King Edward Memorial Hospital

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

Much of the research in epidemiology and clinical science is based upon longitudinal designs which involve repeated measurements of a variable of interest in each of a series of individuals. Such designs can be very powerful, both statistically and scientifically, because they enable one to study changes within individual subjects over time or under varied conditions. However, this power arises because the repeated measurements tend to be correlated with one another, and this must be taken into proper account at the time of analysis or misleading conclusions may result. Recent advances in statistical theory and in software development mean that studies based upon such designs can now be analysed more easily, in a valid yet flexible manner, using a variety of approaches which include the use of generalized estimating equations, and mixed models which incorporate random effects. This paper provides a particularly simple illustration of the use of these two approaches, taking as a practical example the analysis of a study which examined the response of portable peak expiratory flow meters to changes in true peak expiratory flow in 12 children with asthma. The paper takes the reader through the relevant practicalities of model fitting, interpretation and criticism and demonstrates that, in a simple case such as this, analyses based upon these model-based approaches produce reassuringly similar inferences to standard analyses based upon more conventional methods.

OBJECTIVE: To compare the effects of laparoscopic hysterectomy and abdominal hysterectomy in the abdominal trial, and laparoscopic hysterectomy and vaginal hysterectomy in the vaginal trial. DESIGN: Two parallel, multicentre, randomised trials. SETTING: 28 UK centres and two South African centres. PARTICIPANTS: 1380 women were recruited; 1346 had surgery; 937 were followed up at one year. Primary outcome Rate of major complications. RESULTS: In the abdominal trial laparoscopic hysterectomy was associated with a higher rate of major complications than abdominal hysterectomy (11.1% v 6.2%, P = 0.02; difference 4.9%, 95% confidence interval 0.9% to 9.1%) and the number needed to treat to harm was 20. Laparoscopic hysterectomy also took longer to perform (84 minutes v 50 minutes) but was less painful (visual analogue scale 3.51 v 3.88, P = 0.01) and resulted in a shorter stay in hospital after the operation (3 days v 4 days). Six weeks after the operation, laparoscopic hysterectomy was associated with less pain and better quality of life than abdominal hysterectomy (SF-12, body image scale, and sexual activity questionnaires). In the vaginal trial we found no evidence of a difference in major complication rates between laparoscopic hysterectomy and vaginal hysterectomy (9.8% v 9.5%, P = 0.92; difference 0.3%, -5.2% to 5.8%), and the number needed to treat to harm was 333. We found no evidence of other differences between laparoscopic hysterectomy and vaginal hysterectomy except that laparoscopic hysterectomy took longer to perform (72 minutes v 39 minutes) and was associated with a higher rate of detecting unexpected pathology (16.4% v 4.8%, P = < 0.01). However, this trial was underpowered. CONCLUSIONS: Laparoscopic hysterectomy was associated with a significantly higher rate of major complications than abdominal hysterectomy. It also took longer to perform but was associated with less pain, quicker recovery, and better short term quality of life. The trial comparing vaginal hysterectomy with laparoscopic hysterectomy was underpowered and is inconclusive on the rate of major complications; however, vaginal hysterectomy took less time.

