Identification of the optimal growth charts for use in a preterm population: An Australian state-wide retrospective cohort study.

BACKGROUND: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population. METHODS AND FINDINGS: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart. CONCLUSIONS: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality.

Depression across pregnancy and the postpartum, antidepressant use and the association with female sexual function.

BACKGROUND: There is an established relationship between depression and sexual functioning in women. However, there is limited research examining the relationship between perinatal depression and sexual functioning. METHODS: This study draws on the Mercy Pregnancy and Emotional Wellbeing Study and reports on 211 women recruited in early pregnancy and followed to 12 months postpartum. Women were assessed for depression using the Structured Clinical Interview for the DSM-IV, repeated measurement of depressive symptoms using the Edinburgh Postnatal Depression Scale and sexual functioning using the Female Sexual Functioning Inventory. Data were also collected on antidepressant use, mode of delivery, history of childhood trauma, breastfeeding and partner support. RESULTS: Women showed a decline in sexual functioning over pregnancy and the first 6 months postpartum, which recovered by 12 months. For women with depression, sexual functioning was lower throughout pregnancy and continued to be lower at 6 months postpartum than those without depression. Ongoing depressive symptoms at 12 months were also associated with lower sexual functioning. Sexual functioning was not predicted by mode of delivery, antidepressant use or childhood trauma. Breastfeeding predicted lower sexual functioning only at 6 months. Higher partner support predicted higher female sexual functioning. CONCLUSIONS: Pregnancy and the postpartum are a time of reduced sexual functioning for women; however, women with depression are more likely to have lower levels of sexual functioning and this was not predicted by antidepressant use. In women with perinatal depression, consideration of the impact on sexual functioning should be an integral part of care.

Customised growth charts in large-for-gestational-age infants and the association with emergency caesarean section rate.

BACKGROUND AND AIM: Large-for-gestational-age (LGA) infants are at increased risk of intrapartum complications. However, some infants classified as LGA may be appropriate-for-gestational-age (AGA) if adjusted for maternal stature. We determined whether customisation of birthweight centiles by maternal height, or height and weight, improves the detection of LGA infants at risk of complications. METHODS: We conducted a retrospective analysis of 38 246 term, singleton nulliparous women. We compared population birthweight centiles to those customised by height, or height and weight for complications including intrapartum caesarean section, instrumental delivery, postpartum haemorrhage, anal sphincter injury and neonatal outcomes. RESULTS: Those considered LGA when customised for height but AGA by population centiles (LGA-ht-only) were at increased risk of intrapartum emergency caesarean section compared with infants AGA on all charts (AGA-all); odds ratio (OR) 4.64, 95% CI 3.22-6.76. In contrast, infants considered LGA on population charts, but AGA when customised by height (LGA-pop-only) were not at increased risk compared to the AGA-all group (OR 1.43, 95% CI 0.70-1.88). Infants classified as LGA-ht-only compared to LGA-pop-only remained at significantly higher risk after adjustment for potential confounders (aOR 3.27; 95% CI 2.02-5.31). No difference was seen for any other outcomes. No benefit was seen with customisation by both maternal height and weight. CONCLUSION: Women with an infant classified as AGA on population centiles but LGA when customised for height are at increased risk of intrapartum caesarean section. This is a population unrecognised in current practice. Fetal growth should be customised for maternal height when making assessments regarding the LGA infant.

Why we miss fetal growth restriction: Identification of risk factors for severely growth-restricted fetuses remaining undelivered by 40 weeks gestation.

BACKGROUND: Severe fetal growth restriction (FGR) is a leading cause of adverse perinatal morbidity and mortality; however, in Victoria, 35% of severely growth-restricted infants are undelivered by 40 weeks gestation. AIMS: We aimed to identify factors associated with failure to deliver severely growth-restricted fetuses by 40 weeks gestation. METHODS: We conducted a retrospective case-control study of term singletons born <3rd centile for gestation at a single tertiary centre (2010-2017). Infants with a planned delivery for FGR between 37.0-39.6  weeks gestation ('planned birth' group; n = 187) were compared with those undelivered by 40.0  weeks ('undelivered' group; n = 233). Variables assessed included the presence of risk factors for FGR, model of care, symphyseal-fundal height measurements and third trimester ultrasounds. RESULTS: An equivalent proportion of women were 'high-risk' for FGR on history (31.3% vs 38.0%, P = 0.187) in the planned and undelivered groups. Women booked under low-risk models (shared care and midwifery-led care) were significantly more likely to be in the undelivered group compared to those booked under traditional collaborative models (79.8% vs 37.4%, P < 0.001). Women in the undelivered group were less likely to have received a third trimester ultrasound (93.0% vs 40.3%, P < 0.001); however, they were more likely to have had a reassuring ultrasound with an estimation of fetal weight or abdominal circumference >10th centile (78.7% vs 16.1%, P < 0.001). CONCLUSIONS: Failure to deliver the severely growth-restricted fetus before 40.0 weeks is more likely to occur in the following situations: (i) failure to receive an indicated third trimester ultrasound; (ii) the presence of falsely reassuring third trimester ultrasound scan; and (iii) booking under a low-risk rather than traditional collaborative models of care.

