Women and Infants Research Foundation

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1–2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth. As a highly heritable polygenic trait, human height has provided a model for the genetic analysis of complex traits. So far about 700 common genetic variants have been linked to height through genome-wide association studies, but the role of low-frequency and rare variants has not been systematically explored. Guillaume Lettre, Joel Hirschhorn and colleagues in the GIANT Consortium now report their analysis of coding regions in the genomes of 711,418 individuals. They identify 120 loci newly associated with height, including 32 rare and 51 low-frequency coding variants. They highlight 83 candidate genes with low-frequency height-associated variants and implicate biological pathways with known roles in growth disorders as well as new candidates. Their analyses provide insights into the genomic architecture of human height.

OBJECTIVE: We aimed to provide information that can be used as a guide to clinicians when advising breastfeeding mothers on normal lactation with regard to the frequency and volume of breastfeedings and the fat content of breast milk. METHODS: Mothers (71) of infants who were 1 to 6 months of age and exclusively breastfeeding on demand test-weighed their infants before and after every breastfeeding from each breast for 24 to 26 hours and collected small milk samples from each breast each time the infant was weighed. RESULTS: Infants breastfed 11 +/- 3 times in 24 hours (range: 6-18), and a breastfeeding was 76.0 +/- 12.6 g (range: 0-240 g), which was 67.3 +/- 7.8% (range: 0-100%) of the volume of milk that was available in the breast at the beginning of the breastfeeding. Left and right breasts rarely produced the same volume of milk. The volume of milk consumed by the infant at each breastfeeding depended on whether the breast that was being suckled was the more or less productive breast, whether the breastfeeding was unpaired, or whether it was the first or second breast of paired breastfeedings; the time of day; and whether the infant breastfed during the night or not. Night breastfeedings were common and made an important contribution to the total milk intake. The fat content of the milk was 41.1 +/- 7.8 g/L (range: 22.3-61.6 g/L) and was independent of breastfeeding frequency. There was no relationship between the number of breastfeedings per day and the 24-hour milk production of the mothers. CONCLUSIONS: Breastfed infants should be encouraged to feed on demand, day and night, rather than conform to an average that may not be appropriate for the mother-infant dyad.

BACKGROUND: The long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are considered essential for maturation of the developing brain, retina and other organs in newborn infants. Standard infant milk formulae are not supplemented with LCPUFA; they contain only alpha-linolenic acid and linoleic acid, from which formula-fed infants must synthesise their own DHA and AA, respectively. Over the past few years, some manufacturers have added LCPUFA to formula milk and have marketed these products as providing an advantage for the overall development of full-term infants. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is both safe and beneficial for full-term infants, while focusing on effects on visual function, neurodevelopment and physical growth. SEARCH METHODS: Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL; December 2016), MEDLINE (Ovid, 1966 to December 2016), Embase (Ovid, 1980 to December 2016), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1980 to December 2016) and abstracts of the Pediatric Academic Societies (2000 to 2016). We applied no language restrictions. SELECTION CRITERIA: We reviewed all randomised controlled trials (RCTs) evaluating effects of LCPUFA supplemented versus non-supplemented formula milk on visual function, neurodevelopment and physical growth. We did not include trials reporting only biochemical outcomes. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We assessed risk of bias of included studies using the guidelines of the Cochrane Neonatal Review Group. When appropriate, we conducted meta-analysis to determine a pooled estimate of effect. MAIN RESULTS: = 83%; N = 521) and that the two groups showed no significant differences with respect to length and head circumference (z scores). Meta-analysis at 18 months and at two years revealed no significant differences between the two groups with respect to weight (kg), length (cm) and head circumference (cm). GRADE analysis of these outcomes indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Most of the included RCTs reported no beneficial effects or harms of LCPUFA supplementation on neurodevelopmental outcomes of formula-fed full-term infants and no consistent beneficial effects on visual acuity. Routine supplementation of full-term infant milk formula with LCPUFA cannot be recommended at this time.