Why was this consensus statement developed? Advances in clinical practice are sometimes inhibited by a multitude of different options that need to be selected. There has been significant variation in the treatment of spinal anaesthesia-induced hypotension. These guidelines are designed to provide clinicians with specific best-practice plans that will cover a wide range of drug and equipment availability. Detailed recommendations are provided for the management of hypotension in resource-rich and resource-poor environments. How does this consensus statement differ from other available guidelines? The American Society of Anesthesiologists/Society for Obstetric Anesthesia and Perinatology Task Force, and the UK National Institute for Health and Care Excellence, have made generic recommendations on this topic 1, 2. We are unaware of detailed guidelines from any organisations. We aim to offer independent, pragmatic advice that will be of benefit to clinicians and the women we treat. Hypotension is a very common consequence of the sympathetic vasomotor block caused by spinal anaesthesia for caesarean section. Maternal symptoms such as nausea, vomiting and dyspnoea frequently accompany severe hypotension, and adverse effects on the fetus, including depressed Apgar scores and umbilical acidosis, have been correlated with severity and duration of hypotension. Ephedrine, a mixed α- and β-adrenergic agonist, became the drug of choice in obstetric anaesthesia following work that found that it was the best vasopressor for preservation of uterine blood flow in a sheep model of drug-induced hypertension. However, higher doses of ephedrine, used clinically in attempts to reduce hypotension, were found not to improve neonatal acidosis, but rather the reverse 3; this is now acknowledged to be because ephedrine has a direct effect on fetal metabolism that negates any improvement in uterine blood flow produced by normalising blood pressure 4, 5. Clinical work dating from the 2000s indicated that α-adrenergic agonists are effective at reducing hypotension, and associated with less neonatal acidosis than ephedrine 6. National practice guidelines suggest the use of both ephedrine and phenylephrine for the management of hypotension; UK guidelines from 2011 state that: ‘Women who are having a caesarean section under regional anaesthesia should be offered intravenous ephedrine or phenylephrine, and volume pre-loading with crystalloid or colloid to reduce the risk of hypotension occurring during caesarean section’ 2. American guidelines from 2016 provide more detail: ‘Intravenous fluid preloading or co-loading: intravenous fluid preloading or co-loading may be used to reduce the frequency of maternal hypotension after spinal anesthesia for cesarean delivery; do not delay the initiation of spinal anesthesia in order to administer a fixed volume of intravenous fluid. Ephedrine or phenylephrine: either intravenous ephedrine or phenylephrine may be used for treating hypotension during neuraxial anesthesia; in the absence of maternal bradycardia, consider selecting phenylephrine because of improved fetal acid–base status in uncomplicated pregnancies’ 1. Surveys of clinical practice indicate that there has been a shift away from what was the almost universal use of ephedrine as the vasopressor of choice. In the UK, a 1999 survey found that 95% of respondents used ephedrine alone during caesarean section 7; in 2011, 89% of respondents used phenylephrine, and the remainder used metaraminol or ephedrine 8. A survey carried out in the USA in 2007 noted that 32% of respondents used ephedrine for vasopressor prophylaxis and treatment of hypotension, 26% and 23%, respectively, used phenylephrine, and the remainder used either agent according to maternal heart rate 9. Klöhr et al. found 15 different definitions of hypotension in 63 studies of hypotension following spinal or combined spinal-epidural anaesthesia for caesarean section, performed between 1999 and 2009 10. Definitions varied between those using an absolute blood pressure value, ranging from 80 mmHg to 100 mmHg, a decrease of 0–30% from a baseline or a combination of an absolute value and a percentage decrease. Some studies distinguished between severe hypotension and lesser (mild-moderate) degrees. All studies used the systolic arterial pressure (SAP) measured in the arm, in a variety of body positions; all but one 11 used the non-invasive oscillometric method. Baseline blood pressure readings were usually taken just before performing spinal anaesthesia, although occasionally at an earlier stage, such as on admission to the labour ward. The baseline was estimated from one, two or three replicate readings. Applying these different definitions to a cohort of women having elective caesarean section gave incidences for hypotension varying between 7.4% and 74.1% 10. The most common definitions of hypotension used in research studies were either ‘< 80% baseline’, or ‘< 100 mmHg OR < 80% baseline’ 10. A 1999 survey in the UK found that most consultant obstetric anaesthetists use a threshold of either 100 or 90 mmHg 7. The SAP is a less important variable than mean arterial pressure (MAP) as a determinant of organ perfusion; however, because methods used to measure blood pressure in routine clinical practice did not include the mean until recent decades, it is unlikely to be adopted for the definition of obstetric hypotension without considerably more supportive data. Most of the studies identified by Klohr et al. were at elective caesarean section; few included women in labour 12. Arterial pressure increases during labour; using baseline values taken in the antenatal period or at the start of labour was shown to reduce the incidence of recorded hypotension, defined as a decrease < 80% baseline value, after epidural analgesia 13. Many studies of hypotension at caesarean section did not include hypertensive women. The SAP threshold for pregnancy-induced hypertension or pre-eclampsia is > 140 mmHg 14. Nausea and vomiting are significantly more frequent during spinal anaesthesia for caesarean section than during non-obstetric surgery. The aetiology of this is multifactorial 15. Acute hypotension reduces cerebral perfusion, induces transient brainstem ischaemia and activates the vomiting centre. Transient cerebral hypoxia may occur, as studies using near-infrared spectroscopy (NIRS) show that hypotension is accompanied by a significant decrease in maternal regional cerebral blood volume, cerebral oxygen saturation and oxygenation 16. This is consistent with the observation that supplemental oxygen may relieve this nausea 17, 18. Spinal anaesthesia decreases splanchnic blood flow by approximately 20% 19, which may be accentuated by accompanying systemic hypotension. The resulting splanchnic hypoperfusion releases emetogenic factors such as serotonin from the gastro-intestinal tract. Finally, acute sympathetic blockade may cause unopposed vagal action and subsequent hyperactivity in the gastro-intestinal tract 20. Regardless of the aetiology, the use of prophylactic vasopressors significantly reduces the incidence of intra-operative nausea and vomiting during caesarean section 21. Dizziness and decreased levels of consciousness may follow severe and prolonged maternal hypotension, but are blood pressure is The effect of hypotension on fetal during caesarean section in although research that a decrease of > in uterine blood flow in and in a Clinical have from studies that with and without hypotension, or duration of hypotension. of women with hypotension significant acidosis and hypotension of more than duration was associated with a significant in umbilical and of of hypotension may be more important than A transient decrease in blood pressure did not neonatal Apgar incidence of fluid or the need for oxygen in the Hypotension for less than did not neonatal more than of maternal hypotension was associated with at of important in acid–base during spinal anaesthesia for caesarean is the choice of vasopressor used to hypotension. from studies were recent clinical suggest that phenylephrine, as an is associated with neonatal acid–base than ephedrine Ephedrine has higher than phenylephrine, with umbilical arterial of and in doses this is associated with neonatal higher and and levels 5. These of fetal sympathetic metabolism by ephedrine the use of phenylephrine for during caesarean section in umbilical clinical in neonatal have not been these of phenylephrine ephedrine improved clinical in the is as The available studies show in the incidence of fetal acidosis either ephedrine or phenylephrine was used to blood pressure during spinal anaesthesia for caesarean both in or those with acute fetal effects on and the of resulting in In such as bradycardia, may from The clinical to α- and β-adrenergic and and fetal effects Ephedrine not has but direct which the and duration of Ephedrine increases heart rate and by has a direct with at clinical at higher than it may with a in maternal et using found the of a phenylephrine to spinal hypotension to be et al. estimated the to spinal hypotension or nausea to be However, doses of this may be associated with increases in systemic and bradycardia, and a of 100 is more common this et al. found benefit using doses of or phenylephrine to hypotension, in with doses of 100 The of phenylephrine to ephedrine for using is is a mixed α- and at doses used has both direct and it sympathetic it for to as a A recent used a of for is the by is a agonist, with with direct in higher heart than with doses of phenylephrine The for of hypotension is et al. found a of for In has for and at are more significant at higher is a mixed α- and β-adrenergic that has both direct and effects to the of and is available and fetal effects although it is a agent in a of and of this drug is that it does not The of clinical management is the of maternal blood on of the adverse effects of hypotension. However, from research studies that is an important The effect of spinal anaesthesia in a is a decrease in systemic to with a of There is a in heart rate and volume, which increases a spinal block to the sympathetic may be resulting in a of However, heart rate does not with block a of bradycardia, to is The aim of vasopressor treatment should to systemic which is best using with However, on doses of vasopressors to blood without other may to et al. used the and to measure in a of phenylephrine and ephedrine used in elective caesarean section. the decrease in systemic and hypotension more than there was between the percentage in heart rate and after the vasopressor of vasopressor that heart not is the best for the is not measured et al. found in both maternal heart rate and measured with three different of The rate both and heart rate by > This the that heart rate may indicate phenylephrine doses that are a to or hypotension and include methods to reduce and in the as as fluid the is for uterine is used to reduce with a of This of is associated with higher maternal SAP and and doses of phenylephrine than the but is in practice the is to is for may for the however, it be used during the period of before and at the before has been at that of the may be than at reducing hypotension at caesarean section but it is to during surgery. has been shown to be more effective than in hypotension, although a of that may on the and of used or to be of the lesser effect of with after spinal A between and did not show a in blood pressure found that to after spinal anaesthesia significant decrease in incidence of hypotension a found a in hypotension that an important between the studies was that crystalloid was used in the but in the crystalloid in the was performed using until a in this practice studies that it has very at reducing the incidence or severity of hypotension and is may be more effective at hypotension and vasopressor than pre-loading 63 or fluid a benefit pre-loading a recent a benefit on of vasopressor provided that a volume is under pressure during the after the spinal is more effective than crystalloid for of hypotension A of by in combination with prophylactic of phenylephrine, was associated with a significantly incidence of hypotension with a of as as less hypotension In a of colloid as effective as a of crystalloid both be to improve the provided by vasopressor have been as of hypotension, on of However, these have not been by more specific does not the frequency and severity of hypotension caesarean is associated with less hypotension than elective This is to be more to the of labour A wide variety of methods have been to the of hypotension after spinal anaesthesia These include that are not of routine and other baseline heart rate was found to be a of hypotension in studies but a of have not this > during a period in combined with > or > mmHg in SAP after from to for severe hypotension Baseline < 80% baseline < baseline Baseline > 90 for hypotension Baseline < 90 for hypotension > 100 Hypotension