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International audience; This paper depicts an overview of debates that have taken place during the 14 years of the International Workshops on Reproductive Immunology/Immunological Tolerance and Immunology of Preeclampsia. This 8th event in 2012 (Reunion island, overseas department of France in the Indian Ocean) witnessed a consensus among immunologists on the key role of regulatory T-cells in the orchestration of trophoblastic invasion at the maternal–fetal interface, while they represent some 10% of the immunological cellular repertoire at the site of implantation (NK cells representing 70%). On the vascular side, the upregulation of carbon monoxide CO, metabolite of heme oxygenase-1 (HO-1; by inhibiting soluble Flt-1, SFlt-1, and soluble endoglin, SEng, release), explains the very promising protective and potentially therapeutic effect of pravastatin in preeclampsia and the paradoxical strong protective effect of cigarette smoking on preeclampsia. Finally, there was, through a study performed on Mauritius island a great interest in the inositol phosphoglycans P-type (IPG-P) as a reliable, cheap, and predictive urinary test in preeclamptic women (a few weeks before the clinical onset of the disease). Besides the interest of a specific test, IPG-P may also partially explain the global endothelial cell disease encountered in preeclampsia. Furthermore, the Appendix of this paper lists the programs of all the workshops that have taken place since 1998.

We aimed to determine whether the ACE A11860G genotype is associated with small for gestational age babies (SGA) and to determine whether the association is affected by environmental factors and fetal sex. Overall, 3234 healthy nulliparous women with singleton pregnancies, their partners and babies were prospectively recruited in Adelaide, Australia and Auckland, New Zealand. Data analyses were con- fined to 2121 Caucasian parent-infant trios, among which 216 were pregnancies with SGA infants and 1185 were uncomplicated pregnancies. Women with the ACE A11860G GG genotype in the combined and Adelaide cohorts had increased risk for SGA (odds ratios (OR) 1.5, 95% confidence interval (CI) 1.1 -2.1 and OR 2.0, 95% CI 1.3- 3.3, respectively) and delivered lighter babies (P ¼ 0.02; P ¼ 0.007, respectively) com- pared with those with AA/AG genotypes. The maternal ACE A11860G GG genotype was associated with higher maternal plasma ACE concen- tration at 15 weeks' gestation than AA/AG genotypes (P , 0.001). When the Adelaide cohort was stratified by maternal socio-economic index (SEI) and pre-pregnancy green leafy vegetable intake, the ACE A11860G GG genotype was only associated with an increased risk for SGA (OR 4.9, 95% CI 1.8-13.4 and OR 3.3, 95% CI 1.6-7.0, respectively) and a reduction in customized birthweight centile (P ¼ 0.006 and P ¼ 0.03) if super- imposed on maternal SEI ,34 or pre-pregnancy green leafy vegetable intake ,1 serve/day. Furthermore, the associations of maternal ACE A11860G with customized birthweight centile observed among Adelaide women with SEI ,34 or pre-pregnancy green leafy vegetable intake ,1 serve/day were female specific. The current study identified a novel association of maternal ACE A11860G with SGA. More interestingly, this association was modified by environmental factors and fetal sex, suggesting ACE A11860G -environment -fetal sex interactions. Trial Registry Name: Screening nulliparous women to identify the combinations of clinical risk factors and/or biomarkers required to predict pre- eclampsia, SGA babies and spontaneous preterm birth. URL: http://www.anzctr.org.au. Registration number: ACTRN12607000551493.

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy. Refereed/Peer-reviewed

Summary The disparate results reported in the literature on the effects of low dose aspirin in preventing pre-eclampsia might be caused by non-compliance in the more recent large trials in low-risk patients. All the earlier small trials were done on identified high-risk patients who consider themselves as patients, as do their doctors. Compliance in these patients will be very high. In fact, the only study in healthy subjects in which aspirin intake was controlled for ( Hauth et al, 1993 ) showed a marked reduction in the incidence of pre-eclampsia. However, the recent large trials have demonstrated, without any doubt, that low dose aspirin is not a miracle drug. The combined literature points at a 25% reduction in the incidence of pre-eclampsia in association with the use of aspirin ( Collins, 1994 ). The correct indication for the use of low-dose aspirin appears to be the patient that is at very high risk of developing early-onset (less than 32 weeks gestation) pre-eclampsia. Since early-onset pre-eclampsia can begin at any time after 20 weeks gestation, it is necessary to initiate low-dose aspirin therapy early in pregnancy, preferably at 10–14 weeks gestation. The results of the recent large trials emphasize the need for a reliable, sensitive method of predicting or detecting pre-eclampsia at a very early gestational age ( Dekker and Sibai, 1991 ). Valensise et al (1993) recently confirmed earlier studies ( McParland et al, 1990 ) on the useful combination of uteroplacental Doppler flow velocimetry and aspirin in low-risk primigravidae. Results from current large-scale trials, such as the ECPPA, the BLASP, the WHO Jamaica and the second NICHHD studies, will be available in the near future. The results of especially the second NICHHD study on low-dose aspirin, in more than 2000 high-risk women (previous pre-eclampsia/eclampsia, chronic hypertension, class B to F diabetes or multiple gestation), will hopefully give us a more definitive picture on the potential benificial effects of low-dose aspirin in high-risk patients. The effect of aspirin on placental TXA2 deserves further studies. It might be that the optimal level to inhibit placental TXA2 and lipid peroxide production is actually higher than the minimal effective doses of aspirin that are needed to inhibit platelet TXA2 production ( Walsh, 1994 ). Low-dose aspirin appears to be safe for the fetus and neonate. If there is an increased risk of abruptio placentae, this risk appears to be minimal. The final word on the use of low-dose aspirin has not yet been reached; however, we may be getting closer to profiling patients for whom the therapy may be efficacious and beneficial to both mother and fetus. Further studies are also necessary on combinations of aspirin and other antithrombotic drugs, such as heparin or ketanserin ( Tanaka et al, 1993 ; Bolte et al, 1994 ; North et al, 1994 ). North et al (1994) demonstrated that treatment of women with severe renal disease with heparin plus aspirin reduced the prevalence of superimposed pre-eclampsia, compared with no treatment or aspirin alone. Next to low-dose aspirin, there appear to be several new and promising pharmaceutical approaches for reducing the consequences of EC dysfunction. Among these are selective TXA2-synthetase or TXA2-receptor antagonists, Serotonin2-receptor blockers, stable PGI2 analogues and NO donors.

