Assessment of perinatal anxiety: diagnostic accuracy of five measures.

BACKGROUND: Anxiety in pregnancy and after giving birth (the perinatal period) is highly prevalent but under-recognised. Robust methods of assessing perinatal anxiety are essential for services to identify and treat women appropriately. AIMS: To determine which assessment measures are most psychometrically robust and effective at identifying women with perinatal anxiety (primary objective) and depression (secondary objective). METHOD: We conducted a prospective longitudinal cohort study of 2243 women who completed five measures of anxiety and depression (Generalized Anxiety Disorder scale (GAD) two- and seven-item versions; Whooley questions; Clinical Outcomes in Routine Evaluation (CORE-10); and Stirling Antenatal Anxiety Scale (SAAS)) during pregnancy (15 weeks, 22 weeks and 31 weeks) and after birth (6 weeks). To assess diagnostic accuracy a sample of 403 participants completed modules of the Mini-International Neuropsychiatric Interview (MINI). RESULTS: The best diagnostic accuracy for anxiety was shown by the CORE-10 and SAAS. The best diagnostic accuracy for depression was shown by the CORE-10, SAAS and Whooley questions, although the SAAS had lower specificity. The same cut-off scores for each measure were optimal for identifying anxiety or depression (SAAS ≥9; CORE-10 ≥9; Whooley ≥1). All measures were psychometrically robust, with good internal consistency, convergent validity and unidimensional factor structure. CONCLUSIONS: This study identified robust and effective methods of assessing perinatal anxiety and depression. We recommend using the CORE-10 or SAAS to assess perinatal anxiety and the CORE-10 or Whooley questions to assess depression. The GAD-2 and GAD-7 did not perform as well as other measures and optimal cut-offs were lower than currently recommended.

The deleterious effects of cannabis during pregnancy on neonatal outcomes.

OBJECTIVES: To evaluate whether cannabis use during pregnancy is associated with adverse neonatal outcomes that are independent of cigarette smoking. DESIGN: Prospective cohort study. SETTING: Adelaide (Australia), Auckland (New Zealand), Cork (Ireland), and Leeds, London and Manchester (United Kingdom). PARTICIPANTS: 5610 pregnant nulliparous women with low risk pregnancies recruited for the Screening for Pregnancy Endpoints (SCOPE) study, November 2004 - February 2011. At 14-16 weeks of pregnancy, women were grouped by self-reported cannabis use. MAIN OUTCOME MEASURES: Infant birthweight, head circumference, birth length, gestational age, and severe neonatal morbidity or mortality. RESULTS: 314 women (5.6%) reported using cannabis in the 3 months before or during their pregnancy; 97 (31%) stopped using it before and 157 (50%) during the first 15 weeks of pregnancy, while 60 (19%) were still using cannabis at 15 weeks. Compared with babies of mother who had never used cannabis, infants of those who still used it at 15 weeks had lower mean values for birthweight (adjusted mean difference [aMD], -127 g; 95% CI, -238 to -17 g), head circumference (aMD, -0.5 cm; 95% CI, -0.8 to -0.1 cm), birth length (aMD, -0.8 cm; 95% CI, -1.4 to -0.2 cm), and gestational age at birth (aMD, -8.1 days; 95% CI, -12.1 to -4.0 days). The differences for all outcomes except gestational age were greater for women who used cannabis more than once a week than for those who used it less frequently. CONCLUSIONS: Continuing to use cannabis during pregnancy is an independent risk factor for poorer neonatal outcomes.

Metabolic syndrome in pregnancy and risk for adverse pregnancy outcomes: A prospective cohort of nulliparous women.

