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1.  Coagulation and Placenta-Mediated Complications 
Pregnancy is a physiological hypercoagulable state, preparing the mother for the hemostatic challenge of delivery. However, this is associated with an increased risk of venous thrombosis and placenta-mediated complications, which present major challenges for mother and fetus. Although these conditions are heterogeneous in their pathophysiology, hereditary and acquired thrombophilia has been associated with recurrent pregnancy loss and gestational vascular complications, such as early-onset pre-eclampsia and placental abruption. Prevention of such placenta-mediated complications, which collectively complicate up to 15% of pregnancies, is a major issue for women’s health. Prospective interventional studies stratified by current knowledge of pathophysiological mechanisms related to placental and systemic hemostatic alterations will impact on the management of pregnancies at risk of these complications.
doi:10.5041/RMMJ.10168
PMCID: PMC4222423  PMID: 25386350
Placenta-mediated complications; recurrent pregnancy loss; thrombophilia
2.  PREECLAMPSIA IS ASSOCIATED WITH COMPROMISED MATERNAL SYNTHESIS OF LONG CHAIN POLYUNSATURATED FATTY ACIDS LEADING TO OFFSPRING DEFICIENCY 
Hypertension  2012;60(4):1078-1085.
Obesity and excessive lipolysis are implicated in preeclampsia. Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with preeclampsia (n=62) or intrauterine growth restriction (n=23) compared to healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid metabolizing enzymes and placental fatty acid transporters were compared. Mothers with preeclampsia had higher plasma triglyceride (21%, p<0.001) and non-esterified fatty acid (50%, p<0.001) concentrations than Controls. Concentrations of major n-6 and n-3 long chain polyunsaturated fatty acids in erythrocytes were 23-60% lower (all p<0.005) in preeclampsia and intrauterine growth restriction mothers and offspring compared to Controls. Subcutaneous adipose tissue Δ-5 and Δ-6 desaturase and very long chain fatty acid elongase mRNA expression was lower in preeclampsia than Controls [Control 3.38(2.96) vs preeclampsia 1.83(1.91), p=0.030; 3.33(2.25) vs 1.03(0.96), p<0.001; 0.40 (0.81) vs 0.00 (0.00), p=0.038 (square root) expression relative to control gene respectively]. Low maternal and fetal long chain polyunsaturated fatty acid concentrations in preeclampsia may be the result of decreased maternal synthesis.
doi:10.1161/HYPERTENSIONAHA.112.197897
PMCID: PMC3604624  PMID: 22949531
fatty acid; pregnancy; pre-eclampsia; intrauterine growth restriction
3.  Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 
BMC Geriatrics  2011;11:8.
Background
Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.
Methods
This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.
Results
There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.
Conclusions
Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.
Trial Registration
Not applicable when study undertaken.
doi:10.1186/1471-2318-11-8
PMCID: PMC3053238  PMID: 21342490
4.  The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies 
PLoS Medicine  2010;7(6):e1000292.
Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.
Background
Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications.
Methods and Findings
A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06–2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89–1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80–1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79–1.99) or SGA (OR 1.25, 95% CI 0.92–1.70).
Conclusions
Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The death of a baby at any stage of pregnancy is heartbreaking and, sadly, a quarter of women lose their baby during pregnancy or birth. A pregnancy can go wrong for many reasons but complications that are caused by problems with the placenta affect more than one in 20 pregnancies. The placenta is the organ that links the mother to her baby. It is full of blood vessels that transfer oxygen and nutrients from the mother to her baby and that take carbon dioxide and waste products away from the baby. If the placenta does not circulate blood efficiently between the mother and baby (placental insufficiency), the result can be pregnancy loss (spontaneous miscarriage or still birth), pre-eclampsia (a sudden rise in blood pressure in late pregnancy that is life-threatening for both mother and baby), a small for gestational age pregnancy (the baby does not grow properly during pregnancy), or placental abruption (separation of the placenta from the wall of the womb, a condition that deprives the baby of oxygen and nutrients and can cause severe maternal blood loss).
Why Was This Study Done?
One possible cause of placental insufficiency is inherited thrombophilia, an increased tendency to form blood clots that occurs in more than 10% of people. The commonest inherited thrombophilias are factor V Leiden (FVL) and prothrombin gene mutation (PGM). Comparisons of the frequencies of these thrombophilias in women who have had placenta-mediated pregnancy complications with the frequencies in women who have not had complications (“retrospective case control studies”) have found an association between thrombophilia and pregnancy complications. As a result, doctors sometimes give heparin to women with thrombophilia who have had a poor pregnancy outcome to reduce blood clotting during subsequent pregnancies (anticoagulant therapy). However, a better way to determine whether thrombophilia and pregnancy problems are associated is to recruit groups of women with and without thrombophilia and follow them during pregnancy to see whether they develop complications —“prospective cohort studies.” In this study, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of studies) of prospective cohort studies to estimate the risk of placenta-mediated pregnancy complications in women with FVL or PGM.