CONTEXT: The polycystic ovary syndrome (PCOS) is the commonest endocrine abnormality in women of reproductive age. OBJECTIVE: To determine the rate of hospital admissions for women with PCOS in Western Australian population in comparison to women without PCOS. DESIGN: A population-based retrospective cohort study using data linkage in a statewide hospital morbidity database system. SETTING: All hospitals within Western Australia. PARTICIPANTS: A total of 2566 women with PCOS hospitalized from 1997-2011 and 25 660 randomly selected age-matched women without a PCOS diagnosis derived from the electoral roll. MAIN OUTCOME MEASURES: Hospitalizations by ICD-10-M diagnoses from 15 years were compared. RESULTS: Hospitalizations were followed until a median age of 35.8 years (interquartile range, 31.0-39.9). PCOS was associated with more nonobstetric and non-injury-related hospital admissions (median, 5 vs 2; P < .001), a diagnosis of adult-onset diabetes (12.5 vs 3.8%), obesity (16.0 vs 3.7%), hypertensive disorder (3.8 vs 0.7%), ischemic heart disease (0.8 vs 0.2%), cerebrovascular disease (0.6 vs 0.2%), arterial and venous disease (0.5 vs 0.2% and 10.4 vs 5.6%, respectively), asthma (10.6 vs 4.5%), stress/anxiety (14.0 vs 5.9%), depression (9.8 vs 4.3%), licit/illicit drug-related admissions (8.8 vs 4.5%), self-harm (7.2 vs 2.9%), land transport accidents (5.2 vs 3.8%), and mortality (0.7 vs 0.4%) (all P < .001). Women with PCOS had a higher rate of admissions for menorrhagia (14.1 vs 3.6%), treatment of infertility (40.9 vs 4.6%), and miscarriage (11.1 vs 6.1%) and were more likely to require in vitro fertilization (17.2 vs 2.0%). CONCLUSION: PCOS has profound medical implications for the health of women, and health care resources should be directed accordingly.

OBJECTIVE: To determine the effect of maternal pre-pregnancy BMI on pregnancy outcomes. METHODS: Pregnancy cohort recruited pregnancies between 16 and 18 weeks. BMI evaluated underweight, BMI<18.5, normal, BMI 18.5-25, overweight BMI 25-30, and obese BMI>30 women. RESULTS: Pre-pregnancy BMI classified 331 women as underweight (11.7%), 1982 normal (69.9%), 326 overweight (11.5%), and 188 as obese (6.6%). Obese women were more likely to develop gestational diabetes (p<0.001), hypertension (p<0.001), preeclampsia (p<0.001), need labor induction (p<0.001), cesarean delivery for fetal distress (p<0.001), postpartum hemorrhage (p=0.003), need neonatal resuscitation (p=0.001) and deliver hypoglycemic infants (p=0.007). Being underweight is correlated with fetal growth restriction (p=0.001). CONCLUSION: Pre-pregnancy obesity is a risk factor for gestational diabetes, preeclampsia, labor induction, cesarean for fetal distress, postpartum hemorrhage and neonatal hypoglycemic and need for resuscitation. Being underweight is risk factor for fetal growth restriction.

BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina. OBJECTIVES: To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants. SEARCH METHODS: Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied. SELECTION CRITERIA: All randomised trials evaluating the effect of LCPUFA-supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%). Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta-analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low. Neurodevelopment Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI -1.42 to 3.34; P = 0.43; I² = 71% - Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI -2.77 to 3.22; P = 0.88; I² = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI -0.33 to 5.12; P = 0.08; I² = 0% - PDI: MD 0.74, 95% CI -1.90 to 3.37; P = 0.58; I² = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low. Physical growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I² = 69% - Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I² = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD -0.10, 95% CI -0.31 to 0.12; P = 0.34; I² = 65% - Length: MD 0.25; 95% CI -0.33 to 0.84; P = 0.40; I² = 71% - Head circumference: MD -0.15, 95% CI -0.53 to 0.23; P = 0.45; I² = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD -0.14, 95% CI -0.39 to 0.10; P = 0.26; I² = 66% - Length: MD -0.28, 95% CI -0.91 to 0.35; P = 0.38; I² = 90% - Head circumference: MD -0.18, 95% CI -0.53 to 0.18; P = 0.32; I² = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