SAP < 100 mmHg significant hypotension hypotension as with symptoms hypotension SAP < 80 mmHg for clinically significant hypotension Baseline heart rate > Baseline methods not et al. found that was associated with a decrease in SAP than although the incidence of hypotension was not Some studies have occurring after the spinal as an of hypotension. and that provide an of hypotension, with a decrease in saturation hypotension by a et al. noted that in heart rate after the spinal were found in women who more severe hypotension a and available of hypotension is we suggest that there is a of hypotension the baseline heart rate is or there is a and recent of non-invasive blood pressure is an in heart rate after the spinal may the of hypotension. A vasopressor with is the choice to reverse the effects of spinal phenylephrine has the most use However, and decreased associated with phenylephrine have research on and which have to β-adrenergic effects in to studies to phenylephrine in the of obstetric spinal anaesthesia have found that may be a to phenylephrine however, there are the use of such a agent in a such as the labour studies of and metaraminol A survey found that there are of phenylephrine available in the UK 8. The most common is a which is a of to a of 100 are the other used usually for rather than 8. should be in for of that in order to reduce the risk of drug should consider the of or noted a of definitions of hypotension are et al. that there were in the incidence of nausea and vomiting SAP was at the baseline with < or < 80% baseline there were in neonatal umbilical blood We suggest that the aim should be to SAP of an measured baseline until of the with the of reducing the frequency and duration of of significant hypotension < 80% arterial pressure values < 80% should be usually with a vasopressor for blood pressure in practice for a period without or although this is unlikely to be in the of surgery. the other a is that the baseline blood pressure should be taken under to those after for with to studies a of in with to an baseline blood the oscillometric blood pressure et al. the to until three values of SAP were with a of < between The baseline pressure was to be the mean of those three and heart rate was as the mean of the three readings routine clinical most anaesthetists will one baseline of blood However, should be performed the value is higher than in a not to be or in a who is in it does not the from the and consider using this as the measure non-invasive blood pressure blood pressure is measured the is in one or other the non-invasive blood pressure should be on the to reduce from effects et al. performed a that included of prophylactic phenylephrine with vasopressor treatment hypotension treatment a benefit with to the incidence of hypotension both before and after as as nausea and phenylephrine in the of higher doses of phenylephrine with the risk of maternal hypertension and were A subsequent to this prophylactic variable rate and phenylephrine with This that the was more effective at spinal hypotension, nausea and with clinical Most studies have a prophylactic of vasopressor with There are prophylactic phenylephrine with prophylactic phenylephrine A by et al. found that of phenylephrine at hypotension, nausea and vomiting with a prophylactic of phenylephrine et al. having a phenylephrine with those having an prophylactic of phenylephrine, by doses the phenylephrine used in these studies be to be a of 100 is more used both to and spinal hypotension the other a phenylephrine was with from blood pressure in the this it that a prophylactic phenylephrine is to and that the start of the in reducing the incidence of hypotension. In clinical vasopressor at the of a blood pressure will not be as as in research and will not be the the will be for delay in with subsequent hypotension, in with The is that the should be after the of the et al. prophylactic phenylephrine The having and to SAP > 80% with the having 100 In the and 100 higher incidences of hypertension to start an at a rate of and to variable rate are to fixed in order to the of phenylephrine a vasopressor is at a fixed rate after spinal there will be a delay in effective blood a of vasopressor after the spinal will more et al. that an phenylephrine of by an at SAP without any adverse effects work is to an for a prophylactic and that there is not a risk of hypertension and There are studies of used as a agent after the of an using an as the doses of ephedrine are to SAP < baseline combined with a heart in order to blood pressure and There is to indicate the heart rate threshold in the absence of severe hypotension; clinicians should use clinical significant with hypotension, an or may be There is to routine use of for the of hypotension not used to hypotension, has a in hypotension and after spinal research is to vasopressor use a to the of vasopressor according to maternal blood There are of that may be using The may an or a the the a fixed of vasopressor it blood pressure a threshold for the the vasopressor by is varied in with the of hypotension, for between and 100 The may the vasopressor as a or as an in to blood pressure is more with doses of using of with phenylephrine, in this include in blood pressure and higher for the and and levels for the blood pressure between the and of hypotension the use of a blood pressure may with delay and non-invasive blood pressure on the or have been including the the and These have the to blood pressure including et al. used for but a that phenylephrine or ephedrine according to heart to reduce found with phenylephrine This most recent included a that of doses blood pressure is with a This was to 80% of all SAP readings > 80% with maternal and fetal These suggest a for of vasopressor with non-invasive blood pressure to more of of these in the of to be increases during the of it has not been that ephedrine is than phenylephrine for neonatal in this ephedrine acidosis phenylephrine to be the best vasopressor choice in the of significant fetal caesarean section is for a in hypotension after spinal anaesthesia is with elective is to start a vasopressor at a rate than for elective in the of an should not delay other taken to of the The rate and severity of hypotension is after spinal and combined spinal epidural anaesthesia with combined spinal-epidural and epidural combined spinal-epidural and spinal provide with for vasopressor with severe pre-eclampsia less hypotension and have vasopressor during spinal anaesthesia, with women caesarean section These suggest that women with pre-eclampsia either have or are more to with women. There are few studies vasopressors in women with A the status of 15 women with severe pre-eclampsia having spinal anaesthesia for caesarean section for a maternal found that phenylephrine to spinal hypotension and systemic but did not significantly the volume or In a subsequent spinal anaesthesia for caesarean section in severe the maternal effects of ephedrine and phenylephrine were a colloid a of phenylephrine the spinal anaesthesia-induced in systemic heart rate and baseline more than 15 ephedrine A of ephedrine and phenylephrine for the treatment of hypotension after spinal anaesthesia in women with pre-eclampsia found in neonatal umbilical did a in women that included an of women with pre-eclampsia A recent has shown that in with severe pre-eclampsia and fetal fetal acid–base status is of the use of ephedrine phenylephrine to spinal hypotension These studies suggest that phenylephrine is the vasopressor to reverse the maternal by spinal anaesthesia in women with severe The of phenylephrine may be than in a prophylactic vasopressor may not be should be at a with the effect on blood pressure The choice of by or does not to neonatal The blood pressure for women with hypertension is of < mmHg are for SAP The aim should be to SAP to as a decrease in blood are frequently used in women with caesarean section in clinical In women with there is a during caesarean section with neuraxial with anaesthesia spinal anaesthesia is best in women with significant the and associated with spinal anaesthesia are with or fixed or neuraxial such as combined spinal-epidural or spinal anaesthesia, are There are studies the vasopressor to or hypotension after neuraxial anaesthesia in women with caesarean section. are on from and with caesarean section with neuraxial anaesthesia have been with phenylephrine by or non-invasive However, the phenylephrine should not be to all women with The of the specific and the by neuraxial anaesthesia, should the of the most vasopressor is the agent of choice in women with as it has in to ephedrine, may A decrease in systemic after neuraxial anaesthesia in the of fixed such as severe or are best or with by ephedrine may status in with phenylephrine may be in women with should be to increases in oxygen and blood the other ephedrine may be to phenylephrine in with should be may be as either are although or In the there are in of and and and may as a of antenatal with and be to of spinal to anaesthesia and should be non-invasive oscillometric blood pressure is this should be to not the or should the blood pressure as frequently as using the available at until having caesarean section need a of volume including vomiting and prolonged The of the of heart as an of in women with is now is an absolute to spinal anaesthesia for caesarean section; to in splanchnic and of blood the In this following spinal anaesthesia cause in and A of is usually for caesarean section. This may be or decreased for of but does not need to be for body is administer is an is although there are to less is to with to a for of with to a of with have been but there are be including and a and be taken to drug and with There is for the management of hypotension after spinal anaesthesia in resource-poor environments. A recent has the use of a fixed phenylephrine to provide with as This is an for the than a with a risk of In are on in resource-rich and for on is to with spinal anaesthesia without the of a vasopressor and an The vasopressor of is however, may mean that other may have to be These in order of other ephedrine and with a fluid such as is is an anaesthesia, and with 15 one the spinal is Spinal anaesthesia has been in because it in than However, spinal anaesthesia has the cause of maternal in because of hypotension or a combination of the two guidelines have been to anaesthetists or in the of block to and the of to spinal anaesthesia for caesarean section are This is the to spinal and to a lesser reduces systemic a in an in The are by an In the of or blood pressure the vasopressor should be to reduce the heart rate to the baseline not administer in to the blood pressure is to be this cause and in with caused by a rather than and in the body in to hypotension, the This should be by ephedrine, in to the there is a to vasopressors or the status of the should be heart and heart should be may include or on the Hypotension and are with other of and and decreased treatment to the is with including research is on the for a the for combined The more of that vasopressor may improve blood pressure after spinal The of such as in to important maternal and fetal for these are best used for research in order to and In non-invasive or including be indicated to hypotension be were and a variety of practice In the may to vasopressors We and for the of these and are of and this has has from has from has from for and for and has in has from and The for vasopressor at elective caesarean section under spinal-epidural phenylephrine to a of to a of phenylephrine of 100 In a of the phenylephrine an to the and with the vasopressor in the a or to intravenous crystalloid to a that has a with an the vasopressor to the to the and the crystalloid start colloid aim to before spinal non-invasive blood pressure the following values the baseline are the the vasopressor at a rate of between 15 and the to crystalloid by the to a pressure to the maternal SAP at the is for of the from the for at of the or a the vasopressor be although of effects of at the is and hypotension be the for of blood pressure to the there are symptoms such as nausea and vomiting with hypotension as the is for blood the of the the vasopressor should be and the should be to that there is vasopressor in the there is a for vasopressor at the of elective a of the should be with to the and fluid for management of hypotension after spinal anaesthesia for caesarean section in environments. of volume The vasopressor of is phenylephrine: A of options are such intravenous using of at non-invasive blood pressure the following vasopressor at the the to blood pressure until or the is crystalloid 15 by the to a pressure hypotension and to the SAP of baseline SAP and the heart rate of baseline heart as for hypotension the of nausea, is or is to not for readings before vasopressor in these the is for of the from the by at of the a or an is this or hypotension for a as

