Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.

Protocol for a multicentre prospective observational study of families with full-term infants on postnatal wards and in the community to capture feeding practices across the first year of life: the Mother Infant Lactation Questionnaire (MILQ) study.

INTRODUCTION: Breastmilk is considered the gold standard for infant nutrition. Breast feeding is recommended as the sole source of nutrition between birth until around 6 months of age and should be continued beyond this age as complementary foods are introduced. While breast feeding initiation is generally high in developed countries, continuation of breast feeding appears to drop rapidly. This is a prospective observational study of life that aims to characterise a current picture of infant feeding practices across the first year, and motivations for feeding practices, and to identify barriers and enablers for breast feeding. METHODS AND ANALYSIS: Caregivers with newborn singleton infants of normal birth weight are approached on the postnatal units of three hospitals in South Australia, or through targeted online advertising campaigns promoting the study. Caregivers are asked to complete surveys when their infant reaches 3, 5 and 7 weeks', and at 3, 4, 5, 6, 9 and 12 months of age. Initially, baseline characteristics, intentions and preferences for infant milk feeds, as well as reasons for preferences are captured. Latter surveys query how infants are being fed, difficulties or barriers to breast feeding, as well as any enablers (if breast feeding). Once infants reach 5 months of age, surveys capture complementary feeding. A large opportunistic sample from the Adelaide community with a minimum of 1000 mother-infant pairs will be enrolled. The data will be analysed descriptively and using regression models. ETHICS AND DISSEMINATION: Women's and Children's Health Network Human Research Ethics Committee reviewed and approved the study (approval no HREC/19/WCHN/140, approval date: 22 November 2019). Study results will be disseminated through academic meetings, peer-reviewed journals, in-services for postnatal healthcare services, results letters for participants and social media. TRIAL REGISTRATION NUMBER: ACTRN12620000529943.

Primary sclerosing cholangitis: A rare cause of liver dysfunction in pregnancy.

Primary sclerosing cholangitis is an uncommon condition with few cases reported in pregnancy. We present the case and outcome of a 28-year-old female presenting in her second pregnancy with new onset liver dysfunction, eventually diagnosed with primary sclerosing cholangitis. She went into spontaneous preterm labour and delivered a healthy infant but has subsequently continued to deteriorate and underwent a liver transplant 11 months post-delivery.

PrEggNut Study: protocol for a randomised controlled trial investigating the effect of a maternal diet rich in eggs and peanuts from <23 weeks' gestation during pregnancy to 4 months' lactation on infant IgE-mediated egg and peanut allergy outcomes.

INTRODUCTION: Clinical studies supported by immunological data indicate early life intervention strategies to be promising in reducing the growing global burden of food allergies. The events that predispose to food allergy, including the induction of allergen-specific immune responses, appear to be initiated early in development. Early exposure to food allergens in utero and via breast milk is likely to be important in initiating oral tolerance. We aim to determine the effectiveness of higher maternal food allergen consumption during pregnancy and lactation on infant food allergy outcomes. METHODS AND ANALYSIS: This is a multisite, parallel, two-arm (1:1 allocation), single-blinded (outcome assessors, statistical analyst and investigators), randomised controlled trial. Pregnant women (<23 weeks' gestation) whose (unborn) infants have at least two biological family members (mother, father or siblings) with medically diagnosed allergic disease are eligible to participate. After obtaining written informed consent, pregnant women are randomised to either a high egg and peanut diet (at least 6 eggs and 60 peanuts per week) or standard (low) egg and peanut diet (no more than 3 eggs and 30 peanuts per week). The women are asked to follow their allocated diet from <23 weeks' gestation to 4 months' lactation. The primary outcome is food challenge proven IgE-mediated egg and/or peanut allergy in the infants at 12 months of age. Key secondary outcomes include infant sensitisation to egg and/or peanut and infant eczema. Our target sample size is 2136 women. Analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Human Research Ethics Committee (approval number HREC/18/WCHN/42). Trial results will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12618000937213.

Perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures.