CONTEXT: In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or occult thyroid failure. METHODS: We measured serum TSH, free T(4), thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469. RESULTS: At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter [95% confidence interval (CI) 0.27, 0.38, P < 0.001], whereas mean free T(4) concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype. CONCLUSIONS: Aging is associated with increased serum TSH concentrations, with no change in free T(4) concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

BACKGROUND: Postnatal depression can cause adverse effects on both mother and infant, but its impact on breastfeeding duration is poorly understood. The aim of this study was to investigate the relationship between maternal postnatal depression and breastfeeding duration. METHODS: A cohort of 1745 women was recruited on the postnatal wards of two large Australian obstetric hospitals. Self-report questionnaires were completed at recruitment, and at 2, 6, and 12 months postpartum. Breastfeeding status was determined at each follow-up, and the Edinburgh Postnatal Depression Scale was used to screen for symptoms of depression. Diagnostic psychological interviews were conducted on a subsample of women at each interval. RESULTS: Breastfeeding was initiated by 96 percent of the participants; at 2 months 79 percent were still breastfeeding, 57 percent at 6 months, and 22 percent at 12 months. Of the 18 percent of participants diagnosed with postnatal depression, the onset occurred before 2 months in 63 percent of cases. Median duration of breastfeeding was 26 weeks for women with early-onset depression, 28 weeks for women with late-onset depression, and 39 weeks for women without depression. After adjustment for confounding factors, early cessation of breastfeeding was found to be significantly associated with postnatal depression (adjusted hazard ratio 1.25, 95% CI 1.03-1.52). Onset of postnatal depression occurred before cessation of breastfeeding in most cases. CONCLUSIONS: Postnatal depression has a significant negative impact on breastfeeding duration. Assistance with breastfeeding issues should be included in the management of postnatal depression.

OBJECTIVE: The objective of this study was to determine the influence of birth weight and postnatal weight gain on age at menarche. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study where girls from the West Australian Pregnancy (Raine) Cohort Study were followed prospectively from fetal life (18 wk of pregnancy) to adolescence (12-14 yr). MAIN OUTCOME MEASURE: Age at menarche was the main outcome measure. RESULTS: Growth status at birth was judged by expected birth weight ratio (EBW; a ratio of observed infant's birth weight over median birth weight appropriate for maternal age, weight, height, parity, infant sex, and gestational age). Postnatal growth status was judged by body mass index (BMI). Both EBW (P = 0.020) and BMI in childhood (8 yr of age) (P < 0.001) were associated with age at menarche. Menarche occurred earlier in girls with lower EBW and higher BMI. CONCLUSIONS: We have demonstrated for the first time that both birth weight and weight gain in childhood are associated with age at menarche. Weight gain before birth and subsequent weight gain up to the age of 8 yr were found to have opposing influences on the timing of menarche. Lower EBW combined with higher BMI during childhood predicted early age at menarche, and this relationship existed across normal birth weight and BMI ranges.