The prediction of type 2 diabetes in women with previous gestational diabetes mellitus using lipidomics.

AIMS/HYPOTHESIS: The risk of developing diabetes is greater for women with previous gestational diabetes mellitus (GDM). In the general population, plasma lipidomic analysis can identify individuals at risk of developing type 2 diabetes. The aim of this study was to determine whether circulating lipid levels 12 weeks following a GDM pregnancy were associated with an increased risk of developing type 2 diabetes. METHODS: Plasma lipid profiles containing >300 lipids were measured in 104 normal glucose-tolerant women 12 weeks following an index GDM pregnancy using electrospray-ionisation tandem mass spectrometry. Women were assessed for 10 years for development of overt type 2 diabetes. RESULTS: Among the 104 women with previous GDM, 21 (20%) developed diabetes during the median follow-up period of 8.5 years. Three lipid species, the cholesteryl ester species CE 20:4, the alkenylphosphatidylethanolamine species PE(P-36:2) and the phosphatidylserine species PS 38:4, were independently and positively associated with the development of type 2 diabetes. In a clinical model of prediction of type 2 diabetes that included age, BMI, and levels of pregnancy fasting glucose, postnatal fasting glucose, triacylglycerol and total cholesterol, the addition of these three lipid species resulted in an improvement in the net reclassification index of 22.3%. CONCLUSIONS/INTERPRETATION: The lipid species CE 20:4, PE(P-36:2) and PS 38:4 were significant risk factors for the development of type 2 diabetes in women with a previous history of GDM. This report is the first to use plasma lipidomic analysis to identify individual lipids as potential biomarkers for the prediction of type 2 diabetes in women with a history of GDM.

Pregnancy outcome at term in low-risk population: study at a tertiary obstetric hospital.

AIM: The aim of this study was to evaluate the risk of perinatal death and peripartum morbidity at term amongst the models of care at a single tertiary hospital. MATERIAL AND METHODS: This is a 10-year population study of singleton births at term at the Mercy Hospital for Women comparing the mixed-risk models of care (private obstetrician and a conventional collaborative model of obstetricians and midwives) with the low-risk models (team midwifery and family birth center). Outcome measures included rates of perinatal death, low Apgar scores and obstetric procedures. RESULTS: Data on 44 557 normal term singletons were available for study. Overall, the hospital has a substantially lower term singleton perinatal mortality (1.3/1000) than the reported rate from the state of Victoria over an overlapping period (2.4/1000). The perinatal mortality amongst women selected for low obstetric risk (2.3/1000) was significantly higher than the perinatal mortality in other patients (1.2/1000; P = 0.03). Low Apgar scores at 5 min were also significantly more likely in women selected for low obstetric risk (9.0 vs 6.7/1000; P = 0.03). The differences could not be attributed to socioeconomic status, as this was higher in the low obstetric risk group. Obstetric procedures (induction of labor, cesarean section and instrumental birth) were substantially less common in the low-risk-care patients, as is expected for a low-risk population. CONCLUSION: Women selected for low-risk under midwife-led models of care do not appear to have better outcomes than women with all levels of perinatal risk cared for under traditional obstetrician-led models of care.

Concordance of maternal and paternal decision-making and its effect on choice for vaginal birth after caesarean section.