OBJECTIVE: Systematic reviews of randomized, controlled trials (RCTs) indicate lower mortality and necrotizing enterocolitis (NEC) and shorter time to full feeds after probiotic supplementation in preterm (<34 weeks' gestation) very low birth weight (VLBW; birth weight <1500 g) neonates. The objective of this study was to update our 2007 systematic review of RCTs of probiotic supplementation for preventing NEC in preterm VLBW neonates. METHODS: We searched in March 2009 the Cochrane Central register; Medline, Embase, and Cinahl databases; and proceedings of the Pediatric Academic Society meetings and gastroenterology conferences. Cochrane Neonatal Review Group search strategy was followed. Selection criteria were RCTs of any enteral probiotic supplementation that started within first 10 days and continued for > or =7 days in preterm VLBW neonates and reported on stage 2 NEC or higher (Modified Bell Staging). RESULTS: A total of 11 (N = 2176), including 4 new (n = 783), trials were eligible for inclusion in the meta-analysis by using a fixed-effects model. The risk for NEC and death was significantly lower. Risk for sepsis did not differ significantly. No significant adverse effects were reported. Trial sequential analysis) showed 30% reduction in the incidence of NEC (alpha = .05 and .01; power: 80%). CONCLUSIONS: The results confirm the significant benefits of probiotic supplements in reducing death and disease in preterm neonates. The dramatic effect sizes, tight confidence intervals, extremely low P values, and overall evidence indicate that additional placebo-controlled trials are unnecessary if a suitable probiotic product is available.