This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy.A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases.Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing.Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.

To compare oral iron to intravenous iron administration to women in late pregnancy and/or after labor to correct iron deficiency.271 anemic women (148 pregnant women and 123 women post lower segment caesarean section) with hemoglobin (Hb) levels below 110 g/L were enrolled over a two-year period and randomized to receive either two tablets FGF (ferrous sulfate with folic acid) or 400 mg of intravenous iron sucrose plus folic acid 600 µg. Treatment effectiveness was assessed by measuring Hb and ferritin postpartum on day 1, day 14 and day 42. Transfusions of red blood cells and adverse drug reactions were recorded.Data of 214 women were available for analysis. Both forms of iron replacement therapy led to increased hemoglobin and ferritin levels over the testing period. Ferritin was significantly higher in the i.v. iron treatment group compared to the oral iron treatment group (p = 0.004) two weeks after delivery, while Hb values did not differ between the groups. No serious adverse drug reactions were observed. Red blood cell transfusion rate was low (1.9%), with equal rates observed in both treatment groups.Intravenous and oral irons were both effective in correcting peripartum anemia, although intravenous iron restored stores faster than oral iron.

Objective There is discrepancy in the literature on the definitions of severe and early-onset pre-eclampsia. We aimed to determine those definitions for clinical purposes and to introduce them in the classification of the hypertensive disorders of pregnancy for publication purposes. Methods We circulated a questionnaire to the International Committee of the International Society for the Study of Hypertension in Pregnancy focusing on the thresholds for defining severe preeclampsia and the gestation at which to define early-onset preeclampsia, and on the definition and inclusion of the HELLP syndrome or other clinical features in severe preeclampsia. The questions were closed, but all answers had space for more open detailed comments. Results There was a general agreement to define preeclampsia as severe if blood pressure was >160mmHg systolic or 110mmHg diastolic. There was scarce agreement on the amount of proteinuria to define severity. The HELLP syndrome was considered a feature to include in the severe classification. Most investigators considered early-onset preeclampsia as that occurring before 34weeks. Conclusions A definition of pre-eclampsia is paramount for driving good clinical practice. Classifications on the other hand are useful to enable international comparisons of clinical data and outcomes. We used the results of this survey to update our previous classification for the purposes of providing clinical research definitions of severe and early onset pre-eclampsia that will hopefully be accepted in the international literature.

Objective Excessive gestational weight gain (GWG) is an important contributing factor to the obesity epidemic in women and is associated with pregnancy complications. We investigated the relationship between GWG and caesarean delivery in labour, large for gestational age (LGA), small for gestational age (SGA) infants and pregnancy-induced hypertension by maternal pre-pregnancy body mass index (BMI) in a contemporary nulliparous cohort. Study design Using 2009 Institute of Medicine guidelines, participants in the SCOPE study (from Cork, Ireland, Auckland, New Zealand and Adelaide, Australia) were classified into GWG categories (low, normal and high) according to pre-pregnancy BMI. Maternal characteristics and pregnancy outcomes were compared between weight gain categories. SGA and LGA were defined as 90th customised birthweight centile. Multivariable analysis adjusted for confounding factors that impact on GWG including BMI. Results Of 1950 participants, 17.2% ( n = 335) achieved the recommended GWG, 8.6% ( n = 167) had low and 74.3% ( n = 1448) had high GWG. Women with high GWG had increased rates of LGA infants [adjusted OR 4.45 (95% CI 2.49–7.99)] and caesarean delivery in labour [aOR 1.46 (1.03–2.07)]. SGA was increased in women with low GWG [aOR 1.79 (1.06–3.00)]. Conclusion Three quarters of participants had high GWG, which was associated with an independent risk of LGA infants and caesarean in labour. Low GWG was associated with SGA infants. These adverse outcomes are potentially modifiable by achievement of normal GWG, which should be an important focus of antenatal care.

Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination.Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots.CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71-2.76)].Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.

Introduction: Pregnancies complicated by preeclampsia and small-for-gestational-age (SGA) infants share placental vascular abnormalities and both disorders confer increased risk of later life coronary artery disease. Kinase insert domain receptor (KDR) is the main receptor for vascular endothelial growth factor A, a potent angiogenic factor which regulates the development of the placental vasculature. Two polymorphisms in KDR (-604T/C and Val297Ile) are known to be associated with coronary artery dis- ease. We investigated the association of these polymorphisms with preeclampsia, gestational hypertension, and SGA infants. Method: Nulliparous pregnant women, their partners, and infants were recruited to a prospective cohort study (n ¼ 1169). Doppler ultrasound of the uterine and umbilical arteries was performed at 20 weeks of gestation. Preeclampsia, gestational hypertension, and SGA were defined according to international guidelines. DNA extracted from peripheral venous or cord blood was genotyped using the Sequenom MassARRAY system. Multivariable logistic regression was used to compare the odds for the pregnancy complications between the genotype groups adjusting for potential confounders. Results :A mong 937 Caucasian pregnancies, 427 (45.6%) were uncomplicated, 75 (8.0%) developed preeclampsia, 102 (10.9%) developed gestational hypertension, and 72 (7.7%) had SGA infants in the absence of maternal hypertensive disease. Paternal and neonatal KDR-604T/ C was associated with preeclampsia (adjusted odds ratio (aOR) 1.6, 95% confidence interval (CI) 1.0-3.0 and aOR 2.2, 95% CI 1.0-4.4), SGA (aOR 1.9, 95% CI 1.1-3.3 and aOR 2.2, 95% CI 1.2-3.9), and SGA with abnormal Doppler (aOR 2.7, 95% CI 1.2-5.9 and aOR 3.2, 95% CI 1.2-5.9).Conclusion: Paternal and neonatal carriage of theKDR-604T/Cpolymorphism is associated with the risk of preeclampsia and SGA infants.