BACKGROUND: Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes, in nulliparous pregnant women, has not been investigated. METHODS AND FINDINGS: Low-risk, nulliparous women were recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) cohort between 11 November 2004 and 28 February 2011. Women were assessed for a range of demographic, lifestyle, and metabolic health variables at 15 ± 1 weeks' gestation. MetS was defined according to International Diabetes Federation (IDF) criteria for adults: waist circumference ≥80 cm, along with any 2 of the following: raised trigycerides (≥1.70 mmol/l [≥150 mg/dl]), reduced high-density lipoprotein cholesterol (<1.29 mmol/l [<50 mg/dl]), raised blood pressure (BP) (i.e., systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg), or raised plasma glucose (≥5.6 mmol/l). Log-binomial regression analyses were used to examine the risk for each pregnancy outcome (GDM, PE, large for gestational age [LGA], small for gestational age [SGA], and spontaneous preterm birth [sPTB]) with each of the 5 individual components for MetS and as a composite measure (i.e., MetS, as defined by the IDF). The relative risks, adjusted for maternal BMI, age, study centre, ethnicity, socioeconomic index, physical activity, smoking status, depression status, and fetal sex, are reported. A total of 5,530 women were included, and 12.3% (n = 684) had MetS. Women with MetS were at an increased risk for PE by a factor of 1.63 (95% CI 1.23 to 2.15) and for GDM by 3.71 (95% CI 2.42 to 5.67). In absolute terms, for PE, women with MetS had an adjusted excess risk of 2.52% (95% CI 1.51% to 4.11%) and, for GDM, had an adjusted excess risk of 8.66% (95% CI 5.38% to 13.94%). Diagnosis of MetS was not associated with increased risk for LGA, SGA, or sPTB. Increasing BMI in combination with MetS increased the estimated probability for GDM and decreased the probability of an uncomplicated pregnancy. Limitations of this study are that there are several different definitions for MetS in the adult population, and as there are none for pregnancy, we cannot be sure that the IDF criteria are the most appropriate definition for pregnancy. Furthermore, MetS was assessed in the first trimester and may not reflect pre-pregnancy metabolic health status. CONCLUSIONS: We did not compare the impact of individual metabolic components with that of MetS as a composite, and therefore cannot conclude that MetS is better at identifying women at risk. However, more than half of the women who had MetS in early pregnancy developed a pregnancy complication compared with just over a third of women who did not have MetS. Furthermore, while increasing BMI increases the probability of GDM, the addition of MetS exacerbates this probability. Further studies are required to determine if individual MetS components act synergistically or independently.

Pre-pregnancy fast food and fruit intake is associated with time to pregnancy.

