrombosis in women undergoing cesarean delivery.

INTRODUCTION: Venous thromboembolism (VTE) is one of the leading causes of maternal mortality in the United States. Cesarean delivery is a known risk factor. This study was to determine the incidence of deep vein thrombosis (DVT) post cesarean delivery. MATERIALS AND METHODS: This was a prospective cohort study where two patients having undergone cesarean delivery each day were randomly selected. A lower extremity compression ultrasound was performed prior to hospital discharge. If no DVT was detected, participants were asked to return for a second ultrasound two weeks postpartum. Participants were also telephone-interviewed at three months for reported VTE. RESULTS: Of the 194 patients who consented to study participation, only one participant developed DVT after cesarean delivery, giving an overall incidence of 0.5% (95% CI, 0.1 to 2.8%). There were no DVT identified on the second ultrasound nor VTE reported 3 months postpartum. CONCLUSIONS: We found the DVT rate after cesarean delivery to be 0.5%.

Early onset preeclampsia and second trimester serum markers.

OBJECTIVE: To examine serum markers measured in the second trimester to identify women who subsequently develop preeclampsia. METHODS: Clinically defined preeclampsia was confirmed in 45 women who had provided a serum sample as part of Down syndrome screening. Preeclampsia was categorized as mild or severe, as well as early (<32 weeks) or late onset. Each case was matched with five controls based on gestational age and date of serum collection. Stored sera were retrieved and tested for inhibin A, soluble vascular endothelial growth factor receptor 1 (sVEGF R1), placental growth factor (PlGF), and endoglin. Results were converted to multiples of the median (MoM) and compared in case and control pregnancies. Univariate analysis was used to identify the strongest markers, which were then used in a multivariate model. RESULTS: Inhibin A, PlGF, and endoglin were consistently associated with preeclampsia, especially for early onset disease. A multivariate model using the three markers could identify 50% of the pregnancies with early onset preeclampsia with a 2% false positive rate. CONCLUSION: The levels of inhibin A, PlGF, and endoglin in the second trimester can be combined using a predictive model to provide individualized risk estimates for early onset preeclampsia.

Inherited thrombophilia and pregnancy complications revisited.

Inherited thrombophilias are not yet established as a cause of placenta-mediated pregnancy complications, such as fetal growth restriction, preeclampsia, abruption, and pregnancy loss. An inherited thrombophilia is only one of many factors that lead to development of these diseases and is unlikely to be the unique factor that should drive management in subsequent pregnancies. The paucity of evidence for benefit, coupled with a small potential for harm, suggests that low molecular weight heparin should be considered an experimental drug for these indications until data from controlled trials are published. At present, women with a history of placenta-mediated pregnancy complications, with or without a thrombophilia, should be followed closely without routine prophylactic low molecular weight heparin other than for prevention of venous thromboembolism in limited circumstances.

Obstructive sleep apnea in pregnancy is associated with adverse maternal outcomes: a national cohort.

OBJECTIVE: Pregnancy and the obesity epidemic impacting women of reproductive age appear to predispose women to obstructive sleep apnea (OSA) in pregnancy. The aim of this study is to examine the association between OSA and adverse maternal outcomes in a national cohort. METHODS: The National Perinatal Information Center in the US was used to identify women with a delivery discharge diagnosis of OSA from 2010 to 2014. We used the International Classification of Diseases, ninth Revision to classify OSA diagnosis and maternal outcomes. MEASUREMENTS: The sample consisted of 1,577,632 gravidas with a rate of OSA of 0.12% (N = 1963). There was a significant association between OSA and preeclampsia (adjusted odds ratio (aOR) 2.22, 95% confidence interval (CI) 1.94-2.54), eclampsia (aOR 2.95, 1.08-8.02), and gestational diabetes (aOR 1.51, 1.34-1.72) after adjusting for a comprehensive list of covariates which includes maternal obesity. OSA status was also associated with a 2.5-3.5-fold increase in risk of severe complications such as cardiomyopathy, congestive heart failure, and hysterectomy. Length of hospital stay was significantly longer (5.1 + 5.6 vs 3.0 + 3.0 days, p < 0.001) and odds of an admission to an intensive care unit higher (aOR 2.74, 2.36-3.18) in women with OSA. CONCLUSIONS: Compared to pregnant women without OSA, pregnant women with OSA have a significantly higher risk of pregnancy-specific complications such as gestational hypertensive conditions and gestational diabetes, and rare medical and surgical complications such as cardiomyopathy, pulmonary edema, congestive heart failure, and hysterectomy. OSA diagnosis was also associated with a longer hospital stay and significantly increased odds for admission to the intensive care unit.

Bone density changes in women who receive thromboprophylaxis in pregnancy.