BACKGROUND: Down syndrome (DS) affects approximately 1 per 650-1000 live births and is the most common known genetic cause of intellectual disability. A highly significant change in the survival of people with DS has occurred during the last two generations, with life expectancy estimates increasing from 12 to nearly 60 years of age. SUBJECTS AND METHODS: Detailed information on 1332 people in Western Australia with DS was abstracted from a specialist statewide database for the period 1953-2000 and electronically linked with three other state or national health and mortality data sources and the state Birth Defects Registry. RESULTS: Over the last 25 years the percentage of women over 35 years giving birth increased from 4.8 to 18.6%, accompanied by an increase in the overall prevalence of DS from 1.1 to 2.9 per 1000 births. Four life stages of DS were identified: prenatal, childhood and early adulthood, adulthood, and senescence. Although pneumonia, or other types of respiratory infections, was the most common cause of death across the entire lifespan, ranging from 23% of deaths in adulthood to 40% in senescence, each life stage exhibited a particular profile of comorbidities. Congenital heart defects were common causes in childhood (13%) and adulthood (23%), whereas in senescence coronary artery disease (10%) and cardiac, renal, and respiratory failure (9%) were leading causes of mortality. CONCLUSIONS: A major re-appraisal in attitudes towards DS is required to ensure that the medical and social needs of people with the disorder are adequately met across their entire lifespan. In particular, specific recognition of the comorbidities that can arise at different ages is needed, accompanied by the provision of appropriate levels of care and management.

Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings.

BACKGROUND: What constitutes respectful maternity care (RMC) operationally in research and programme implementation is often variable. OBJECTIVES: To develop a conceptualisation of RMC. SEARCH STRATEGY: Key databases, including PubMed, CINAHL, EMBASE, Global Health Library, grey literature, and reference lists of relevant studies. SELECTION CRITERIA: Primary qualitative studies focusing on care occurring during labour, childbirth, and/or immediately postpartum in health facilities, without any restrictions on locations or publication date. DATA COLLECTION AND ANALYSIS: A combined inductive and deductive approach was used to synthesise the data; the GRADE CERQual approach was used to assess the level of confidence in review findings. MAIN RESULTS: Sixty-seven studies from 32 countries met our inclusion criteria. Twelve domains of RMC were synthesised: being free from harm and mistreatment; maintaining privacy and confidentiality; preserving women's dignity; prospective provision of information and seeking of informed consent; ensuring continuous access to family and community support; enhancing quality of physical environment and resources; providing equitable maternity care; engaging with effective communication; respecting women's choices that strengthen their capabilities to give birth; availability of competent and motivated human resources; provision of efficient and effective care; and continuity of care. Globally, women's perspectives of what constitutes RMC are quite consistent. CONCLUSIONS: This review presents an evidence-based typology of RMC in health facilities globally, and demonstrates that the concept is broader than a reduction of disrespectful care or mistreatment of women during childbirth. Innovative approaches should be developed and tested to integrate RMC as a routine component of quality maternal and newborn care programmes. TWEETABLE ABSTRACT: Understanding respectful maternity care - synthesis of evidence from 67 qualitative studies.