STUDY QUESTION: Is preconception dietary intake associated with reduced fecundity as measured by a longer time to pregnancy (TTP)? SUMMARY ANSWER: Lower intake of fruit and higher intake of fast food in the preconception period were both associated with a longer TTP. WHAT IS KNOWN ALREADY: Several lifestyle factors, such as smoking and obesity, have consistently been associated with a longer TTP or infertility, but the role of preconception diet in women remains poorly studied. Healthier foods or dietary patterns have been associated with improved fertility, however, these studies focused on women already diagnosed with or receiving treatments for infertility, rather than in the general population. STUDY DESIGN, SIZE, DURATION: This was a multi-center pregnancy-based cohort study of 5628 nulliparous women with low-risk singleton pregnancies who participated in the Screening for Pregnancy Endpoints (SCOPE) study. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 5598 women were included. Data on retrospectively reported TTP and preconception dietary intake were collected during the first antenatal study visit (14-16 weeks' gestation). Dietary information for the 1 month prior to conception was obtained from food frequency questions for fruit, green leafy vegetables, fish and fast foods, by a research midwife. Use of any fertility treatments associated with the current pregnancy was documented (yes, n = 340, no, n = 5258). Accelerated failure time models with log normal distribution were conducted to estimate time ratios (TR) and 95% CIs. The impact of differences in dietary intake on infertility (TTP >12 months) was compared using a generalized linear model (Poisson distribution) with robust variance estimates, with resulting relative risks (RR) and 95% CIs. All analyses were controlled for a range of maternal and paternal confounders. Sensitivity analyses were conducted to explore potential biases common to TTP studies. MAIN RESULTS AND THE ROLE OF CHANCE: Lower intakes of fruit and higher intakes of fast food were both associated with modest increases in TTP and infertility. Absolute differences between the lowest and highest categories of intake for fruit and fast food were in the order of 0.6-0.9 months for TTP and 4-8% for infertility. Compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day (TR = 1.06, 95% CI: 0.97-1.15), 1-6 times/week (TR = 1.11, 95% CI: 1.01-1.22) or <1-3 times/month (TR = 1.19, 95% CI: 1.03-1.36), corresponded to 6, 11 and 19% increases in the median TTP (Ptrend = 0.007). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2-<4 times/week (TR = 0.89, 95% CI: 0.81-0.98), >0-<2 times/week (TR 0.79, 95% CI 0.69-0.89) or no fast food (TR = 0.76, 95% CI: 0.61-0.95), corresponded to an 11, 21 and 24% reduction in the median TTP (Ptrend <0.001). For infertility, compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day, 1-6 times/week or <1-3 times/month corresponded to a 7, 18 and 29% increase in risk of infertility (Ptrend = 0.043). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2-<4 times/week, >0-<2 times/week, or no fast food, corresponded to an 18, 34 and 41% reduced risk of infertility (Ptrend <0.001). Pre-pregnancy intake of green leafy vegetables or fish were not associated with TTP or infertility. Estimates remained stable across a range of sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION: Collection of dietary data relied on retrospective recall and evaluated a limited range of foods. Paternal dietary data was not collected and the potential for residual confounding cannot be eliminated. Compared to prospective TTP studies, retrospective TTP studies are prone to a number of potential sources of bias. WIDER IMPLICATIONS OF THE FINDINGS: These findings underscore the importance of considering preconception diet for fecundity outcomes and preconception guidance. Further research is needed assessing a broader range of foods and food groups in the preconception period. STUDY FUNDING/COMPETING INTEREST(S): The SCOPE database is provided and maintained by MedSciNet AB (http://medscinet.com). The Australian SCOPE study was funded by the Premier's Science and Research Fund, South Australian Government (http://www.dfeest.sa.gov.au/science-research/premiers-research-and-industry-fund). The New Zealand SCOPE study was funded by the New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council (04/198); Evelyn Bond Fund, Auckland District Health Board Charitable Trust. The Irish SCOPE study was funded by the Health Research Board of Ireland (CSA/2007/2; http://www.hrb.ie). The UK SCOPE study was funded by National Health Service NEAT Grant (Neat Grant FSD025), Biotechnology and Biological Sciences Research council (www.bbsrc.ac.uk/funding; GT084) and University of Manchester Proof of Concept Funding (University of Manchester); Guy's and St. Thomas' Charity (King's College London) and Tommy's charity (http://www.tommys.org/; King's College London and University of Manchester); and Cerebra UK (www.cerebra.org.uk; University of Leeds). L.E.G. is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (ID 1070421). L.J.M. is supported by a SACVRDP Fellowship; a program collaboratively funded by the National Heart Foundation, the South Australian Department of Health and the South Australian Health and Medical Research Institute. L.C.K. is supported by a Science Foundation Ireland Program Grant for INFANT (12/RC/2272). C.T.R. was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (GNT1020749). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Antenatal risk factors associated with neonatal morbidity in large-for-gestational-age infants: an international prospective cohort study.