What Did the Researchers Do and Find?
The researchers identified ten prospective cohort studies that examined the association between FVL/PGM and placenta-mediated pregnancy complications and that met their predefined criteria. In their meta-analysis of these studies, they estimated that the absolute risk of pregnancy loss in women with FVL was 4.2% whereas the absolute risk of pregnancy loss in women without FVL was 3.2%. In other words, women with FVL had a 52% higher risk of pregnancy loss than women without FVL (an odds ratio of 1.52). The absolute increased risk, however, was 1%. There was no significant association (a significant association is one that is unlikely to have occurred by chance) between PGM and pregnancy loss. Similarly, there was no significant association between either of the thrombophilias and pre-eclampsia, small for gestational age pregnancies, or placental abruption. Finally, there was no significant association between either FVL or PGM and the composite outcome of any placenta-mediated pregnancy complication (pregnancy loss, pre-eclampsia, small for gestational age, and placental abruption).
What Do These Findings Mean?
These findings suggest that women with FVL have a small absolute increased risk of pregnancy loss but that neither FVL nor PGM increase a woman's risk of pre-eclampsia or of giving birth to a small for gestational age infant. Although there seems to be no increased risk of pregnancy loss with PGM, more research is needed to confirm this finding and to confirm the lack of an association between thrombophilia and placental abruption. The researchers also warn that all these reassuring findings should be treated cautiously because of variability between the studies in how complications were defined. Importantly, however, these findings suggest that the introduction of anticoagulant therapies for women with thrombophilia and a history of pregnancy complications on the basis of retrospective case control studies might have been premature. Anticoagulant therapy should be considered experimental, therefore, until controlled trials of the approach have been completed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000292.
Womenshealth.gov, a US Department of Health and Human Services resource, provides information on pregnancy complications
Tommys, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on problems in pregnancy
The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, also has information on complications during pregnancy, including a fact sheet on thrombophilias and pregnancy
The US National Alliance for Thrombosis and Thrombophilia has detailed information on thrombophilia and an article on the evolving story of thrombophilia and pregnancy outcomes
doi:10.1371/journal.pmed.1000292
PMCID: PMC2885985  PMID: 20563311
5.  Contribution of smoking during pregnancy to inequalities in stillbirth and infant death in Scotland 1994-2003: retrospective population based study using hospital maternity records 
Objective To quantify the contribution of smoking during pregnancy to social inequalities in stillbirth and infant death.
Design Population based retrospective cohort study.
Setting Scottish hospitals between 1994 and 2003.
Participants Records of 529 317 singleton live births and 2699 stillbirths delivered at 24-44 weeks’ gestation in Scotland from 1994 to 2003.
Main outcome measures Rates of stillbirth and infant, neonatal, and post-neonatal death for each deprivation category (fifths of postcode sector Carstairs-Morris scores); contribution of smoking during pregnancy (“no,” “yes,” or “not known”) in explaining social inequalities in these outcomes.
Results The stillbirth rate increased from 3.8 per 1000 in the least deprived group to 5.9 per 1000 in the most deprived group. For infant deaths, the rate increased from 3.2 per 1000 in the least deprived group to 5.4 per 1000 in the most deprived group. Stillbirths were 56% more likely (odds ratio 1.56, 95% confidence interval 1.38 to 1.77) and infant deaths were 72% more likely (1.72, 1.50 to 1.97) in the most deprived compared with the least deprived category. Smoking during pregnancy accounted for 38% of the inequality in stillbirths and 31% of the inequality in infant deaths.
Conclusions Both tackling smoking during pregnancy and reducing infants’ exposure to tobacco smoke in the postnatal environment may help to reduce stillbirths and infant deaths overall and to reduce the socioeconomic inequalities in stillbirths and infant deaths perhaps by as much as 30-40%. However, action on smoking on its own is unlikely to be sufficient and other measures to improve the social circumstances, social support, and health of mothers and infants are needed.
doi:10.1136/bmj.b3754
PMCID: PMC2755727  PMID: 19797343
6.  Effects of algorithm for diagnosis of active labour: cluster randomised trial 
Objective To compare the effectiveness of an algorithm for diagnosis of active labour in primiparous women with standard care in terms of maternal and neonatal outcomes.
Design Cluster randomised trial.
Setting Maternity units in Scotland with at least 800 annual births.