BACKGROUND: Endometriomata are endometriotic deposits within the ovary. The surgical management of these blood filled cysts is controversial. The laparoscopic approach to the management of endometriomata is favoured over a laparotomy approach as it offers the advantage of a shorter hospital stay, faster patient recovery and decreased hospital costs. Currently the commonest procedures for the treatment of ovarian endometriomata are either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. OBJECTIVES: The objective of this review was to determine the most effective technique of treating an ovarian endometrioma; either excision of the cyst capsule or drainage and electrocoagulation of the cyst wall. The end-points assessed were the relief of pain, recurrence of the endometrioma, recurrence of symptoms and in women desiring to conceive the subsequent pregnancy rate, either spontaneous or as part of fertility treatment. SEARCH STRATEGY: The reviewers searched the Cochrane Menstrual Disorders and Subfertility Group specialised register of trials (searched 3rd March 2007), the Cochrane Register of Controlled Trials (The Cochrane Library, Issue 3, 2007), MEDLINE (1966-August 2007), EMBASE (1980- March 2007) and reference lists of articles, the handsearching of relevant journals and conference proceedings and by contacting leaders in the field of endoscopic surgery throughout the world. The Cochrane Menstrual Disorders and Subfertility Group Trials Register is based on regular searches of MEDLINE, EMBASE, CINHAL and CENTRAL. SELECTION CRITERIA: Randomised controlled trials of excision of the cyst capsule versus drainage and electrocoagulation of the cyst in the management of ovarian endometriomata. DATA COLLECTION AND ANALYSIS: Reviewers assessed eligibility and trial quality. MAIN RESULTS: No randomised studies of the management of endometriomata by laparotomy were found. Two randomised studies of the laparoscopic management of ovarian endometriomata of greater than 3cm in size, for the primary symptom of pain were included. Laparoscopic excision of the cyst wall of the endometrioma was associated with a reduced recurrence rate of the symptoms of dysmenorrhea (OR 0.15 CI 0.06-0.38), dyspareunia (OR 0.08 CI 0.01-0.51) and non-menstrual pelvic pain (OR 0.10 CI 0.02-0.56), a reduced rate of recurrence of the endometrioma (OR 0.41 CI 0.18-0.93) and with a reduced requirement for further surgery (OR 0.21 CI 0.05-0.79) than surgery to ablate the endometrioma. For those women subsequently attempting to conceive it was also associated with a subsequent increased spontaneous pregnancy rate in women who had documented prior sub-fertility (OR 5.21 CI 2.04-13.29). A further randomised study was identified that demonstrated an increased ovarian follicular response to gonadotrophin stimulation for women who had undergone excsional surgery when compared to ablative surgery (WMD 0.6 CI 0.04-1.16). There is insufficient evidence to favour excisional surgery over ablative surgery with respect to the chance of pregnancy after controlled ovarian stimulation and intra-uterine insemination (OR 1.40 CI 0.47-4.15) . AUTHORS' CONCLUSIONS: There is good evidence that excisional surgery for endometriomata provides for a more favourable outcome than drainage and ablation with regard to the recurrence of the endometrioma, recurrence of pain symptoms, and in women who were previously subfertile, subsequent spontaneous pregnancy . Consequently this approach should be the favoured surgical approach. However in women who may subsequently may undergo fertility treatment insufficient evidence exists to determine the favoured surgical approach.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

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.

BACKGROUND: Nitrous oxide is widely used in anesthesia, often administered at an inspired concentration around 70%. Although nitrous oxide interferes with vitamin B12, folate metabolism, and deoxyribonucleic acid synthesis and prevents the use of high inspired oxygen concentrations, the consequences of these effects are unclear. METHODS: Patients having major surgery expected to last at least 2 h were randomly assigned to nitrous oxide-free (80% oxygen, 20% nitrogen) or nitrous oxide-based (70% N2O, 30% oxygen) anesthesia. Patients and observers were blind to group identity. The primary endpoint was duration of hospital stay. Secondary endpoints included duration of intensive care stay and postoperative complications; the latter included severe nausea and vomiting, and the following major complications: pneumonia, pneumothorax, pulmonary embolism, wound infection, myocardial infarction, venous thromboembolism, stroke, awareness, and death within 30 days of surgery. RESULTS: Of 3,187 eligible patients, 2,050 consenting patients were recruited. Patients in the nitrous oxide-free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56-0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31-0.51; P < 0.001), but median duration of hospital stay did not differ substantially between groups (7.0 vs. 7.1 days; P = 0.06). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide-free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05-1.73; P = 0.02). CONCLUSIONS: Avoidance of nitrous oxide and the concomitant increase in inspired oxygen concentration decreases the incidence of complications after major surgery, but does not significantly affect the duration of hospital stay. The routine use of nitrous oxide in patients undergoing major surgery should be questioned.

BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.

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.

A series of 62 women were managed in the University of Western Australia/PIVET Laboratory in-vitro fertilization programme. In 60 of them follicle growth was stimulated with clomiphene citrate with or without additional human menopausal gonadotrophin (hMG) and in two with hMG alone. Follicles were aspirated at laparoscopy following an hCG trigger injection and occasionally following a spontaneous luteinizing hormone (LH) surge. Oocytes were inseminated with 0.5 X 10(5)-10(5) sperm/ml 3-6 h later. A significant reduction (P less than 0.001) in the fertilization rate of mature oocytes was observed in those patients whose basal serum LH values were greater than 1 SD above the mean. Fifty-nine women subsequently had embryo transfer and of 10 clinical pregnancies, none occurred in those with elevated LH values. Reduced fertilization may be a reflection of premature oocyte maturation or ageing. This may have clinical implications in the management of some patients with unexplained infertility.