INTRODUCTION: Large-for-gestational-age infants are associated with increased risk of neonatal morbidity and mortality. However, most of them will not have adverse outcomes. Our aim was to identify antenatal clinical factors associated with neonatal morbidity in large-for-gestational-age infants. MATERIAL AND METHODS: Nulliparous women from the Screening for Pregnancy Endpoints (SCOPE) study were included. We compared maternal and fetal factors between large-for-gestational-age infants (birthweight >90th customized centile) with and without neonatal morbidity, defined as admission to a neonatal intensive care unit or severe neonatal morbidity. Factors were selected based on a priori hypotheses of association and included maternal demography, anthropometric measures and self-reported physical activity (15 and 20 weeks), fetal biometry (20 weeks), and clinical information. Multivariable logistic regression was used to identify risk factors. Stratified analyses were performed by maternal obesity and physical activity. RESULTS: Among term pregnancies, prevalence of large-for-gestational-age infants was 9.3% (491/5255), with 11.8% (58/491) prevalence of neonatal morbidity. Random glucose at 20 weeks (odds ratio 1.52; 95% confidence interval 1.17-1.97, per 1 mmol/L increase) and no regular physical activity at 20 weeks (odds ratio 3.93; 95% confidence interval 1.75-8.83) were associated with increased risk of neonatal morbidity after adjustment for birthweight, gestational age at delivery and gestational diabetes. The increased risk associated with higher glucose levels was not evident in women with regular physical activity or without obesity. CONCLUSIONS: Regular physical activity in mid-pregnancy is associated with lower risk for neonatal morbidity in large-for-gestational-age infants and seems to offer protection against the increased risk associated with higher maternal glucose levels.

Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study.

STUDY QUESTION: Which variables at 15 and 20 weeks' gestation, particularly those amenable to modification before pregnancy, are associated with a subsequent uncomplicated pregnancy? SUMMARY ANSWER: Normalising body mass index, increasing fruit intake before pregnancy, reducing blood pressure, stopping misuse of drugs, and being in paid employment are all associated with subsequent uncomplicated pregnancy outcomes.

Pregnancy loss managed by cervical dilatation and curettage increases the risk of spontaneous preterm birth.

STUDY QUESTION: Do women with a previous miscarriage or termination of pregnancy have an increased risk of spontaneous preterm birth and is this related to previous cervical dilatation and curettage? SUMMARY ANSWER: A single previous pregnancy loss (termination or miscarriage) managed by cervical dilatation and curettage is associated with a greater risk of SpPTB. WHAT IS KNOWN ALREADY: Miscarriage affects ∼20% of pregnancies and as many as a further 20% of pregnancies undergo termination. STUDY DESIGN, SIZE, DURATION: We utilized data from 5575 healthy nulliparous women with singleton pregnancies recruited to the Screening for Pregnancy Endpoints (SCOPE) study, a prospective cohort study performed between November 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome was spontaneous preterm birth (defined as spontaneous preterm labour or preterm premature rupture of membranes (PPROM) resulting in preterm birth <37 weeks' gestation). Secondary outcomes included PPROM, small for gestational age, birthweight, pre-eclampsia and placental abruption. MAIN RESULTS AND THE ROLE OF CHANCE: Women with previous pregnancy loss (miscarriage or termination) were compared with those with no previous pregnancy loss. There were 4331 (78%) women who had no previous pregnancy loss, 974 (17.5%) who had one early previous pregnancy loss, 249 (4.5%) who had two and 21 (0.5%) who had three or four losses. Women with two to four previous losses, but not those with a single loss, had an increased risk of spontaneous preterm birth (adjusted OR 2.12; 95% CI 1.55, 2.90) and/or placental abruption (adjusted OR 2.30; 95% CI 1.36, 3.89) compared with those with no previous pregnancy. A single previous miscarriage or termination of pregnancy where the management involved cervical dilatation and curettage was associated with an increased risk of spontaneous preterm birth (adjusted OR 1.64; 95% CI 1.08, 2.50; 6% absolute risk and adjusted OR 1.83; 95% CI 1.35, 2.48; 7% absolute risk, respectively) compared with those with no previous pregnancy losses. This is in contrast with women with a single previous miscarriage or termination managed non-surgically who showed no increase risk (adjusted OR 0.86; 95% CI 0.38, 1.94; 3.4% absolute risk and adjusted OR 0.87; 95% CI 0.69, 1.12; 3.8% absolute risk, respectively). LIMITATIONS, REASONS FOR CAUTION: Although every effort was made to record accurate previous pregnancy data, it was not feasible to confirm the history and management of previous pregnancy loss by hospital records. This may have introduced recall bias. WIDER IMPLICATIONS OF THE FINDINGS: This large prospective cohort study of healthy nulliparous women has demonstrated that women with either a previous miscarriage or termination of pregnancy were at increased risk of spontaneous preterm birth if they were managed by procedures involving cervical dilatation and curettage. However, overall, women with a single pregnancy loss did not have an increased risk of having any other of the adverse pregnancy outcomes examined. In contrast, two to four previous pregnancy losses were associated with an increased risk of having a pregnancy complicated by spontaneous preterm birth and/or placental abruption. Research is required to determine whether non-surgical management of miscarriage or termination of pregnancy should be advocated over surgical treatment. STUDY FUNDING/COMPETING INTEREST(S): New Zealand: New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council; Evelyn Bond Fund, Auckland District Health Board Charitable Trust. Australia: Premier's Science and Research Fund, South Australian Government. Ireland: Health Research Board. Leeds: Cerebra Charity, Carmarthen. Manchester: National Health Service NEAT Grant; Manchester Biotechnology and Biological Sciences Research Council; University of Manchester Proof of Concept Funding. King's College London: Guy's and St Thomas' Charity. King's College London and Manchester: Tommy's-The Baby Charity. TRIAL REGISTRATION NUMBER: N/A.