Participants 4503 women giving birth for the first time, in 14 maternity units. Seven experimental clusters collected data from a baseline sample of 1029 women and a post-implementation sample of 896 women. The seven control clusters had a baseline sample of 1291 women and a post-implementation sample of 1287 women.
Intervention Use of an algorithm by midwives to assist their diagnosis of active labour, compared with standard care.
Main outcomes Primary outcome: use of oxytocin for augmentation of labour. Secondary outcomes: medical interventions in labour, admission management, and birth outcome.
Results No significant difference was found between groups in percentage use of oxytocin for augmentation of labour (experimental minus control, difference=0.3, 95% confidence interval −9.2 to 9.8; P=0.9) or in the use of medical interventions in labour. Women in the algorithm group were more likely to be discharged from the labour suite after their first labour assessment (difference=−19.2, −29.9 to −8.6; P=0.002) and to have more pre-labour admissions (0.29, 0.04 to 0.55; P=0.03).
Conclusions Use of an algorithm to assist midwives with the diagnosis of active labour in primiparous women did not result in a reduction in oxytocin use or in medical intervention in spontaneous labour. Significantly more women in the experimental group were discharged home after their first labour ward assessment.
Trial registration Current Controlled Trials ISRCTN00522952.
doi:10.1136/bmj.a2396
PMCID: PMC2601030  PMID: 19064606
7.  Centile charts for birthweight for gestational age for Scottish singleton births 
Background
Centile charts of birthweight for gestational age are used to identify low birthweight babies. The charts currently used in Scotland are based on data from the 1970s and require updating given changes in birthweight and in the measurement of gestational age since then.
Methods
Routinely collected data of 100,133 singleton births occurring in Scotland from 1998–2003 were used to construct new centile charts using the LMS method.
Results
Centile charts for birthweight for sex and parity groupings were constructed for singleton birth and compared to existing charts used in Scottish hospitals.
Conclusion
Mean birthweight has been shown to have increased over recent decades. The differences shown between the new and currently used centiles confirm the need for more up-to-date centiles for birthweight for gestational age.
doi:10.1186/1471-2393-8-5
PMCID: PMC2268653  PMID: 18298810
8.  Obesity and reproduction 
BMJ : British Medical Journal  2006;333(7579):1159-1162.
doi:10.1136/bmj.39049.439444.DE1
PMCID: PMC1676144  PMID: 17138998
9.  IMOP: randomised placebo controlled trial of outpatient cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour – clinical trial with analyses of efficacy, cost effectiveness and acceptability 
Background
There is increasing interest in carrying out pre-induction cervical ripening on an outpatient basis. However, there are concerns about the use of prostaglandins, the agents commonly used in hospital settings for this indication, because prostaglandins induce uterine contractions that may lead to fetal hypoxia. Indeed, in a recent study we demonstrated abnormalities in 9% of fetal heart rate tracings performed following prostaglandin induced cervical ripening at term. In contrast, we confirmed in the same study that isosorbide mononitrate (IMN) (administered on an inpatient basis) was both effective in inducing cervical ripening at term, and was associated with no associated fetal heart rate abnormalities.
Methods/design
The aim of this study is to determine whether IMN self administered by women on an outpatient basis improves the process of induction of labour. Specifically, we hypothesise that the use of outpatient IMN will result in a shorter inpatient stay before delivery, decreased costs to the health service and greater maternal satisfaction with ripening and induction of labour, compared with placebo treatment.
In the study described here (the "IMOP" study), women scheduled for induction of labour at term, and who require pre-induction cervical ripening will be randomised to self-administer at home either IMN 40 mg, or a placebo, each vaginally, at 48 hours, 32 hours and 16 hours before scheduled hospital admission.
After admission to hospital, treatment will revert to the usual induction of labour protocol. We will compare the primary outcomes of the elapsed time interval from hospital admission to vaginal delivery, the costs to the health service of induction of labour, and women's experience of induction of labour in the two groups.
Discussion
This trial will provide evidence on the efficacy of outpatient IMN for pre-induction cervical ripening at term. We will study a formulation of IMN which is cheap and widely available. If the treatment is effective, acceptable to women, and cost effective, it could be implemented into obstetric practice worldwide.
Trial registration
The trial has been registered on the International Standard Randomised Controlled Trial Number Register (ISRCTN) and given the registration number ISRTN39772441.
doi:10.1186/1471-2393-6-25
PMCID: PMC1569865  PMID: 16869966
10.  Pre-eclampsia matters 
BMJ : British Medical Journal  2005;330(7491):549-550.
PMCID: PMC554013  PMID: 15760971

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