Introduction This study aimed to determine the association of AGTR1 and AGTR2 polymorphisms with preeclampsia and whether these are affected by environmental factors and fetal sex. Methods Overall 3234 healthy nulliparous women, their partners and babies were recruited prospectively to the SCOPE study in Adelaide and Auckland. Data analyses were confined to 2121 Caucasian parent-infant trios, among whom 123 had preeclamptic pregnancies. 1185 uncomplicated pregnancies served as controls. DNA was extracted from buffy coats and genotyped by utilizing the Sequenom MassARRAY system. Doppler sonography on the uterine arteries was performed at 20 weeks' gestation. Results Four polymorphisms in AGTR1 and AGTR2 genes, including AGTR1 A1166C , AGTR2 C4599A , AGTR2 A1675G and AGTR2 T1134C , were selected and significant associations were predominately observed for AGTR2 C4599A . When the cohort was stratified by maternal BMI, in women with BMI ≥ 25 kg/m 2 , the AGTR2 C4599A AA genotype in mothers and neonates was associated with an increased risk for preeclampsia compared with the CC genotype [adjusted OR 2.1 (95% CI 1.0–4.2) and adjusted OR 3.0 (95% CI 1.4–6.4), respectively]. In the same subset of women, paternal AGTR2 C4599A A allele was associated with an increased risk for preeclampsia and uterine artery bilateral notching at 20 weeks' gestation compared with the C allele [adjusted OR 1.9 (95% CI 1.1–3.3) and adjusted OR 2.1 (95% CI 1.3–3.4), respectively]. Conclusion AGTR2 C4599A in mothers, fathers and babies was associated with preeclampsia and this association was only apparent in pregnancies in which the women had a BMI ≥ 25 kg/m 2 , suggesting a gene–environment interaction.

To examine whether single-nucleotide polymorphisms (SNPs) in VEGFA (-2578 C/A and +936 C/T) associate with small-for-gestational-age (SGA) pregnancies and to identify their effects on first-trimester placental VEGFA expression.Multicenter prospective cohort study.Adelaide, Australia, and Auckland, New Zealand.A total of 3234 nulliparous pregnant women, their partners, and their infants.The SNPs in the parent-infant trios and first-trimester placentae (n = 74) were genotyped. Placental VEGFA messenger RNA expression was determined by quantitative reverse transcription-polymerase chain reaction. Small for gestational age was defined as a birth weight less than the 10th customized birth weight percentile adjusted for maternal height, weight, parity, and ethnicity and for gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 weeks' gestation, and resistance indices greater than the 90th percentile were considered abnormal.Of 2123 pregnancies, 1176 (55.4%) were uncomplicated and 216 (10.2%) had SGA infants. Neonatal VEGFA +936 C/T SNP associates with SGA (adjusted odds ratio [aOR], 1.6; 95% CI, 1.0-2.3), SGA with abnormal Doppler findings (aOR, 3.5; 95% CI, 1.8-7.1), lower birth weight (P = .006), customized birth weight percentile (P = .049), and abnormal uterine artery Doppler findings (OR, 2.5; 95% CI, 1.2-5.4). Maternal VEGFA +936 C/T associates with abnormal umbilical artery Doppler findings (OR, 1.5; 95% CI, 1.1-2.2). VEGFA +936 CT+TT first-trimester placentae have 36% lower VEGFA messenger RNA expression compared with CC (P = .045).Neonatal VEGFA +936 C/T associates with SGA, and the association is stronger for SGA with abnormal uterine or umbilical artery Doppler findings. The SNP also associates with reduced first-trimester placental VEGFA expression, suggesting that it may have a role in the pathogenesis of SGA. Trial Registration clinicaltrials.gov Identifier: ACTRN12607000551493.

Venous thromboembolism (VTE) in pregnancy and the postpartum is an important cause of maternal morbidity and mortality; yet, there are few robust data from clinical trials to inform an approach to diagnosis and management. Failure to investigate symptoms suggestive of pulmonary embolism (PE) is a consistent finding in maternal death enquiries, and clinical symptoms should not be relied on to exclude or diagnose VTE. In this consensus statement, we present our recommendations for the diagnosis and management of acute deep venous thrombosis (DVT) and PE. All women with suspected DVT in pregnancy should be investigated with whole leg compression ultrasonography. If the scan is negative and significant clinical suspicion remains, then further imaging for iliofemoral DVT maybe required. Imaging should be undertaken in all women with suspected PE, as the fetal radiation exposure with both ventilation/perfusion scans and CT pulmonary angiography is within safe limits. Low-molecular-weight heparin (LMWH) is the preferred therapy for acute VTE that occur during pregnancy. In observational cohort studies, using once-daily regimens appears adequate, in particular with the LMWH tinzaparin; however, pharmacokinetic data support twice-daily therapy with other LMWH and is recommended, at least initially, for PE or iliofemoral DVT in pregnancy. Treatment should continue for a minimum duration of six months, and until at least six weeks postpartum. Induction of labour or planned caesarean section maybe required to allow an appropriate transition to unfractionated heparin to avoid delivery in women in therapeutic doses of anticoagulation.

Summary. Introduction: Thrombospondin-1 (TSP-1) is a prothrombotic and anti-angiogenic glycoprotein expressed in the placenta. A functional single nucleotide polymorphism in the TSP-1 gene (TSP-1 A2210G) is a risk factor for familial premature myocardial infarction. Small for gestational age (SGA) infants are at increased risk of coronary artery disease in adult life and common genetic factors may underlie both conditions. We investigated the association of TSP-1 A2210G in SGA infants and their parents. Method: The 3234 nulliparous pregnant women, their partners and babies were recruited in Adelaide and Auckland to a prospective multicenter cohort study. Amongst 2123 Caucasian women, 216 (10.2%) delivered an SGA infant, defined as birth weight

Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design Prospective multicentre cohort. Setting Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants 3572 “healthy” nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure Pre-eclampsia defined as ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks’ gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37 +0 weeks’ gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks’ gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added. Trial registration ACTRN12607000551493.