AIM: To investigate pre- and postpartum levels of childbirth fear in a cohort of childbearing women and explore the relationship to birth outcomes. BACKGROUND: While results are mixed, there is evidence that fear of childbirth is associated with mode of birth. Limited theoretical work around childbirth fear has been undertaken with Australian women. DESIGN: A prospective correlation design. Method. Women (n = 401) completed the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) version A at 36 weeks gestation, with 243 (61%) women also completing version B at six weeks postpartum. Scores were summarised with means and standard deviations. Content analysis of the free statements identified nine issues of concern. RESULTS: Twenty-six per cent of pregnant women reported low levels of childbirth fear, 48% were moderately fearful and 26% were highly fearful. Fear decreased after birth for those women in the high antenatal fear group, however surgical intervention at birth (n = 238, anova, F(1,230) = 12.39, p = 0.001) and suspected fetal compromise (F(1,230) = 4.33, p = 0.039) increased levels of postpartum fear. Univariately, high antenatal fear was associated with emergency caesarean delivery (n = 324, Wald 5.05, p = 0.025) however after adjustment for nulliparity and fetal compromise the association disappeared. Australian-born women were more likely to report higher levels of fear and experience higher rates of caesarean section than participants of non-Australian origin. CONCLUSIONS: Results support those from earlier studies in showing that nulliparous women experience more fear than parous women before birth and that there is no difference in levels of postpartum fear between these two groups. Fear levels were higher in Australian women when compared to a Swedish sample. RELEVANCE TO CLINICAL PRACTICE: The results of this study add to our preliminary understanding of the phenomena of childbirth fear within an Australian context and are particularly useful in profiling women for whom secondary fear of childbirth is more likely to occur.

OBJECTIVE: To compare the effects of single and repeated courses of corticosteroids on brain growth in fetal sheep. METHODS: Pregnant sheep were given intramuscular betamethasone (0.5 mg/kg) at 104 days' gestation followed at 111, 118, and 124 days by equivalent volumes of sterile normal saline (n = 12) or betamethasone (n = 12). Controls received equivalent volumes of sterile normal saline at all four intervals (n = 12). Lambs were delivered at 125 (preterm) or 145 (term) days. After perfusion, we measured weights (grams) for whole brain, cerebrum, cerebellum, and brain stem, volumes (milliliters) for whole brain and cerebrum, and maximum cerebral anterior-posterior length, width, and depth (centimeters). RESULTS: In the single-injection group at preterm, there were no significant differences (P = .070) in whole-brain weight between the corticosteroid-treated animals (38.0 +/- 1.81 g) and controls (42.5 +/- 1.65 g). Cerebral length and depth were significantly reduced in the corticosteroid group (P < .05); other measures were not significantly different. At term, whole-brain weight was significantly lower (47.5 +/- 1.70 g; P = .022) compared with controls (53.4 +/- 1.73 g). All other measures were significantly reduced (P < .05) except cerebral and brain-stem weights and cerebral length. In the group that received repeated injections at preterm, whole-brain weight was significantly reduced (35.5 +/- 1.65 g; P = .005) compared with controls (42.5 +/- 1.65 g). All other measures were significantly reduced (P < .05) except cerebellar and brain-stem weights. At term, whole-brain weight was also significantly reduced (42.4 +/- 1.52 g; P = .001) compared with controls (53.4 +/- 1.73 g) as were all other measures (P < .05). CONCLUSION: Administration of single and repeated courses of corticosteroids to pregnant sheep retarded fetal brain growth.

Maternal administration of corticosteroids is used to promote lung maturation in human infants considered at risk of preterm delivery [1]. Randomised trials of a single course of corticosteroid treatment have indicated no adverse long-term neurological or cognitive sequelae [2-5]. However, the current trend in many obstetric centres is to use repeated courses in cases where preterm birth has not eventuated, but the risk persists 7 days beyond administration of the original course [6-7]. This practice has not yet been subject to randomised trials of outcome. We have examined the effect of repeated injections of corticosteroids on the development of the optic nerve in prenatal fetal sheep and report a significant delay in the myelination of optic axons. Our results, together with those from other animal studies [8], show that repeated courses of corticosteroids may be detrimental to central nervous system (CNS) development. Clinical practice should balance the known beneficial effects on lung maturation of a single course of corticosteroid against the potential damage to the CNS of repeated courses.