BACKGROUND: Developments in ultrasound assessment of pregnancy has resulted in the increasing diagnosis of antenatal fetal issues. Many structural fetal conditions as well as complications associated with multiple pregnancies have the potential for in-utero treatment to improve both pregnancy and neonatal outcomes. Procedures such as laser ablation for twin-twin syndrome or cord occlusion for selective fetal termination require fetal immobilisation. Immobilisation of the fetus can occur through administration of medication to the mother or directly to the fetus. This improves procedural success and reduces the ongoing risk to the pregnancy. Evidence regarding the best medication and mode of delivery helps to ensure the optimal decision is made for both the mother and the fetus. OBJECTIVES: To assess the effects of perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures on fetal, neonatal, and maternal outcomes.  SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 May 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) which compared different classes of medication administered to the mother or fetus to allow in-utero procedures to be performed. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. MAIN RESULTS: One study with three trial reports met the inclusion criteria. This involved 54 women with a multiple pregnancy. The study was conducted in a tertiary European hospital maternal-fetal medicine unit and compared remifentanil to diazepam for fetal immobilisation and maternal sedation during fetoscopic surgery.   Low-certainty evidence suggested that remifentanil may reduce fetal movement more than diazepam for two outcomes of fetal movement, one of fetal immobilisation at 40 minutes using a visual analogue score (VAS) (where 0 = immobile and 100 = baseline mobility), and one of gross body and limb movements (score was absolute number of movements), both assessed by a sonographer evaluating a taped ultrasound sequence (mean difference (MD) -65.00, 95% confidence interval (CI) -69.38 to -60.62 and MD -10.00, 95% CI -11.62 to -8.38; 1 study, 50 women).  Surgeons may also report being more satisfied with the procedure when using remifentanil rather than diazepam (risk ratio (RR) 2.88, 95% CI 1.60 to 5.15; 1 study, 50 women; low-certainty evidence). However, maternal respiratory rate may decrease more during the surgical procedure with remifentanil compared with diazepam (MD -6.00, 95% CI -8.29 to -3.71; 1 study, 50 women; low-certainty evidence). Maternal sedation may also be worse with remifentanil compared with diazepam (RR 0.09, 95% CI 0.01 to 0.65; 1 study, 50 women; low-certainty evidence) measured using an observer assessment of alertness/sedation (where a score of < 4 equates to profound sedation and > 4 equates to insufficient sedation). Perinatal mortality and time taken to perform the procedure were not reported in the trial.  We prespecified 20 outcomes and planned to use GRADE for 6 of them, all other outcomes were not able to be reported against for the purpose of meta-analysis due to data not being provided or unable to be interpreted. We assessed the included study at low risk of selection bias (appropriate random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (outcome assessors were blinded), attrition bias (incomplete outcome data minimal), and reporting bias.  Our GRADE assessment for certainty of the evidence indicates that there is low certainty of the evidence. AUTHORS' CONCLUSIONS: We were only able to include one study with a small number of women, from a single centre, a European tertiary hospital. This study was published in 2005 with an abstract of this trial published in 2004. This study evaluated two intravenous medications administered to the mother - remifentanil and diazepam. This study reported our prespecified primary outcome but only evaluated several of our secondary outcomes, which limited further assessment. Low-certainty evidence suggested that remifentanil may be better at reducing fetal movements and surgeons were more satisfied with the procedure. However, maternal sedation and depression of breathing may be worse with remifentanil.  Further high-quality RCTs assessing both fetal and maternal medications are required to evaluate their efficacy for fetal immobilisation as well as safety for both mother and fetus.

Change in timing of induction protocol in nulliparous women to optimise timing of birth: results from a single centre study.