Hypertensive disorders of pregnancy constitute the most common medical complication of pregnancy. It is essential to recognise that pre-eclampsia is more than simply gestational or pregnancy-induced hypertension. Because the aetiology of pre-eclampsia is yet unknown, primary prevention is not feasible at this moment. With respect to secondary prevention the focus of attention is on low-dose aspirin and calcium supplementation.

Preeclampsia is characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. On the basis of the hypothesis that preeclampsia is at least partially caused by an increase in thromboxane A2, some studies attempted to correct this pathologic condition by pharmacologic manipulation with low-dose aspirin. The current literature suggests that the use of low-dose aspirin during pregnancy is safe with regard to congenital anomalies and fetal, neonatal, and maternal cardiovascular physiologic state and hemostasis. Aspirin at least partially corrects the pathologic increase in angiotensin II sensitivity that precedes the clinical development of preeclampsia. In addition, some clinical trials have demonstrated that low-dose aspirin is effective in reducing the incidence of preeclampsia and/or fetal growth retardation in selected high-risk women. Currently, large clinical trials are in progress to evaluate the effectiveness and side effects of the use of low-dose aspirin in preventing preeclampsia and/or fetal growth retardation. Until these studies have been completed, it will remain unclear whether antiplatelet therapy, such as low-dose aspirin, should be adopted for the prevention of either preeclampsia or fetal growth retardation.

Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal–paternal relationship is appreciated, and as such also the specific ‘genetic conflict' that is characteristic of haemochorial placentation. From that perspective preeclampsia can also been seen as a disease of an individual couple with primarily maternal and fetal manifestations. Factors that are unique to a specific couple would include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-b and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years. The maternal and fetal genomes perform different roles during development. Inheritable paternal, rather than maternal, imprinting of the genome is necessary for normal trophoblast development. Preeclampsia may relate to a ‘hefty' genetic conflict, or a mother unable to cope with a ‘physiologic' genetic conflict. The paternal contribution to preeclampsia, in addition to the actual act of fertilization is demonstrated by: 1.The effect of the length of sexual relationship. After the landmark retrospective study by Pierre Robillard in the mid 1990s, the SCOPE consortium has recently published the results of a large prospective study in nulliparous women demonstrating the short sexual relationships prior to conceiving are definitely independent risk factors for both preeclampsia and "placental" small for gestational age. 2.The concept of primipaternity versus primigravidity in 2002. The primipaternity concept was recently challenged by Skjaerven et al. [35]. These investigators used data from the Medical Birth Registry of Norway, a population-based registry that includes births that occurred between 1967 and 1998. According to these authors, prolonged birth interval and not paternity change was the explanation for the increased preeclampsia risk in multiparous women with a new partner. More critical analysis of their data and various subsequent studies have clearly demonstrated that the primipaternity concept still stands. 3.Existence of the so-called 'dangerous' father has been demonstrated in various large population studies. Men who fathered one preeclamptic pregnancy are nearly twice as likely to father a preeclamptic pregnancy in a differentwoman.

To investigate the roles of inherited polymorphisms in the MBL2 gene and exposure to viral infection in the development of a range of adverse pregnancy outcomes, including birthweight 10th percentile (small-for-gestational age, SGA), antepartum hemorrhage (APH), pregnancy-induced hypertensive disorders (PIHD), and preterm birth (PTB).This was a case-control study using DNA from newborn screening cards of 717 cases (babies with at least one of the adverse pregnancy outcomes listed above) and 609 controls, to screen for six polymorphisms within the MBL2 gene. These combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL2 levels.Significant associations were found between variant MBL2 haplotypes and SGA (LYPA 32 weeks OR 5.37, 95% CI 1.50-17.27), antepartum hemorrhage (LYPA 37 weeks OR 2.29, 95% CI 1.25-4.18), and PIHD (LYQC 32 weeks (OR 17.89, 95% CI 2.20-139.57). Evidence of exposure to infection increased the effect of these associations, (SGA OR 17.00, 95% CI 1.03-252.48; APH OR 5.67, 95% CI 1.73-18.84; PIHD OR 23.80, 95% CI 1.08-1414.76), while no evidence of exposure to infection demonstrated no associations. PTB was significantly associated with the defective HYPD haplotype with evidence of exposure to infection (OR 6.14, 95% CI 1.21-29.89).This research suggests that the combination of fetal MBL2 haplotypes and exposure to in utero viral infection increases the risk of adverse pregnancy outcomes, including PTB, antepartum hemorrhage, small-for-gestational age and PIHD.

Our aims were to investigate whether men who fathered small for gestational age (SGA) infants themselves had lower birthweight, were more likely to be obese, have central adiposity and elevated blood pressure in adult life compared with men who fathered non-SGA infants. A total of 2,002 couples participating in the Screening for Pregnancy Endpoints (SCOPE) study were enrolled in early pregnancy and pregnancy outcome data collected prospectively. SGA was defined as birthweight10th customized centile, obesity as BMI ≥30 kg/m(2), central adiposity as waist circumference102 cm. Logistic regression was used to compare rates of obesity, and central adiposity between men who fathered SGA infants compared with those with non-SGA infants and the final model was adjusted for maternal and paternal confounders. The men who fathered an SGA infant (209 (10.4%)) themselves had lower mean birthweight (3,291 (530) g vs. 3,472 (584) g, P0.0001), were more likely to be obese (50 (24.8%) vs. 321 (18.3%), adjusted odds ratio (OR) 1.50, 95% confidence interval 1.05-2.16, adjusted for maternal and paternal factors) and to have central adiposity (52 (25.1%) vs. 341 (19.2%), adjusted OR 1.53, 95% confidence interval 1.06-2.20) compared with men who fathered a non-SGA infant. Elevated paternal blood pressure was not associated with SGA. In conclusion, we report a novel relationship between paternal obesity/central adiposity and birth of an SGA infant, which appears to be independent of maternal factors associated with fetal growth restriction.