BACKGROUND: The proportion of women who plan for a repeat elective caesarean section (CS) is one of the major determinants of the overall rate of CS, and programs aiming to reduce the rate of CS have not been greatly successful. To date, there appear to have been no large studies directly addressing paternal influences on decision-making regarding vaginal birth after caesarean (VBAC). This study aimed to compare the reactions of fathers and mothers to the prospect of VBAC. METHODS: Couples were recruited from three Australian hospitals and were eligible with a singleton pregnancy, a normal morphology ultrasound, and where there was no condition in the new pregnancy that would preclude a vaginal birth. Questionnaires were scheduled for 20 weeks' gestation, 32-36 weeks' gestation and six weeks postnatal and were sent separately to each partner. RESULTS: Seventy-five couples completed the full sets of questionnaires during the study period. In total, 31 women (41%) ultimately attempted vaginal delivery, and 44 (59%) were delivered by planned CS. When the paternal rating of risk fell between the second and third trimesters, the couple were likely to attempt VBAC (P < 0.05). Where the maternal rating of importance was 3 or less, 92% had a planned CS compared to 63% for the same paternal scores (P = 0.02). CONCLUSION: This study suggests that interventions that improve the paternal perceptions of risk during a pregnancy might increase the chance that a couple will attempt VBAC.

Perinatal mortality by birthweight centile.

BACKGROUND: Detection of abnormal fetal growth is vital to antenatal care, and traditionally birthweights that are <10th or >90th centile are classified as small or large for gestational age (LGA). Evidence regarding outcomes for birthweight centiles outside these extremes remains unclear. AIMS: To evaluate the relationship between birthweight centile and perinatal death and determine the 'optimum' birthweight centile with the lowest rate of perinatal mortality. METHOD: Data on all Victorian births from 1999 to 2008 were stratified into smaller subsets than the traditional small for gestational age (SGA) (<10th centile), appropriate for gestational age (AGA) (10-90th centile) and LGA (>90th centile) and analysed by all gestations, for term births alone, and using the 'fetus at risk' approach. Multiple logistic regression was used to adjust for age, parity and co-morbidities. RESULTS: For term births, the 'optimum' birthweight centile was the 50-90th range (1.1 perinatal deaths/1000 births). Lower birthweight centiles had significantly higher rates of perinatal death - even those that would be classified as AGA. Babies with a 10-25th birthweight centile had a two-fold increased risk of perinatal death (AOR 2.10, 95% CI 1.6, 2.7). Even those with a 25-50th birthweight centile had higher perinatal mortality rates (AOR 1.58, 95% CI 1.3, 2.0). There was no strong evidence of higher perinatal mortality in larger birthweight centiles, except term births >99th centile. The 'fetus at risk' analysis showed a rise in perinatal mortality after 37 weeks' gestation for all birthweight centiles, particularly for SGA babies. CONCLUSION: Babies with a birthweight below the 50th centile are at greater risk of perinatal mortality compared with the 'optimum' ≥50 to <90th centile group.

Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes.

A significant obstetric complication facing contemporary materno-fetal medicine is preterm premature rupture of the fetal membranes (preterm PROM), which occurs in 30% of all preterm births. The objective of this study was to identify differentially expressed proteins in the cervicovaginal fluid of asymptomatic women before the clinical manifestation of preterm PROM. The preterm PROM group comprised of women with samples collected 6-23 days before PROM, who subsequently delivered preterm (n=5). Women who spontaneously delivered at term served as gestation-matched controls (n=10). Two-dimensional difference in-gel electrophoresis was used to distinguish differential expression between the pooled groups and fold changes were subsequently confirmed by two-dimensional PAGE of individual samples. Spots of interest were identified by mass spectrometry. Proteins that were significantly reduced with impending preterm PROM included the following: thioredoxin (2.7-fold), interleukin 1 receptor antagonist (1.7-fold), fatty acid-binding protein 5 (2.1-fold), cystatin A (dimer; 1.9-fold), monocyte/neutrophil elastase inhibitor (1.6-fold), squamous cell carcinoma antigen-1 (2.1-fold) and γ-glutamyl cyclotransferase (3.0-fold). By contrast, annexin A3 (3.7-fold) and vitamin D binding protein (3.9-fold) were significantly increased with impending preterm PROM. Western blot analysis was also performed on an independent cohort of preterm PROM and control samples to validate these candidate biomarkers. These proteins have known biological functions in oxidative balance, anti-inflammatory activity, metabolism or protease inhibition that may facilitate membrane rupture.

Prediction of spontaneous preterm labour in at-risk pregnant women.