BACKGROUND: Induction of labour (IOL) is a common obstetric intervention. When planning IOL, especially in women at risk for complications at delivery, the aim should be for delivery to occur when senior staff are available to optimise safe care. METHODS: A change in timing of IOL protocol at our institution was introduced in November 2018 aiming to increase births occurring "in-hours" defined as 08:00 to 20:00 h. This retrospective cohort study compares the odds of "in-hours" birth before and after the intervention and the association on birth outcomes. The study compared outcomes during the new IOL pathway period to a historical birth cohort from January to December 2017. Inclusion criteria were nulliparous women undergoing planned IOL at term with a cephalic singleton pregnancy. Logistic regression was used to compare odds of in-hours birth for the 2 periods with adjustment for maternal age at delivery, gestation, more than 2 cervical ripening agents required, undergoing IOL for post-dates pregnancy, mode of birth, whether or not IOL proceeded according to planned protocol and missing values using multiple imputation. RESULTS: The rate of deliveries occurring in-hours were higher following the intervention; n = 118/285 (45.6%) pre-intervention versus n = 251/470 (53.4%) post-intervention; adjusted OR = 1.47, 95% CI = 1.07-2.01, p = 0.02). The percentage of caesarean sections (CS) occurring in-hours was significantly lower in the pre-intervention group n = 71/153 (28.3%) compared with the post intervention group = 35/132(46.4%) (p < 0.001)). The rate of CS was higher in the pre intervention n = 132/285(46.3%) compared with the post intervention group n = 153/470 (32.4%)). CONCLUSIONS: The change in induction procedures was associated with a significantly higher rate of births occurring in-hours and a lower rate of overall of CS. This policy change led to a better pattern of timing of birth for nulliparous women undergoing IOL.

A comparison of praevia and non-praevia outcomes in placenta accreta spectrum cases: A single centre analysis.

BACKGROUND: Placenta accreta spectrum (PAS) causes severe maternal morbidity and mortality. Antenatal diagnosis can optimise maternal outcomes and reduce the risk of complications. PAS cases where the placenta is not low lying are suggested to be more difficult to diagnose antenatally and are potentially associated with different outcomes. AIM: The aim was to compare factors associated with births in PAS pregnancies with and without placenta praevia at a single tertiary centre over 15 years. MATERIALS AND METHODS: A retrospective review of all births complicated by PAS was conducted from a site-specific database. Cases with and without a placenta praevia were analysed to compare differences in maternal risk factors, outcomes and histological diagnosis. RESULTS: Between June 2006 and July 2020 there were 134 cases of PAS, 106 with placenta praevia. Cases without praevia were less likely to have a history of previous caesarean section and to be admitted for delivery planning or with antepartum haemorrhage. A higher proportion of cases without praevia were delivered at term, with no overall difference in emergency or elective deliveries. There was a significantly lower rate of hysterectomy in the non-praevia group. The overall estimated blood loss was significantly lower in those without praevia. CONCLUSION: Suspected PAS without placenta praevia is at lower risk of hysterectomy and massive blood loss. The management approach can be tailored accordingly, with good operative outcomes with transverse abdominal and uterine incisions. Antenatal diagnosis can be difficult to accurately predict the degree of invasion, and a higher level of suspicion is required.

Nifedipine for primary dysmenorrhoea.