STUDY QUESTION: Is in vitro maturation (IVM) as successful as standard in vitro fertilization (IVF) for the treatment of patients with polycystic ovaries (PCO) in terms of fresh, frozen and cumulative pregnancy outcomes? SUMMARY ANSWER: There was no difference in clinical pregnancy rates in fresh or frozen embryo transfer (FET) cycles between the two treatment groups however, the IVM group showed a lower clinical pregnancy rate cumulatively. There was significantly fewer live births resulting from IVM treatment for both fresh and cumulative cycle outcomes however, there was no difference in live birth rates resulting from FETs between IVM and IVF treatment. WHAT IS KNOWN ALREADY: IVM is well recognized as the only treatment option to eliminate completely the incidence of ovarian hyperstimulation syndrome. However, historically IVM has been less successful than standard IVF in terms of clinical pregnancy, implantation and live birth rates. STUDY DESIGN, SIZE, AND DURATION: This paper represents a retrospective case-control study. The study involved 121 participants who underwent 178 treatment cycles. Cycles were completed between March 2007 and December 2012. All fresh cycles and subsequent FET cycles were included in the analysis to calculate cumulative outcomes. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: All participants were prospectively diagnosed with PCO morphology or polycystic ovarian syndrome (PCOS) and underwent either IVM or standard IVF treatment. Their treatment outcomes were analysed with regard to embryological data, and the rate of biochemical pregnancy, clinical pregnancy and live birth, in addition maternal and neonatal outcomes were assessed. Fifty-six patients underwent 80 cycles of IVM treatment and 65 patients underwent 98 cycles of standard IVF treatment. MAIN RESULTS AND THE ROLE OF CHANCE: For fresh cycles, the differences in the biochemical pregnancy, clinical pregnancy or miscarriage rates between the two treatment groups were not statistically significant. The IVM group showed significantly lower live birth rates in fresh cycles in comparison to standard IVF treatment (18.8 versus 31.0%, P = 0.021). For frozen embryo transfer (FET) cycles the differences in biochemical pregnancy, clinical pregnancy, live birth or miscarriage rates between the two treatments groups were not statistically significant. The cumulative biochemical pregnancy (67.5 versus 83.7%, P = 0.018), clinical pregnancy (51.3 versus 65.3%, P = 0.021) and live birth rates (41.3 versus 55.1%, P = 0.005) were significantly lower in the IVM group in comparison to the standard IVF treatment group. There was no overall difference in the cumulative miscarriage rates between the two treatment groups. There was no difference between treatment methods with regard to the neonatal outcomes, and the IVM group had a significantly lower rate of ovarian hyperstimulation syndrome (0 versus 7.1%, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: This was an observational study and further randomized clinical trials are required to clarify the difference in outcomes between standard IVF and IVM for patients with PCO/PCOS. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to compare IVM with standard IVF in PCO/PCOS patients using blastocyst development and single embryo transfer. Furthermore, it is the first study to show the results of fresh, frozen and cumulative treatment cycle outcomes between the two groups. Our results show similar success rates to those reported from other groups, particularly in relation to the incidence of miscarriage in fresh IVM cycles and improved success from FET cycles. Maternal and neonatal outcomes are consistent with the limited literature available. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Women's and Infant's Research Foundation of Western Australia. Professor Hart is Medical Director of Fertility Specialists of Western Australia (FSWA) and a shareholder Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. T.H. is a consultant with FSWA and a shareholder in Western IVF. She has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. The other authors have no competing interests.