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.

BACKGROUND: Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS: We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS: 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION: The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING: Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

Sex- and growth-specific characteristics of small for gestational age infants: a prospective cohort study.

BACKGROUND: Asymmetric fetal growth and male sex are both associated with adverse neonatal outcome. However, less is known about the influence of asymmetric growth and fetal sex within SGA neonates, a group of infants already at increased risk for adverse neonatal outcomes. The aim of the present study was to provide insight into variance in risk factors for SGA in a fetal sex- and growth symmetry-specific way. METHODS: For this prospective, multicenter cohort study, data from the Screening for Pregnancy Endpoints (SCOPE) study were used with 5628 nulliparous participants, of which 633 (11.3%) pregnancies were complicated with SGA and 3376 (60.0%) women had uncomplicated pregnancies. Association between risk factors for SGA, SGA subgroups, and uncomplicated pregnancies were assessed with multivariable analyses. RESULTS: Prevalence of asymmetric growth varied from 45.8% of SGA infants to 5.5% of infants with a customized birthweight > 90th percentile (p < 0.001). Significantly more SGA males had asymmetric growth compared to SGA female infants (51.2% vs 40.4%, p = 0.009). Maternal pre-pregnancy diet and BMI < 20 and ≥ 30 were significantly associated with symmetric SGA but not with asymmetric SGA. Asymmetric SGA infants had not only lower customized birthweight percentile (4.4 (SD 2.8) vs 5.0 (SD 3.0), p < 0.001), but also lower rates of stillbirth (p = 0.041) and less often Apgar scores < 7 (p = 0.060). CONCLUSIONS: Among SGA infants, low customized birthweight percentiles and male sex are associated with asymmetric growth. Only symmetric SGA is significantly associated with maternal risk factors in early pregnancy. There is a substantial variance in risk factors and neonatal outcomes for SGA based on growth symmetry, implying a different pathogenesis. TRIAL REGISTRATION: ACTRN12607000551493.

Gestational effects on host inflammatory response in normal and pre-eclamptic pregnancies.