Genome stability is essential for normal foetal growth and development. To date, genome stability in human lymphocytes has not been studied in relation to late pregnancy diseases, such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR), which can be life-threatening to mother and baby and together affect >10% of pregnancies. We performed a prospective cohort study investigating the association of maternal chromosomal damage in mid-pregnancy (20 weeks gestation) with pregnancy outcomes. Chromosome damage was measured using the cytokinesis-block micronucleus cytome (CBMNcyt) assay in peripheral blood lymphocytes. The odds ratio for PE and/or IUGR in a mixed cohort of low- and high-risk pregnancies (N = 136) and a cohort of only high-risk pregnancies (N = 91) was 15.97 (P = 0.001) and 17.85 (P = 0.007), respectively, if the frequency of lymphocytes with micronuclei (MN) at 20 weeks gestation was greater than the mean + 2 SDs of the cohort. These results suggest that the presence of lymphocyte MN is significantly increased in women who develop PE and/or IUGR before the clinical signs or symptoms appear relative to women with normal pregnancy outcomes. The CBMNcyt assay may provide a new approach for the early detection of women at risk of developing these late pregnancy diseases and for biomonitoring the efficacy of interventions to reduce DNA damage, which may in turn ameliorate pregnancy outcome.

Pre-eclampsia is the most common medical complication of pregnancy. Immunologic maladaptation has been suggested to play a role in the etiology of pre-eclampsia. The putative misalliance of fetal trophoblast with maternal tissue in the uteroplacental vascular bed may give rise to an increase in oxygen free radicals. Oxygen free radicals and lipid peroxides might form the link between the hypothetical immunologic maladaptation and the endothelial cell damage known to occur in pre-eclampsia. Recent studies have demonstrated the existence of increased oxygen free radical production in pre-eclampsia. Oxygen free radicals and lipid peroxides decrease vascular prostacyclin and EDRF release and increase thromboxane A 2 and endothelin release. The hypothesis is put forward that in pre-eclampsia a proposed immunologic maladaptation causes an increase in oxygen free radicals by decidual lymphoid cells. A decrease in vasodilatory autocoids, prostacyclin and EDRF may result from the endothelial cell damage induced by oxygen free radicals. Uteroplacental prostacyclin production might be essential as escape mechanism. The adequacy as escape mechanism seems to determine the final clinical outcome.

The renin-angiotensin-aldosterone system plays an integral role in the (patho)physiology of pregnancy and pregnancy-induced hypertensive disease. The current review concerns the renin-angiotensin-aldosterone system in relation to other vasoactive substances in normal pregnancy and preeclampsia.

Plasma endothelin levels were studied in 29 pregnancies. Levels were found to be increased in 9 pregnancies complicated by pregnancy-induced hypertensive disease and/or pre-eclampsia as compared to levels in 14 normotensive pregnancies with gestational age varying between 24–40 weeks with normal Doppler flow velocity waveforms of the uterine arcuate arteries, and 6 normotensive pregnancies with abnormal Doppler flow velocity waveforms at 24 weeks' gestation. Two patients with severe pre-eclampsia showed a rise in plasma endothelin levels, suggesting a correlation between plasma endothelin levels and the disease process. Endothelin is produced by endothelial cells of blood vessels; it is the most potent vasoconstrictor known to date. For this reason it has been suggested that endothelin might be important in the control of systemic blood pressure and local blood flow, both disturbed in pre-eclampsia. The conclusion of this study is that the venous plasma level of endothelin would seem to be a marker for severe disease, however, without any predictive value.

Objectives This study was undertaken to test novel genetic polymorphisms involved in 1-carbon metabolism for a potential association with increased risk of developing pregnancy complications associated with uteroplacental insufficiency. Study Design This was a prospective cohort study consisting of 50 women at low risk and 93 women at high risk for having a pregnancy complication develop. Maternal and fetal DNA samples were genotyped for methionine synthase ( MTR ) A2756G, methionine synthase reductase ( MTRR ) A66G and methylenetetrahydrofolate dehydrogenase ( MTHFD1 ) G1958A. A chi squared or χ 2 analysis was used to compare genotypes and pregnancy outcome, 1-way analysis of variance and linear regression were used to compare genotype with continuous variables. Results The fetal MTR 2756 G allele was associated with uteroplacental insufficiency ( P = .022, likelihood ratio=10.4) and maternal homocysteine ( P = .017). The maternal MTR A2756G polymorphism was associated with uteroplacental insufficiency ( P = .049, likelihood ratio=6.0), but only in mothers not supplementing with high-dose B-vitamins. The maternal MTHFD1 AA genotype was associated with intrauterine growth restriction ( P = .047, likelihood ratio=5.8). Conclusion This study suggests the maternal and fetal MTR 2756 G allele is an important risk factor in the development of uteroplacental insufficiency. In addition, the maternal MTHFD1 1958 AA genotype may be associated with intrauterine growth restriction.

SummaryIt was the objective of this study to analyse the influence of confounders, such as ethnicity, severity of illness and method of testing, in articles concerning the still moot relationship of thrombophilias to adverse pregnancy outcome (APO). Relevant casecontrol studies were identified using Medline and EMBASE databases between 1966 and 2006. Search terms were recurrent fetal loss, intrauterine fetal death, preeclampsia, HELLP-syndrome, eclampsia, fetal growth restriction, abruptio placentae, combined with maternal thrombophilias. Data was extracted from the articles per subgroup ofAPO regardless of confounder. These subgroups were tested if they fulfilled the heterogeneity testing criterion (I2 > 35%) to weigh the influence of the confounder. Confounders were selected and examined with Mantel- Haenszel method. Increased thrombophilia prevalence was confirmed in most adverse pregnancy outcomes. Ethnicity, genetic testing only and severity of illness were confounders in the various forms of APO. Stronger relationships between factor V Leiden and severity of disease were found in 2nd and 3rd trimester than 1st trimester recurrent fetal loss, in preeclampsia with: blood pressure ≥160/110 mmHg than ≥140/90 mmHg; proteinuria ≥5 grams per day than < 5 grams; onset before than after 28 weeks, in fetal growth restriction

An angiotensin II sensitivity test and a supine pressor test were done consecutively at 28 weeks gestation in 90 healthy, normotensive nulliparous women. None of the supine pressor tests was positive, applying the predefined threshold of a rise of 20 mmHg in diastolic blood pressure after rolling over; nine tests were positive using a corrected 9 mmHg cut-off level. Ten women had a positive angiotensin sensitivity test using a threshold of the effective pressor dose of 8 ng/kg/min; 22 women were positive using an effective pressor dose of less than or equal to 10 ng/kg/min. Later in pregnancy 12 women (13%) developed pregnancy-induced hypertensive disease (PIH). The specificity of both tests of predicting the development of PIH was about 90%. The sensitivity of the angiotensin sensitivity test at the 10 ng/kg/min level was 92%. Because of its low sensitivity of 25% the supine pressor test appears to have no value for the prediction of PIH. There was a significant positive association between angiotensin II refractoriness and birthweight.