OBJECTIVE: The purpose of this study was to compare unfractionated heparin therapy to the low molecular weight heparin, enoxaparin sodium, and their effects on bone mineral density over the course of pregnancy. STUDY DESIGN: Pregnant patients whose condition required thromboprophylaxis were recruited in this prospective randomized controlled trial and were assigned to receive either unfractionated heparin therapy or low molecular weight heparin therapy. Bone mineral density was measured by dual energy x-ray absorptiometry at the proximal femur on enrollment and again shortly after delivery. RESULTS: One hundred twenty women were enrolled, and 98 women completed the study. There was no difference in the change in bone mineral density at the femoral neck (P = .054) or total proximal femur (P = .584) between groups. Only 1 of 40 patients (2.5%) who received unfractionated heparin therapy and 1 of 49 patients (2.0%) who received low molecular weight heparin therapy (P = 1.0) experienced bone loss of > or = 10% at the femoral neck. CONCLUSION: In this study, the incidence of clinically significant bone loss (> or = 10%) in the femur in women who received thromboprophylaxis in pregnancy is approximately 2% to 2.5% and appears to be similar, regardless of whether the patient receives low molecular weight heparin therapy or unfractionated heparin therapy.

Use of first or second trimester serum markers, or both, to predict preeclampsia.

OBJECTIVES: Preeclampsia is a serious complication of pregnancy, threatening fetal and maternal health. The aim of our study is to examine the association between preeclampsia and biochemical markers, in matched first and second trimester maternal serum samples. STUDY DESIGN: This is a nested case/control study derived from the cohort of pregnancies delivering at Women & Infants Hospital. Cases were identified at a clinic or by hospital codes, and individually confirmed by record review. Stored samples were available from 'integrated' Down syndrome screening. Results were expressed as multiples of the median (MoM). MAIN OUTCOME MEASURES: Preeclampsia was classified as early/severe, late/severe, or mild based on professional guidelines. An additional adverse outcome group had only gestational hypertension. RESULTS: Ninety-eight cases were each matched with five control pregnancies. Population distribution parameters and within and between trimester correlations were derived for cases and controls for six markers, as well as in case subgroups. The strongest associations were for early/severe preeclampsia with second trimester PAPP-A (rank sum test 2.30, p<0.01); PlGF (2.60, p<0.05) inhibin A (4.45, p<0.05) and endoglin (4.25, p<0.05). No strong associations were found for sVEGF-R and FLRG. Second trimester associations were stronger than those in the first (e.g., PAPP-A 2.45, p<0.01). No between-trimester associations were found that would provide important improvements in prediction. CONCLUSIONS: This matched analysis of the serum markers in early pregnancy allows for direct comparison of first and second trimester associations with preeclampsia. PAPP-A and PlGF are equally and highly predictive of early/severe preeclampsia.

Special hematologic issues in the pregnant patient.

Evaluation and treatment of hematologic disorders in pregnancy requires an understanding of normal physiologic changes during pregnancy. Hematologic disorders may be caused by preexisting conditions, normal physiologic changes, or can be acquired. A multidisciplinary approach is often necessary for monitoring and treatment of both the mother and the fetus. In general, outcomes are good for both the mother and the fetus.

The impact of an educational pamphlet on knowledge and anxiety in women with preeclampsia.

OBJECTIVE: This study was undertaken to evaluate whether or not an educational pamphlet could improve knowledge without increasing anxiety in women with preeclampsia. METHODS: One hundred women recruited from an inpatient setting with suspected or proven preeclampsia were asked to answer a questionnaire assessing demographics, knowledge (primary outcome), anxiety and satisfaction (secondary outcomes) after being randomized to an intervention group (who received a pamphlet) or a control group (who did not received a pamphlet). The pamphlet and questionnaire, both designed by a multidisciplinary team, were read and answered at the same time. RESULTS: Baseline and demographic characteristics were similar between the two groups. Knowledge about the symptoms of pre-eclampsia was excellent in both groups (61% to 100% correct answers). Women in both groups were well aware that preeclampsia in the past (P = 0.22) and a family history of preeclampsia (P = 0.57) were risk factors. There was a significant difference in knowledge about the risk of some fetal complications, including death (90% versus 39%, P < 0.01) and all maternal complications (P < 0.05) favouring the intervention group. Despite increased knowledge about preeclampsia and its risks, anxiety was not greater in the intervention group. Overall, there was a trend towards less knowledge in vulnerable subgroups (non-white, low income and schooling levels), but the improvement of knowledge with the pamphlet was equivalent. Baseline anxiety was higher in the vulnerable groups, but was generally not increased by the pamphlet. CONCLUSION: An educational pamphlet for women with suspected preeclampsia was able to increase knowledge without increasing anxiety.