OBJECTIVE: Pre-eclampsia (PET) remains a leading cause of maternal and neonatal morbidity and mortality. Although its pathophysiology involves an underlying inflammatory dysfunction, it is unclear how this may be affected by increasing gestational age, particularly in relation to the time of onset of disease. Murine studies have indicated that a progressive increase in serum inflammatory profile is a physiological feature of normal gestation. The present study aimed to investigate this phenomenon in women in relation to normal and pre-eclamptic pregnancies. STUDY DESIGN: Control and PET groups (each n=20) were divided into early and late pregnancy (before and after 34 weeks gestation, respectively). Whole blood was diluted 1:1 with RPMI 1640 medium with/without 1 microg/ml lipopolysaccharide at 37 degrees C for 24 h under a humidified 5% CO(2) atmosphere. Samples were collected at 0, 2, 6 and 24 h and analysed for interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-gamma, monocyte chemotactic protein (MCP-1), macrophage inflammatory protein (MIP)-1beta and tumour necrosis factor (TNF)-alpha by fluid-phase multiplex immunoassay. RESULTS: This study confirms that pregnancy features an increasing inflammatory response with advancing gestational age, which was seen in both control and PET pregnancies (P<0.01). CONCLUSIONS: This increase in inflammatory responsiveness with advancing gestation may provide an explanation for the incidence of late onset PET in the absence of placental pathology, as well as serving as a potential physiological priming mechanism geared towards increasing maternal sensitivity to the fetal triggers of labour.

Regulation of maternal serum and amniotic fluid cytokine profiles in the mouse: possible roles in the onset of labour.

Murine pregnancy is characterised by marked increases in serum cytokine profiles with advancing gestation, but whether these changes reflect concentrations in amniotic fluid is unknown. This study therefore profiled 23 cytokines by fluid-phase multiplex immunoassay of amniotic fluid and serum collected from naturally mated mice during mid- and late pregnancy (days 11 and 18, respectively). The marked increase in serum profile of many cytokines from days 11 to 18 was not reflected in amniotic fluid, wherein most cytokine concentrations were lower on day 18. Serum and amniotic fluid cytokine concentrations were largely inversely related, indicating separate, localised regulatory mechanisms geared towards the maintenance of pregnancy, modulation of immune effector cell function and optimisation of fetal development. We suggest that, while maternal systemic inflammatory priming prepares the mother for birth, the amniotic compartment exhibits a tightly regulated inflammatory quiescence. These findings are discussed in relation to the onset of labour, which ultimately results in the elevated cytokine amniotic levels traditionally associated with the final stages of pregnancy.

Plasma from women with preeclampsia has a low lipid and ketone body content--a nuclear magnetic resonance study.

OBJECTIVE: Using (1)H-nuclear magnetic resonance spectroscopy and chemometrics, we sought to establish the metabolic profile for preeclampsia and to identify biomarkers that would permit a distinction between women with a normal pregnancy and those suffering from preeclampsia. METHODS: Plasma samples from 11 normotensive pregnant women and 11 women with preeclampsia were analyzed. Principal component analysis was applied to differentiate between the two groups of patients. RESULTS: Lipid concentrations were found to be significantly lower in the plasma of patients suffering from preeclampsia than those in normotensive pregnant women (p = 0.031). There is also evidence to suggest that ketone body constituents may contribute to the discrimination. CONCLUSION: (1)H-nuclear magnetic resonance-based metabolic profiling can detect patients with preeclampsia.

Uterine and serum cytokine arrays in the mouse during estrus.

Cytokines govern uterine immunology and embryo receptivity and are increasingly recognized for their embryotrophic roles. While supplementing culture media with cytokines may improve embryo development/viability in vitro, little is known about their physiological profiles in vivo, and hence which are likely to be uterine immunoregulators and embryotrophins. Therefore, this study profiled 23 cytokines in uterine fluid and serum from individual naturally cycling estrous mice. Samples were analyzed by fluid-phase multiplex immunoassays for interleukin (IL)-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, eotaxin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-gamma, keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha MIP)-1beta regulated upon activation, normal T-cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-alpha. There was a marked divergence in cytokine concentrations between uterine fluid and serum. The former was dominated by G-CSF, eotaxin, KC and IL-1alpha, and had significantly higher levels of IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-9, GM-CSF, MIP-1alpha, MIP-1beta and RANTES. Serum had significantly higher IL-12 (p40), IL-12 (p70), IL-17 and IFN-gamma concentrations. No significant differences in IL-5, IL-10, IL-13, MCP-1 or TNF-alpha profiles were noted. These data indicated a strict compartmentalization of uterine cytokines, with G-CSF as a major cytokine at estrous. Results are discussed with respect to immune cell function, post-coital paternal antigen processing, estrous cyclicity, and endometrial angiogenesis, cell turnover and differentiation.