OBJECTIVE: Overview of the mechanisms governing gas transport, mechanical factors influencing the transmission of pressure and flow to the lung, and the measurement of lung mechanics during high-frequency oscillatory ventilation (HFOV) in acute respiratory distress syndrome. DATA SOURCES AND STUDY SELECTION: Studies indexed in PubMed illustrating key concepts relevant to the manuscript objectives. Pressure transmission during HFOV in the adult lung was simulated using a published theoretical model. DATA SYNTHESIS: Gas transport during HFOV is complex and involves a range of different mechanisms, including bulk convection, turbulence, asymmetric velocity profiles, pendelluft, cardiogenic mixing, laminar flow with Taylor dispersion, collateral ventilation, and molecular diffusion. Except for molecular diffusion, each mechanism involves generation of convective fluid motion, and is influenced by the mechanical characteristics of the intubated respiratory system and the ventilatory settings. These factors have important consequences for the damping of the oscillatory pressure waveform and the drop in mean pressure from the airway opening to the lung. New techniques enabling partitioning of airway and tissue properties are being developed for measurement of lung mechanics during HFOV. CONCLUSIONS: Awareness of the different mechanisms governing gas transport and the prevailing lung mechanics during HFOV represents essential background for the physician planning to use this mode of ventilation in the adult patient. Monitoring of lung volume, respiratory mechanics, and ventilation homogeneity may facilitate individual optimization of HFOV ventilatory settings in the future.

BACKGROUND: The use of antenatal steroid therapy is common in pregnancy. In early pregnancy, steroids may be used in women for the treatment of recurrent miscarriage or fetal abnormalities such as congenital adrenal hyperplasia. In mid-late pregnancy, the antenatal administration of corticosteroids to expectant mothers in anticipation of preterm birth is one of the most important advances in perinatal medicine; antenatal corticosteroids are now standard care for pregnancies at risk of premature delivery in high- and middle-income countries. The widespread uptake of this therapy is due to a compelling body of evidence demonstrating improved neonatal outcomes following antenatal corticosteroid exposure, stemming most notably from corticosteroid-driven maturation of fetal pulmonary function. As we approach the 50th anniversary of landmark work in this area by Liggins and Howie, it is apparent that much remains to be understood with regards to how we might best apply antenatal corticosteroid therapy to improve pregnancy outcomes at both early and mid to late gestation. METHODS: Drawing on advances in laboratory science, pre-clinical and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the benefits, risks and uncertainties regarding antenatal corticosteroid use in pregnancy. Three, well-established therapeutic uses of antenatal steroids, namely recurrent miscarriage, congenital adrenal hyperplasia and preterm birth, were selected to frame the review. RESULTS: Even the most well-established antenatal steroid therapies lack the comprehensive pharmacokinetic and dose-response data necessary to optimize dosing regimens. New insights into complex, tissue-specific corticosteroid signalling by genomic-dependent and independent mechanisms have not been used to inform corticosteroid treatment strategies. There is growing evidence that some fetal corticosteroid treatments are either ineffective, or may result in adverse outcomes, in addition to lasting epigenetic changes in a variety of homeostatic mechanisms. Nowhere is the need to better understand the intricacies of corticosteroid therapy better conveyed than in the findings of Althabe and colleagues who recently reported an increase in overall neonatal mortality and maternal morbidity in association with antenatal corticosteroid administration in low-resource settings. CONCLUSIONS: New research to clarify the benefits and potential risks of antenatal corticosteroid therapy is urgently needed, especially with regard to corticosteroid use in low-resource environments. We conclude that there is both significant scope and an urgent need for further research-informed refinement to the use of antenatal corticosteroids in pregnancy.