The ability to recognise women who are at-risk of preterm labour (PTL) is often difficult. Over 50% of women who are identified with factors associated with an increased risk of preterm birth will ultimately deliver at term. The cervicovaginal fluid (CVF) comprises a range of proteins secreted by gestational tissues, making it an ideal candidate for the screening of differentially expressed proteins associated with PTL. CVF samples were collected from at-risk asymptomatic women. Two-dimensional gel electrophoresis techniques were used to examine the CVF proteome of women who spontaneously delivered preterm 11-22 days later compared with gestation-matched women who delivered at term. Five candidate biomarkers were selected for further validation in a larger independent cohort of asymptomatic women. Thioredoxin (TXN) and interleukin 1 receptor antagonist (IL1RN) concentrations in the CVF were found to be significantly reduced up to 90 days prior to spontaneous PTL compared with women who subsequently delivered at term. TXN was able to predict spontaneous PTL within 28 days after sampling with a high positive predictive value (PPV) and negative predictive value (NPV) of 75.0% and 96.4% respectively. IL1RN also showed comparable PPV and NPV of 72.7% and 95.7% respectively. The discovery of these differentially expressed proteins may assist in the development of a new predictive bedside test in identifying asymptomatic women who have an increased risk of spontaneous PTL.

Measuring thyroid peroxidase antibodies on the day nulliparous women present for management of miscarriage: a descriptive cohort study.

BACKGROUND: There has been recent evidence suggesting the presence of anti-thyroid peroxidase antibodies (TPOAb) increases the risk of miscarriage, and levothyroxine can rescue miscarriages associated with TPOAb. We propose the most clinically pragmatic cohort to screen for TPOAb are women presenting for management of a missed miscarriage and have never birthed a liveborn. We measured serum TPOAb among nulliparous women presenting for management of miscarriage, and compared levels with women who have had 2 or more livebirths (and never miscarried). Given its potential role in immunomodulation, we also measured Vitamin D levels. METHODS: We performed a prospective descriptive cohort study at a tertiary hospital (Mercy Hospital for Women, Victoria, Australia). We measured TPOAb and Vitamin D levels in serum obtained from 118 nulliparous women presenting for management of miscarriage, and 162 controls with 2 or more livebirths (and no miscarriages). Controls were selected from a serum biobank prospectively collected in the first trimester at the same hospital. RESULTS: Nulliparous women with 1 or more miscarriages had higher thyroid peroxidase antibody (TPOAb) levels than those with 2 or more livebirths; TPOAb in miscarriage group was 0.3 mIU/L (interquartile range [IR]: 0.2-0.7) vs 0.2 mIU/L among controls (IR 0.0-0.5; p < 0.0001). We confirmed TPOAb levels were not correlated with serum human chorionic gonadotrophin (hCG) concentrations in either the miscarriage or control groups. In contrast, thyroid stimulating hormone, fT3 and fT4 levels (thyroid hormones) either trended towards a correlation, or were significantly correlated with serum hCG levels in the two groups. Of the entire cohort that was predominantly caucasian, only 12% were Vitamin D sufficient. Low Vitamin D levels were not associated with miscarriage. CONCLUSIONS: We have confirmed the association between miscarriage and increased TPOAb levels. Furthermore, it appears TPOAb levels in maternal blood are not influenced by serum hCG levels. Therefore, we propose the day nulliparous women present for management for miscarriage is a clinically relevant, and pragmatic time to screen for TPOAb.

Integrating parental leave into specialist training: experience of trainees and recently graduated RANZCOG Fellows.

OBJECTIVES: To ascertain the views of trainees and recently graduated Fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists on their experiences of taking parental leave during specialist training. DESIGN: An anonymous online survey, conducted over a 1-month period from 16 August 2012 to 14 September 2012, of participants' experiences of taking parental leave and of the effects of parental leave taken by trainee colleagues on participants' own training. SETTING AND PARTICIPANTS: All trainees undertaking training for the Fellowship of the College, and all Fellows who had graduated in the past 6 years were invited to take part. Of the total 1051 invitees, 261 responded to the survey. MAIN OUTCOME MEASURES: Ease with which parental leave was granted, ability to return to a training post after taking leave, and participants' experiences of views expressed about parental leave in the work environment. RESULTS: Most participants requesting parental leave were able to access it and return to a training post; however, a small proportion experienced difficulties. Among female respondents who had taken parental leave, 28 (26.2%) reported being asked about their intentions for future pregnancy during the training application process, and 45 (42.1%) reported receiving negative comments about this in the work environment. CONCLUSIONS: While in most instances parental leave is accessible automatically, a small but significant number of trainees reported encountering difficulties. These matters are being addressed within our own College, and our results are likely to be relevant to all bodies involved in postgraduate medical training, particularly given the increasing feminisation of the medical workforce.