Clinical, ultrasound and molecular biomarkers for early prediction of large for gestational age infants in nulliparous women: An international prospective cohort study.

OBJECTIVE: To develop a prediction model for term infants born large for gestational age (LGA) by customised birthweight centiles. METHODS: International prospective cohort of nulliparous women with singleton pregnancy recruited to the Screening for Pregnancy Endpoints (SCOPE) study. LGA was defined as birthweight above the 90th customised centile, including adjustment for parity, ethnicity, maternal height and weight, fetal gender and gestational age. Clinical risk factors, ultrasound parameters and biomarkers at 14-16 or 19-21 weeks were combined into a prediction model for LGA infants at term using stepwise logistic regression in a training dataset. Prediction performance was assessed in a validation dataset using area under the Receiver Operating Characteristics curve (AUC) and detection rate at fixed false positive rates. RESULTS: The prevalence of LGA at term was 8.8% (n = 491/5628). Clinical and ultrasound factors selected in the prediction model for LGA infants were maternal birthweight, gestational weight gain between 14-16 and 19-21 weeks, and fetal abdominal circumference, head circumference and uterine artery Doppler resistance index at 19-21 weeks (AUC 0.67; 95%CI 0.63-0.71). Sensitivity of this model was 24% and 49% for a fixed false positive rate of 10% and 25%, respectively. The addition of biomarkers resulted in selection of random glucose, LDL-cholesterol, vascular endothelial growth factor receptor-1 (VEGFR1) and neutrophil gelatinase-associated lipocalin (NGAL), but with minimal improvement in model performance (AUC 0.69; 95%CI 0.65-0.73). Sensitivity of the full model was 26% and 50% for a fixed false positive rate of 10% and 25%, respectively. CONCLUSION: Prediction of LGA infants at term has limited diagnostic performance before 22 weeks but may have a role in contingency screening in later pregnancy.

Clinical and biochemical factors associated with preeclampsia in women with obesity.

OBJECTIVE: To compare early pregnancy clinical and biomarker risk factors for later development of preeclampsia between women with obesity (body mass index, BMI ≥30 kg/m2 ) and those with a normal BMI (20-25 kg/m2 ). METHODS: In 3,940 eligible nulliparous women from the Screening for Pregnancy Endpoints (SCOPE) study, a total of 53 biomarkers of glucose and lipid metabolism, placental function, and known markers of preeclampsia were measured at 14 to 16 weeks' gestation. Logistic regression was performed to identify clinical and biomarker risk factors for preeclampsia in women with and without obesity. RESULTS: Among 834 women with obesity and 3,106 with a normal BMI, 77 (9.2%) and 105 (3.4%) developed preeclampsia, respectively. In women with obesity, risk factors included a family history of thrombotic disease, low plasma placental growth factor, and higher uterine artery resistance index at 20 weeks. In women with a normal BMI, a family history of preeclampsia or gestational hypertension, mean arterial blood pressure, plasma endoglin and cystatin C, and uterine artery resistance index were associated with preeclampsia, while high fruit intake was protective. CONCLUSIONS: Women with obesity and a normal BMI have different early pregnancy clinical and biomarker risk factors for preeclampsia.

Prediction of Small for Gestational Age Infants in Healthy Nulliparous Women Using Clinical and Ultrasound Risk Factors Combined with Early Pregnancy Biomarkers.