Objective The objective of the study was to investigate the associations between infection, polymorphisms in the mannose-binding lectin gene (MBL), and cerebral palsy (CP). Study Design This was a case-control study using deoxyribonucleic acid from newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls to screen for 6 polymorphisms within the MBL gene. These polymorphisms combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL levels. Results χ 2 Analyses demonstrated significant differences between CP cases and controls (less than 37 weeks χ 2 14.99, P = .02; less than 32 weeks χ 2 13.62, P = .02). The MBL haplotype LYPA was associated with CP at all gestations (odds ratio [OR] 1.57, 95% confidence interval [CI], 1.00 to 2.46), less than 37 weeks (OR 2.43, 95% CI, 1.41 to 4.18), and less than 32 weeks (OR 2.54, 95% CI, 1.34 to 4.76). LYPA was also associated with hemiplegic CP for babies born at less than 37 weeks (OR 2.77, 95% CI, 1.02 to 7.26) and less than 32 weeks (OR 4.48, 95% CI, 1.55 to 12.65). HYPD was associated with quadriplegic CP at all gestations (OR 3.47, 95% CI, 1.41 to 8.31) as well as for babies born at less than 32 weeks (OR 7.86, 95% CI, 1.67 to 29.48). Subanalysis on samples previously testing positive for exposure to viral infection demonstrated similar patterns of significance as those presented above, whereas analysis on samples negative for exposure to viral infection showed no positive associations between any of the MBL haplotypes and CP. Potential type I error from multiple analyses is a caveat. Conclusion MBL haplotypes LYPA or HYPD may be associated with an increased risk of CP in the presence of exposure to viral infection and may act as susceptibility factors for CP.

Takotsubo Cardiomyopathy (TCM) is a rarely identified cause of acute heart failure in pregnancy. We describe the demographic characteristics, clinical features and outcomes in reported cases of peripartum TCM. We searched four databases (EMBASE, OVID Medline, PubMed and Google Scholar) from Jan

Objective To investigate the association between cerebral palsy and direct evidence for perinatal exposure to neurotropic viruses. Design Population based case-control study. Setting Adelaide Women9s and Children9s Hospital Research Laboratory. Participants and main outcome measures Newborn screening cards of 443 white case patients with cerebral palsy and 883 white controls were tested for viral nucleic acids from enteroviruses and herpes viruses by using polymerase chain reaction. Herpes group A viruses included herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 8 (HHV-8), and herpes group B viruses included varicella zoster virus (VZV) and human herpes viruses 6 and 7 (HHV-6 and HHV-7). Results The prevalence of viral nucleic acids in the control population was high: 39.8% of controls tested positive, and the prevalence was highest in preterm babies. The detection of herpes group B viral nucleic acids increased the risk of developing cerebral palsy (odds ratio 1.68, 95% confidence interval 1.09 to 2.59). Conclusions Perinatal exposure to neurotropic viruses is associated with preterm delivery and cerebral palsy.

Tumor necrosis factor-alpha (TNF-alpha) is thought to play a role in immune activation in preeclampsia. The objective of this study was to establish if soluble TNF-receptor I (sTNF-rI) levels relate to the onset and severity of preeclampsia.Maternal plasma sTNF-rI levels were studied throughout pregnancy in 68 women with a history of severe preeclampsia or intra-uterine growth restriction (IUGR), and primigravidas with chronic hypertension. Data are presented as mean (SD) in ng/ml.In the second trimester there was a significant difference in sTNF-rI levels between preeclamptic pregnancies with and without IUGR (means 1.33 (0.20) and 1.11 (0.15) respectively, p0.005). In severe preeclampsia with delivery before 34 weeks of gestation, sTNF-rI levels were higher than in mild preeclampsia in the second and third trimesters (means 1.40 (0.16) vs. 1.16 (0.19), p0.02 and 1.82 (0.47) vs. 1.42 (0.22), p0.05, respectively).sTNF-rI levels were higher in preeclampsia with fetal involvement, suggesting that increased TNF-alpha production in preeclampsia is related to impaired placentation rather than to the maternal syndrome.

To describe the prevalence of four inherited thrombophilias and their combinations for the first time in a large Caucasian Australian population.Newborn screening cards of 883 Caucasian babies born in South Australia in 1986-1999 were de-identified and tested for the following inherited thrombophilic polymorphisms: factor V Leiden (G1691A), prothrombin gene mutation (G20210A), methylenetetrahydrofolate reductase gene (MTHFR) C677T and A1298C, as well as compound heterozygosity for the MTHFR polymorphisms.The birth prevalences of heterozygosity and homozygosity for the four thrombophilic polymorphisms were: factor V Leiden 9.5% and 0.7%, prothrombin gene 4.1% and 0.2%, MTHFR C677T 37.3% and 12.4%, and MTHFR A1298C 38.3% and 11.8%, respectively. Compound heterozygosity for MTHFR C677T and A1298C was seen in 16.6% of the population. Overall, 64.2% and 24.5% of the population studied were homozygous and heterozygous, respectively, for at least one of the four polymorphisms studied.Inherited thrombophilic polymorphisms are common in the Caucasian Australian population. Knowledge of the background prevalence of these polymorphisms will allow further study of their associations in future disease research.