The Peri/postnatal Epigenetic Twins Study (PETS).

The Peri/postnatal Epigenetic Twins Study (PETS) is a longitudinal cohort of 250 pairs of Australian twins and their mothers, who were recruited mid-way through pregnancy from January 2007 to September 2009. The study is centered on the developmental origins of health and disease paradigm (DOHaD) in which an adverse intrauterine environment predisposes the individual to complex disease in later life by reducing growth in utero and adversely altering developmental plasticity. Data concerning diet and lifestyle were collected from mothers during pregnancy, and samples of plasma and serum taken at 28 weeks' gestation. We attended 75% of all births, at which time we collected multiple biological samples including placenta, cord blood, and neonatal cheek cells, the latter from 91% of pairs. Chorionicity was recorded and zygosity was determined by DNA testing where necessary. Approximately 40% of the twins are monozygotic, two-thirds of which are dichorionic. Twins were seen again at 18 months of age and repeat blood and cheek swabs taken where possible. Studies of gene expression and the epigenetic marks of DNA methylation have so far revealed that twins exhibit a wide range of epigenetic discordance at birth, that one-third of the epigenome changes significantly between birth and 18 months; shared (maternal) environment, genetic factors, and non-shared intrauterine environment contribute to an increasing proportion of epigenetic variation at birth, respectively, and affect tissues differently, and that within-pair birth weight discordance correlates with epigenetic discordance in genes associated with lipid metabolism, supporting an epigenetic mechanism for DOHaD.

Complement C5A regulates prolabor mediators in human placenta.

Human preterm and term parturition is associated with inflammatory cascades in the uteroplacental unit. Activation of the complement cascade releases potent proinflammatory mediators, including the anaphylatoxin C5a, which exerts its biological effects through its receptors, C5AR (also known as CD88) and C5L2, official symbol GPR77. To date, there are few data available on the role of C5a and CD88 in human pregnancy, so the aim of this study was to determine the effect of C5a and CD88 on some key inflammatory pathways involved in human parturition. Placental tissue samples were obtained from normal pregnancies at the time of Cesarean section. Human placental and fetal membranes were incubated in the absence (basal control) or presence of 0.5 µg/ml (~60 nM) human recombinant C5a for 24 h. Concentrations of proinflammatory cytokines, prostaglandins, and 8-isoprostane (a marker of oxidative stress) were quantified by ELISA and secretory matrix metalloproteinases (MMPs) activity by zymography. NFKB DNA binding activity and NFKBIA (IkappaB-alpha; inhibitor of NFKB) protein degradation were analyzed by ELISA and Western blotting, respectively. In the presence of C5a, proinflammatory cytokines (IL6 and IL8), cyclooxygenase (COX)-2; official symbol PTGS2) expression, and subsequent prostaglandin (PGE(2) and PGF(2alpha)), MMP9 enzyme production, and NFKB DNA activation were all significantly increased. The C5a-induced prolabor responses were significantly reduced by treatment with the selective CD88 antagonist PMX53 and the NFKB inhibitor BAY 11-7082. We conclude that C5a upregulates prolabor mediators in human gestational tissues via CD88-mediated NFKB activation.

2D-PAGE of ovarian cancer: analysis of soluble and insoluble fractions using medium-range immobilized pH gradients.

Ovarian cancer remains a leading cause of cancer death. A comparative proteomic study was performed on normal ovarian tissue (n=5) and grade 3 ovarian tumours (n=5) to search for differentially expressed proteins. In contrast to other studies, here we extracted proteins in soluble and insoluble protein fractions using commercial kits and also utilised three medium-range IPG strips that encompassed the broad pH range of 3-10 (pH 3-6, 5-8 and 7-10). Protein fractions were compared by 2D-PAGE and MALDI-TOF/TOF-MS. Nineteen differentially expressed proteins were identified: HSP60, Grp78, CK19, EF-Tu, MRLC2, prohibitin, Stress-70 protein, TPI and tubulin α6 were up-regulated in grade 3 tumours whereas annexin A2 and A5, antithrombin-III precursor, CBR1, GSTM2, GSTM3, RALDH1, serum albumin precursor, transthyretin precursor and vimentin were found to be down-regulated in grade 3 ovarian tumours. These proteins are associated with cytoskeleton rearrangement, cell metabolism, tumour suppression function, apoptosis and induction of host response.