OBJECTIVE: Most small for gestational age pregnancies are unrecognised before birth, resulting in substantial avoidable perinatal mortality and morbidity. Our objective was to develop multivariable prediction models for small for gestational age combining clinical risk factors and biomarkers at 15±1 weeks' with ultrasound parameters at 20±1 weeks' gestation. METHODS: Data from 5606 participants in the Screening for Pregnancy Endpoints (SCOPE) cohort study were divided into Training (n = 3735) and Validation datasets (n = 1871). The primary outcomes were All-SGA (small for gestational age with birthweight <10th customised centile), Normotensive-SGA (small for gestational age with a normotensive mother) and Hypertensive-SGA (small for gestational age with an hypertensive mother). The comparison group comprised women without the respective small for gestational age phenotype. Multivariable analysis was performed using stepwise logistic regression beginning with clinical variables, and subsequent additions of biomarker and then ultrasound (biometry and Doppler) variables. Model performance was assessed in Training and Validation datasets by calculating area under the curve. RESULTS: 633 (11.2%) infants were All-SGA, 465(8.2%) Normotensive-SGA and 168 (3%) Hypertensive-SGA. Area under the curve (95% Confidence Intervals) for All-SGA using 15±1 weeks' clinical variables, 15±1 weeks' clinical+ biomarker variables and clinical + biomarkers + biometry /Doppler at 20±1 weeks' were: 0.63 (0.59-0.67), 0.64 (0.60-0.68) and 0.69 (0.66-0.73) respectively in the Validation dataset; Normotensive-SGA results were similar: 0.61 (0.57-0.66), 0.61 (0.56-0.66) and 0.68 (0.64-0.73) with small increases in performance in the Training datasets. Area under the curve (95% Confidence Intervals) for Hypertensive-SGA were: 0.76 (0.70-0.82), 0.80 (0.75-0.86) and 0.84 (0.78-0.89) with minimal change in the Training datasets. CONCLUSION: Models for prediction of small for gestational age, which combine biomarkers, clinical and ultrasound data from a cohort of low-risk nulliparous women achieved modest performance. Incorporation of biomarkers into the models resulted in no improvement in performance of prediction of All-SGA and Normotensive-SGA but a small improvement in prediction of Hypertensive-SGA. Our models currently have insufficient reliability for application in clinical practice however, they have potential utility in two-staged screening tests which include third trimester biomarkers and or fetal biometry.

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

A prospective analysis of the role of uterine artery Doppler waveform notching in the assessment of at-risk pregnancies.

OBJECTIVE: To determine the value of second trimester uterine artery Doppler waveform notching in the prediction of adverse pregnancy outcome in a high-risk group. DESIGN: Analysis of data from a consecutively collected cohort. SETTING: St. James University Hospital, Leeds, UK. POPULATION: Three hundred thirty women known to be at risk of preeclampsia (PET) or intrauterine growth restriction (IUGR) were assessed for notching of the uterine artery Doppler waveform between 24-30 weeks of pregnancy. MAIN OUTCOME MEASURES: Preeclampsia (PET), small-for-gestational-age at birth (SGA), preterm delivery (PTD), perinatal death. RESULTS: Two hundred thirty-two women (70.3%) had a normal uterine artery Doppler waveforms, and 98 (29.7%) demonstrated either unilateral or bilateral notching. In women where notching was present, 20 (20%) developed PET compared with 8 (3.5%) in the normal group [Odds ratio (OR) 7.2, CI 3-17]; SGA birthweight was present in 24 (24.5%) of the notched group and in 21 (9%) of normal group (OR 3.3; CI 1.7-6.2); 40 (41%) of the notched group delivered preterm ( < 37 weeks) as compared with 37 (16%) of the normal group (OR 7.9; CI 4.6-13). This difference was even more marked when delivery before 32 weeks was considered, occurring in 8 (8%) of the notched group and 4 (1.7%) of the normal group (OR 11.5; CI 4.5-29.4). Of the six perinatal deaths, five (5.1%) occurred in the notched group (OR 12.4; CI 1.4-108). CONCLUSION: This study demonstrates that the addition of uterine Doppler waveform analysis to the monitoring profile of women at risk of PET, SGA, IUD and preterm delivery can further define those in a higher risk group and the majority that have a risk no higher than the background.