BACKGROUND: It is more common for women in both high- and low-income countries giving birth in health facilities, to labour in bed. There is no evidence that this is associated with any advantage for women or babies, although it may be more convenient for staff. Observational studies have suggested that if women lie on their backs during labour this may have adverse effects on uterine contractions and impede progress in labour, and in some women reduce placental blood flow. OBJECTIVES: To assess the effects of encouraging women to assume different upright positions (including walking, sitting, standing and kneeling) versus recumbent positions (supine, semi-recumbent and lateral) for women in the first stage of labour on duration of labour, type of birth and other important outcomes for mothers and babies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013). SELECTION CRITERIA: Randomised and quasi-randomised trials comparing women randomised to upright versus recumbent positions in the first stage of labour. DATA COLLECTION AND ANALYSIS: We used methods described in the Cochrane Handbook for Systematic Reviews of Interventions for carrying out data collection, assessing study quality and analysing results. Two review authors independently evaluated methodological quality and extracted data for each study. We sought additional information from trial authors as required. We used random-effects analysis for comparisons in which high heterogeneity was present. We reported results using the average risk ratio (RR) for categorical data and mean difference (MD) for continuous data. MAIN RESULTS: Results should be interpreted with caution as the methodological quality of the 25 included trials (5218 women) was variable.For Comparison 1: Upright and ambulant positions versus recumbent positions and bed care, the first stage of labour was approximately one hour and 22 minutes shorter for women randomised to upright as opposed to recumbent positions (average MD -1.36, 95% confidence interval (CI) -2.22 to -0.51; 15 studies, 2503 women; random-effects, T(2) = 2.39, Chi(2) = 203.55, df = 14, (P < 0.00001), I(2) = 93%). Women who were upright were also less likely to have caesarean section (RR 0.71, 95% CI 0.54 to 0.94; 14 studies, 2682 women) and less likely to have an epidural (RR 0.81, 95% CI 0.66 to 0.99, nine studies, 2107 women; random-effects, T(2) = 0.02, I(2) = 61%). Babies of mothers who were upright were less likely to be admitted to the neonatal intensive care unit, however this was based on one trial (RR 0.20, 95% CI 0.04 to 0.89, one study, 200 women). There were no significant differences between groups for other outcomes including duration of the second stage of labour, or other outcomes related to the well being of mothers and babies.For Comparison 2: Upright and ambulant positions versus recumbent positions and bed care (with epidural: all women), there were no significant differences between groups for outcomes including duration of the second stage of labour, or other outcomes related to the well being of mothers and babies. AUTHORS' CONCLUSIONS: There is clear and important evidence that walking and upright positions in the first stage of labour reduces the duration of labour, the risk of caesarean birth, the need for epidural, and does not seem to be associated with increased intervention or negative effects on mothers' and babies' well being. Given the great heterogeneity and high performance bias of study situations, better quality trials are still required to confirm with any confidence the true risks and benefits of upright and mobile positions compared with recumbent positions for all women. Based on the current findings, we recommend that women in low-risk labour should be informed of the benefits of upright positions, and encouraged and assisted to assume whatever positions they choose.

BACKGROUND: It has been 10 years since we carried out a systematic search of the literature on birth defect risk in infants born following assisted reproductive technology (ART) compared with non-ART infants. Because of changes to ART practice since that review and the publication of more studies the objective of this review was to include these more recent studies to estimate birth defect risk after ART and to examine birth defect risk separately in ART singletons and multiples. METHODS: We searched Medline, Embase and Current Contents databases (1978-2012). We used the same data extraction sheet and questionnaire we had used previously with the addition of a quality score to the questionnaire. Pooled relative risk (RR) estimates were calculated using a random effects model. All data were analysed using Comprehensive Meta-Analysis V2. RESULTS: There were 45 cohort studies included in this review. ART infants (n = 92 671) had a higher risk of birth defects [RR 1.32, 95% confidence interval (CI) 1.24-1.42] compared with naturally conceived infants (n = 3 870 760). The risk further increased when data were restricted to major birth defects (RR 1.42, 95% CI 1.29-1.56) or singletons only (RR 1.36, 95% CI 1.30-1.43). The results for ART multiples were less clear. When all data for multiples were pooled the RR estimate was 1.11 (95% CI 0.98-1.26) but this increased to 1.26 (0.99-1.60) when the analysis was restricted to studies of ART twins where some adjustment was made for differences in zygosity distribution between ART and non-ART multiples. CONCLUSIONS: Birth defects remain more common in ART infants. Further research is required to examine risks for important subgroups of ART exposure.

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.