SIRT1 is a novel regulator of key pathways of human labor.

Human sirtuin (SIRT) 1 and SIRT2, which possess nicotinamide adenosine dinucleotide (NAD(+))-dependent deacetylase activity, exhibit anti-inflammatory actions. However, there are no data available on SIRT1 and SIRT2 expression and regulation in human intrauterine tissues. Thus, the aim of this study was to characterize the localization and expression of SIRT1 and SIRT2 in 1) placenta and fetal membranes before and after term spontaneous labor onset, 2) prelabor fetal membranes from the supracervical site (SCS) and a distal site (DS), and 3) in response to proinflammatory stimuli. Further, the effect of SIRT activation using resveratrol and SRT1720 on prolabor mediators was also assessed. SIRT1 and SIRT2 were localized in the syncytiotrophoblast layer and the cytotrophoblasts of the placenta, amnion epithelium, trophoblast layer of the chorion, and decidual cells. Additionally, SIRT2 was found within the endothelial walls of placental vessels. SIRT2, but not SIRT1, staining was significantly lower in amnion and chorion obtained from the SCS compared to a DS. On the other hand, SIRT1, but not SIRT2, gene and/or protein expression was significantly lower in placenta, amnion, and chorion obtained after labor compared to prelabor. SIRT1 expression, but not SIRT2, was down-regulated by lipopolysaccharide (LPS) and proinflammatory cytokines TNF and IL1B. The SIRT1 activators resveratrol and SRT1720 significantly decreased LPS-induced TNF, IL6, and IL8 gene expression and release and PTGS2 mRNA expression and resultant prostaglandin (PG) E(2) and PGF(2α) release from human gestational tissues. In conclusion, SIRT1 possesses anti-inflammatory actions and thus may play a role in regulating pregnancy and parturition.

Association between maternal serum cytokine profiles at 7-10 weeks' gestation and birthweight in small for gestational age infants.

OBJECTIVE: The purpose of this study was to investigate whether birth of a small-for-gestational-age (SGA) baby (birthweight, <10th percentile) is preceded by altered maternal serum cytokine profiles at early pregnancy, compared with control babies (birthweight, 30-80th percentile). STUDY DESIGN: A retrospective case-control study of maternal serum collected prospectively across 7-10 weeks of gestation from women attending their first prenatal visit (SGA, 57 cases; control subjects, 71 cases selected retrospectively). Serum concentrations of 27 cytokines were measured in each sample and analyzed by 2-way analysis of variance and nonparametric tests. Logistic regression was used for predictive modeling. RESULTS: Of 21 detectable cytokines/chemokines, 14 analytes varied significantly (P ≤ .030) among those women who were destined to deliver an SGA baby, when compared with control subjects. Of the cytokines that varied in association with SGA, interferon-γ concentrations increased, and major proinflammatory (interleukin [IL]-2, -7, -12) and antiinflammatory (IL-1 receptor antagonist, -4, -10, -13) cytokine concentrations decreased. Eotaxin and macrophage inflammatory protein-1α were higher; monocyte chemoattractant protein-1 and IL-8 were lower. CONCLUSION: SGA births may be preceded by altered immune cytokine profiles at 7-10 weeks of gestation.

Cystatin A protease inhibitor and cysteine proteases in human cervicovaginal fluid in term pregnancy and labor.

OBJECTIVE: The purpose of this study was to investigate the temporal changes in immunoreactive cystatin A and the enzymatic activity of cathepsins B, H, L, and S in human cervicovaginal fluid (CVF) in late pregnancy and spontaneous labor. STUDY DESIGN: CVF was collected weekly (n = 95 women) from 36 weeks gestation until spontaneous term labor. Cystatin A was quantified using enzyme-linked immunosorbent assay. The enzyme activity of cathepsins B, H, L, and S was measured with fluorometric enzyme assay kits. RESULTS: Cystatin A significantly decreased towards (P = .016, 2-way analysis of variance) and during labor (P < .001, 2-way analysis of variance). Enzymatic activity of cathepsins B, H, and S did not change with labor onset (P = .452, P = .703, P = .411, respectively, 2-way analysis of variance). CONCLUSION: In late gestation, CVF-decreased expression of the cysteine protease inhibitor, cystatin A, is associated with labor. Although the role and contribution of cystatin A to increased extracellular matrix remodeling has yet to be elucidated, the data that were obtained are consistent with this hypothesis.