Preeclampsia is a pregnancy-associated disease with maternal symptoms but placental origin. Epigenetic inheritance is involved in some populations. By sequence analysis of 17 genes in the 10q22 region with maternal effects, we narrowed the minimal critical region linked with preeclampsia in the Netherlands to 444 kb. All but one gene in this region, which lies within a female-specific recombination hotspot, encode DNA- or RNA-binding proteins. One gene, STOX1 (also called C10orf24), contained five different missense mutations, identical between affected sisters, cosegregating with the preeclamptic phenotype and following matrilineal inheritance. Four SIOX1 transcripts are expressed in early placenta, including invasive extravillus trophoblast, generating three different isoforms. All contain a winged helix domain related to the forkhead (FOX) family. The largest STOX1 isoform has exclusive nuclear or cytoplasmic expression, indicating activation and inactivation, respectively, of the PI3K-Akt-FOX pathway. Because all 38 FOX proteins and all 8 STOX1 homologs have either tyrosine or phenylalanine at position 153, the predominant Y153H variation is highly mutagenic by conservation criteria but subject to incomplete penetrance. STOX1 is a candidate for preeclampsia controlling polyploidization of extravillus trophoblast.

Objective This study was undertaken to investigate associations between inherited thrombophilic polymorphisms and cerebral palsy (CP) in a large case-control study. Study design This is a population-based case-control study. Genomic DNA from newborn screening cards of 443 white CP cases and 883 white controls was tested for factor V Leiden (FVL, G1691A), prothrombin gene mutation (PGM, G20210A), and methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C. Results MTHFR C677T was associated with an increased risk of developing any CP (32-36 weeks' gestation, homozygous odds ratio [OR] 2.55, 95% CI 1.12-5.74; heterozygous OR 1.91, 95% CI 1.01-3.66). MTHFR C677T was also associated with diplegia at both less than 32 weeks' gestation (homozygous OR 2.76, 95% CI 1.21-6.12) and all gestations (heterozygous OR 1.58 95%, CI 1.02-2.45). For children less than 32 weeks, FVL homozygosity may be associated with an increase in the risk of developing quadriplegia (OR 9.12, 95% CI 0.86-53.71). MTHFR A1298C (heterozygous) was associated with a reduced risk of diplegia developing at 32 to 36 weeks' gestation (OR 0.16, 95% CI 0.02-0.70). There were no associations between any type of CP and thrombophilia for children born 37 weeks or greater. Heterozygous PGM and homozygous MTHFR C677T combined were associated with quadriplegia at all gestational ages (OR 5.33, 95% CI 1.06-23.25). Conclusion MTHFR C677T approximately doubles the risk of CP in preterm infants. A combination of homozygous MTHFR C677T and heterozygous PGM increases the risk of quadriplegia 5-fold at all gestational ages.

BACKGROUND: Pregnant women with chronic hypertension and thrombophilia have an increased risk for preeclampsia and/or intrauterine growth restriction (IUGR). Ketanserin lowers blood pressure and inhibits serotonin-induced platelet aggregation. CASES: A 38-year-old woman with chronic hypertension had a first pregnancy with severe hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. A second pregnancy with prophylactic oral ketanserin and low-dose aspirin was uneventful. The third pregnancy without oral ketanserin was again complicated by severe superimposed preeclampsia and IUGR. During this pregnancy a prothrombin mutation was found. A 37-year-old woman with chronic hypertension developed severe early-onset superimposed preeclampsia in her first pregnancy. In the 3 consecutive pregnancies, she was treated with low-molecular-weight heparin because of a factor XII deficiency. Only the pregnancy with the use of prophylactic oral ketanserin was uncomplicated. CONCLUSION: Clinical trials are warranted to analyze the role of oral ketanserin in preventing preeclampsia and IUGR.

Liver rupture during pregnancy was first described by Abercrombie in 1844 [1]. Spontaneous liver rupture mostly occurs in women with a pregnancy‐related hypertensive disorder. It is a rare complica...

Objective: To assess the effects on maternal, fetal and neonatal outcomes of nifedipine (and other calcium channel blockers) administered as a tocolytic agent to women in preterm labour. Methods: Standard methods of the Cochrane Collaboration and its Pregnancy and Childbirth Review Group were used. All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in preterm labour between 20 and 36 weeks’ gestation, were considered. Main results: The systematic review includes 12 randomised controlled trials with a total of 1029 participating women. No trials were identified in which calcium channel blockers were compared with a placebo or no alternative tocolytic treatment. Calcium channel blockers appear to be more effective than betamimetic agents in prolonging pregnancy for 7 days or longer, are much less likely to cause maternal side-effects and are associated with reduced neonatal morbidity. Conclusion: Calcium channel blockers (especially nifedipine) can be considered safer and more effective tocolytic agents than betamimetics.

Hypertensive disorders of pregnancy (HDP: pregnancy-induced hypertension, preeclampsia, eclampsia) affect approximately 10% of human births. Women are at increased risk for HDP during their first conception; and/or when the conception is with a new partner (new paternity); when conception occurs very shortly after the beginning of their sexual relationship. A primary cause of preeclampsia is the defect of the normal human-specific deep endovascular invasion of trophoblast, which is a consequence of the nutritional demands of growth of the human fetal brain. The occurrence of preeclampsia represents a reproductive disadvantage unique to humans compared with other mammals. As such, it may have played a significant role in shaping human reproduction and, therefore, human sexuality. This deep implantation/preeclampsia phenomenon may explain many anthropological mysteries of human sexuality that do not exist in other mammalian species (and primates). These include: very low fertility rate, concealed ovulation, all year long 'apparent-waste-of-efficiency' sexuality, absence of sperm competition in human females at the time of conception, and the unexplained testicle size in human males compared with relevant primates. Further, this deep trophoblastic implantation (and its failure in preeclampsia) in humans might be a decisive condition of hominization between great apes and all the other Homo genuses. This frontier might even have occurred inside these Homo lineages: because of their relatively small brains, the first species of Homo might not have presented the deep trophoblastic invasion described in Homo sapiens.