Antenatal exposure to glucocorticoids, amnionitis, intraamniotic interleukin (IL)-1alpha, or endotoxin can improve postnatal lung function after preterm delivery. The relationship between early lung maturation and the dose and duration of a proinflammatory stimulus has not been evaluated. The effects of proinflammatory stimuli on fetal plasma cortisol also have not been evaluated. We hypothesized that intraamniotic endotoxin would induce early lung maturation in fetal sheep without increasing fetal cortisol. Intraamniotic injections of 1, 4, 20, or 100 mg of Escherichia coli 055:beta5 endotoxin caused 2-fold increases in compliance, 4- to 5-fold increases in lung gas volumes, and 20-fold increases in alveolar saturated phosphatidylcholine (Sat PC) when given 7 d before preterm delivery at 125 d gestation. Animals treated with 20 mg endotoxin for treatment to delivery intervals of 5 h to 15 d had no significant elevations in cord plasma cortisol levels. Increases in Sat PC in lung tissue and alveolar washes were detected 2 d after endotoxin treatment and lung function improved 4 d after endotoxin treatment. Two doses of endotoxin given 3 and 7 d or 7 and 15 d before treatment resulted in lung maturation responses equivalent to single dose comparison groups without elevations in cortisol. Early lung maturation induced by intraamniotic endotoxin in fetal sheep occurred without an increase in fetal plasma cortisol, indicating that endotoxin promoted lung maturation by a mechanism independent of cortisol.

OBJECTIVE: To compare the efficacy and patient satisfaction of three methods of labour induction (double balloon catheters, single balloon catheters and prostaglandin gel) in term nulliparous women with unfavourable cervices. DESIGN: Randomised controlled trial. POPULATION: A total of 330 nulliparous women with unfavourable cervices induced at term. METHODS: Three cervical ripening study arms were used: double balloon catheter (107 women); 16F Foley catheter (110 women) and PGE(2) gel (2 mg) (113 women). MAIN OUTCOME MEASURES: Caesarean section, induction to delivery interval, adverse reactions and patient satisfaction. RESULTS: There was no difference in caesarean delivery rates between groups (double balloon 43%, single balloon 36%, PGE(2) 37%, P = 0.567). The induction to delivery interval was longer in the double balloon group (median 24.5; 95% CI 23.7, 30.6 hours) than the single balloon (23.2; 20.8, 25.8 hours) or PGE(2) (23.8; 21.7, 26.8 hours) (P = 0.043). Uterine hyperstimulation occurred in 14% of the PGE(2) group with none occurring with mechanical cervical ripening. Cord blood gases were worse in the PGE(2) group: median arterial pH double balloon 7.26 (range 7.03-7.40); single balloon 7.26 (7.05-7.44); PGE(2) 7.25 (6.91-7.41) (P = 0.050). Cervical ripening with the single balloon catheter was associated with significantly less pain (pain score > or =4: double balloon 55%, single balloon 36%, PGE(2) 63%, P < 0.001). CONCLUSIONS: Labour induction in nullipara with unfavourable cervices results in high caesarean delivery rates. Although all methods in this study had similar efficacy, the single balloon catheter offers the best combination of safety and patient comfort.

BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This difficulty with conception may affect up to a quarter of all couples planning a child. The reported prevalence of subfertility has increased significantly over the past twenty years. It is estimated that for 40% to 50% of couples, subfertility may be a result of female problems, including ovulatory disorders, poor egg quality, fallopian tube damage and endometriosis. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assessed the evidence for the effectiveness of different antioxidants in female subfertility. OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. SEARCH METHODS: We searched the following databases (from inception to April 2013) with no language restrictions applied: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS and OpenSIGLE. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the Trials Registers. Reference lists were checked, and a search on Google was performed. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. Trials comparing antioxidants with fertility drugs alone and trials that exclusively included fertile women attending a fertility clinic because of male partner infertility were excluded. DATA COLLECTION AND ANALYSIS: Three review authors independently screened 2127 titles and abstracts, and 67 of these potentially eligible trials were appraised for inclusion and quality through review of full texts and contact with authors. Three review authors were involved in data extraction and assessment of risk of bias. Review authors also collected data on adverse events as reported from the trials. Studies were pooled using fixed-effect models; however, if high heterogeneity was found, a random-effects model was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. Analyses were stratified by type of antioxidant, by indications for subfertility and by those women also undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection techniques (ICSIs). The overall quality of the evidence was assessed by applying GRADE criteria. MAIN RESULTS: A total of 28 trials involving 3548 women were included in this review. Investigators compared oral antioxidants, including combinations of antioxidants, pentoxifylline, N-acetyl-cysteine, melatonin, L-arginine, vitamin E, myo-inositol, vitamin C, vitamin D+calcium and omega-3-polyunsaturated fatty acids with placebo, with no treatment/standard treatment or another antioxidant.Antioxidants were not associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I(2) = 75%, very low-quality evidence). This suggests that among subfertile women with an expected live birth rate of 37%, the rate among women taking antioxidants would be between 10% and 83%.Antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I(2)= 55%, very low-quality evidence). This suggests that among subfertile women with an expected clinical pregnancy rate of 23%, the rate among women taking antioxidants would be between 22% and 36%.Only one trial reported on live birth in the antioxidant versus antioxidant comparison, and two trials reported on clinical pregnancy in this comparison. Only subtotals were used in this analysis, and meta-analysis was not possible as each trial used a different antioxidant.Pentoxifylline was associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.03, 95% CI 1.19 to 3.44, P = 0.009, 3 RCTs, 276 women, I(2) = 0%).Adverse events were reported by 14 trials in the meta-analysis and included miscarriage, multiple pregnancy, ectopic pregnancy and gastrointestinal effects. No evidence revealed a difference in adverse effects between antioxidant groups and control groups, but these data were limited.The overall quality of evidence was 'very low' to 'low' because of poor reporting of outcomes, the number of small studies included, high risk of bias within studies and heterogeneity in the primary analysis. AUTHORS' CONCLUSIONS: The quality of the evidence in the 'antioxidant versus placebo/no treatment' and in the 'antioxidant versus antioxidant' comparisons was assessed to be 'very low'. Antioxidants were not associated with an increased live birth rate or clinical pregnancy rate. There was some evidence of an association of pentoxifylline with an increased clinical pregnancy rate; however, there were only three trials included in this comparison. Future trials may change this result. Variation in the types of antioxidants given meant that we could not assess whether one antioxidant was better than another. There did not appear to be any association of antioxidants with adverse effects for women, but data for these outcomes were limited.

Abstract Objectives: To determine the demographic, environmental, and medical factors that influence the relative weights of the newborn infant and the placenta and compare this ratio with other factors known to predispose to adult ill health. Design: Prospective cohort study. Setting: The tertiary referral centre for perinatal care in Perth, Western Australia. Subjects: 2507 pregnant women who delivered a single live infant at term. Main outcome measures: Placental weight, birth weight, and the ratio of placental weight to birth weight. Results: By multiple regression analysis the placental weight to birthweight ratio was significantly and positively associated with gestational age, female sex, Asian parentage, increasing maternal body mass index, increased maternal weight at booking, lower socioeconomic status, maternal anaemia, and increasing number of cigarettes smoked daily. There were no consistent relations between the placental weight to birthweight ratio and measures of newborn size. Conclusions: The ratio of placental weight to birth weight is not an accurate marker of fetal growth. In its role as a predictor of adult disease the ratio may be acting as a surrogate for other factors which are already known to influence health and may act before or after birth. Determining the role that relative growth rates of the fetus and placenta have in predisposing to adult disease requires prospective study to account for the many confounding variables which complicate this hypothesis. Key messages Retrospective analyses have identified an association between a raised placental weight to birthweight ratio and hypertension in adulthood Accurate estimation of gestational age is crucial when interpreting the placental weight to birthweight ratio Environmental factors associated with alterations in the placental weight to birthweight ratio may not exert their effects exclusively in the antenatal period As a marker of fetal growth the potential usefulness of the placental weight to birthweight ratio is diminished because the ratio is influenced by a multiplicity of factors Prospective study is required to clarify the role of intrauterine programming in the genesis of adult disease