Objectives: The purpose of this study is to compare the hemodynamic and metabolic changes after ritodrine and nifedipine tocolysis. Methods: For an open randomized study, patients with preterm labor (N = 185) were allocated to groups to receive ritodrine intravenously (N = 90) or nifedipine orally (N = 95). Results: The mean diastolic blood pressure was significantly lower in the ritodrine group 24 h (65 +/- 12 vs. 70 +/- 8, P=0.001) and 48 h (65 +/- 12 vs. 71 +/- 8, P=0.004) after starting tocolysis compared with the nifedipine group. Mean maternal heart rate was significantly higher in the ritodrine group 24 h (105 +/- 17 vs. 86 +/- 13, P

Pre-eclampsia is a major cause of perinatal and maternal morbidity and mortality worldwide. Although knowledge of the precise aetiology remains uncertain a number of risk factors have been described. Thrombophilias have been associated with pre-eclampsia in a number of studies and it is biologically plausible that they may contribute to the uteroplacental thrombosis that is frequently seen in pre-eclampsia. If this association is confirmed, there is the potential to investigate preventive treatments, including low-molecular-weight heparins, aspirin and folate.

Pregnancy is a hypercoagulable state affecting both the coagulation and the fibrinolytic systems. Any exacerbation of the pre-disposing factors for coagulation may well lead to a thrombotic event more often in pregnant women than in the general population. Arterial thrombosis is very rare in pregnancy. Pre-eclampsia may be a risk factor for the development of arterial disease in later life. Venous thromboembolism (VTE) in pregnancy, although still rare, is a major cause of maternal mortality. Risk factors, such as older age, increased weight and emergency Caesarean section, as well as acquired and genetic thrombophilia, often coexist and reinforce each other. Appropriate thromboprophylaxis needs to be considered and applied on an individual basis. Uteroplacental thrombosis provides a common pathophysiological link between various poor pregnancy outcomes, including recurrent miscarriage, stillbirth, placental abruption, fetal growth restriction and pre-eclampsia. Its significance depends on the gestational age. Acquired and genetic thrombophilia may be associated with such conditions, particularly in early-onset disease. More data are required to assess the significance of such thrombophilias in obstetric practice. Any treatment should be in the context of clinical trials.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women in preterm labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's specialised register of controlled trials, the Cochrane Controlled Trials Register (February 2002), MEDLINE, EMBASE, and Current Contents. We also contacted recognised experts and cross referenced relevant material. SELECTION CRITERIA: All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour between 20 and 36 weeks gestation. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data. MAIN RESULTS: Eleven randomised controlled trials involving 870 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within 48 hours (relative risk (RR) 0.73; 95% confidence interval (CI) 0.54, 0.98) and within seven days (RR 0.76; 95% CI 0.59, 0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.15; 95% CI 0.06, 0.43), the frequency of neonatal respiratory distress syndrome (RR 0.64; 95% CI 0.45, 0.91) and neonatal jaundice (RR 0.73; 95% CI 0.57, 0.93). REVIEWER'S CONCLUSIONS: When tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to betamimetic agents. Further research should address the effects of different dosage regimens and formulations of nifedipine on maternal and neonatal outcomes.

To estimate in a cohort of nulliparous women in labor at term whether cesarean delivery rates are increased in first and second stages of labor in overweight and obese women and whether being overweight or obese is an independent risk factor for cesarean delivery.Nulliparous women recruited to the prospective Screening for Pregnancy Endpoints study who went into labor after 37 weeks of gestation were categorized according to ethnicity-specific body mass index (BMI) criteria as normal, overweight, or obese. Normal BMI was the referent. Multivariable analysis, adjusting for known confounders for obesity and cesarean delivery, was performed to estimate if being overweight or obese was associated with an increased risk of cesarean in labor (all cesarean deliveries and in first stage of labor).Of 2,629 participants, 1,416 (54%) had normal BMIs, 773 (29%) were overweight, and 440 (17%) were obese. First-stage cesarean delivery was increased in overweight (n=149 [19%]) and obese (n=137 [31%]) women compared with normal-weight women (n=181 [13%; P.001), whereas second-stage cesarean delivery was similar (normal BMI 76 [6.2%], overweight 45 [7.2%], obese 23 [7.6%], P=.87). Being overweight or obese was an independent risk factor for all cesarean deliveries in labor with adjusted odds ratio (OR) of 1.34 (95% confidence interval [CI] 1.07-1.67) and 2.51 (95% CI 1.94-3.25), respectively. Similarly, being overweight (adjusted OR 1.39; 95% CI 1.09-1.79) or obese (adjusted OR 2.89; 95% CI 2.19-3.80) was associated with increased cesarean delivery during the first stage. Risks of cesarean delivery were similar regardless of whether ethnicity-specific or World Health Organization (WHO) BMI criteria were used.Among nulliparous women in labor at term, being overweight or obese by either WHO or ethnicity-specific BMI criteria is an independent risk factor for cesarean delivery in the first stage but not the second stage of labor.Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, ACTRN12607000551493.

UNLABELLED Cervical incompetence is not a categoric but rather a continuous variable, meaning that there are various degrees in the competency of the cervix. Furthermore, a certain degree of competency of the cervix can be expressed differently in subsequent pregnancies. Women with risk factors for cervical incompetence in their gynecological/obstetric history should be followed by transvaginal ultrasonography. History alone is not an indication for a prophylactic cerclage. Although transvaginal ultrasonography identifies women at high risk of preterm delivery, it does not discriminate between different underlying pathologies. Short cervical length alone is not an indication for a therapeutic cerclage. Serial transvaginal ultrasonographic measurements of cervical length in women with risk factors can identify those women truly at high risk of preterm delivery. A transvaginal cervical cerclage with bed rest reduces preterm delivery and improves perinatal outcome in women with a short cervical length and risk factors for cervical incompetence. TARGET AUDIENCE Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES After completion of this article, the reader will be able to define cervical incompetence, explain the role of transvaginal ultrasonography in the prediction of preterm delivery, and summarize the data on the use of transvaginal cervical cerclage.