BACKGROUND: Dysmenorrhoea (period pain) is a common condition with a substantial impact on the well-being and productivity of women. Primary dysmenorrhoea is defined as recurrent, cramping pelvic pain that occurs with periods, in the presence of a normal uterus, ovaries and fallopian tubes. It is thought to be caused by uterine contractions (cramps) associated with a high level of production of local chemicals such as prostaglandins. The muscle of the uterus (the myometrium) responds to these high levels of prostaglandins by contracting forcefully, causing low oxygen levels and consequently pain. Nifedipine is a calcium channel blocker in widespread clinical use for preterm labour due to its ability to inhibit uterine contractions in that setting. This review addresses whether this effect of nifedipine also helps with relief of the uterine contractions during menstruation OBJECTIVES: To assess the effectiveness and safety of nifedipine for primary dysmenorrhoea. SEARCH METHODS: We searched for all published and unpublished randomised controlled trials (RCTs) of nifedipine for dysmenorrhoea, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist. The following databases were searched to 25 November 2021: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. Also searched were the international trial registers: ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, the Web of Science, OpenGrey, LILACS database, PubMed and Google Scholar. We checked the reference lists of relevant articles. SELECTION CRITERIA: We included RCTs comparing nifedipine with placebo for the treatment of primary dysmenorrhoea. DATA COLLECTION AND ANALYSIS: The primary outcomes to be assessed were pain, and health-related quality of life. Secondary outcomes were adverse effects, satisfaction, and need for additional medication. The two review authors independently assessed the included trials. There were insufficient data to allow meaningful meta-analysis. MAIN RESULTS: The evidence assessed was of very low quality overall. We examined three small RCTs, with a total of 106 participants. Data for analysis could be extracted from only two of these trials (with a total of 66 participants); two trials were published in the 1980s, and the third in 1993. Nifedipine may be effective for "any pain relief" compared to placebo in women with primary dysmenorrhoea (odds ratio (OR) 9.04, 95% confidence interval (CI) 2.61 to 31.31; 2 studies, 66 participants; very low-quality evidence). The evidence suggests that if the rate of pain relief using placebo is 40%, the rate using nifedipine would be between 64% and 95%. For the outcome of "good" or "excellent" pain relief, nifedipine may be more effective than placebo; the confidence interval was very wide (OR 43.78, 95% CI 5.34 to 259.01; 2 studies, 66 participants; very low-quality evidence). We are uncertain if the use of nifedipine was associated with less requirement for additional analgesia use than placebo (OR 0.54, 95% CI 0.07 to 4.20, 1 study, 42 participants; very low-quality evidence). Participants indicated that they would choose to use nifedipine over their previous analgesic if the option was available. There were similar levels of adverse effects and menstruation-related symptoms in the placebo and intervention groups (OR 0.94, 95% CI 0.08 to 10.90; 1 study, 24 participants; very low-quality evidence); if the chance of adverse effects with placebo is 80%, the rate using nifedipine would be between 24% and 98%. There were no results regarding formal assessment of health-related quality of life. AUTHORS' CONCLUSIONS: The evidence is insufficient to confirm whether nifedipine is a possible medical treatment for primary dysmenorrhoea. The trials included in this review had very low numbers and were of low quality. Notably, there was a large imbalance in numbers randomised between placebo and treatment groups in one of the two trials with data available for analysis. While there was no evidence of a difference noted in adverse effects between groups, more data from larger participant numbers are needed for this outcome. Larger, more well-conducted trials are required to elucidate the potential role of nifedipine in the treatment of this common condition, as it could be a useful addition to the therapeutic options available if shown to be well tolerated and effective. The safety of nifedipine in women of reproductive age is well established from trials of its use in preterm labour, and clinicians are accustomed to off-label use for this indication. The drug is inexpensive and readily available. Other options for relief of primary dysmenorrhoea are not suitable for all women; NSAIDs and the oral contraceptive pill (OCP) are contraindicated for some women, and the OCP is not suitable for women who are trying to conceive. In addition, the trials examined suggest there may be a participant preference for nifedipine.

Skin and subcutaneous fascia closure at caesarean section to reduce wound complications: the closure randomised trial.

BACKGROUND: Wound infection is a common complication following caesarean section. Factors influencing the risk of infection may include the suture material for skin closure, and closure of the subcutaneous fascia. We assessed the effect of skin closure with absorbable versus non-absorbable suture, and closure versus non-closure of the subcutaneous fascia on risk of wound infection following Caesarean section. METHODS: Women undergoing caesarean birth at an Adelaide maternity hospital were eligible for recruitment to a randomised trial using a 2 × 2 factorial design. Women were randomised to either closure or non-closure of the subcutaneous fascia and to subcuticular skin closure with an absorbable or non-absorbable suture. Participants were randomised to each of the two interventions into one of 4 possible groups: Group 1 - non-absorbable skin suture and non-closure of the subcutaneous fascia; Group 2 - absorbable skin suture and non-closure of the subcutaneous fascia; Group 3 - non-absorbable skin suture and closure of the subcutaneous fascia; and Group 4 - absorbable skin suture and closure of the subcutaneous fascia. The primary outcomes were reported wound infection and wound haematoma or seroma within the first 30 days after birth. RESULTS: A total of 851 women were recruited and randomised, with 849 women included in the analyses (Group 1: 216 women; Group 2: 212 women; Group 3: 212 women; Group 4: 211 women). In women who underwent fascia closure, there was a statistically significant increase in risk of wound infection within 30 days post-operatively for those who had skin closure with an absorbable suture (Group 4), compared with women who had skin closure with a non-absorbable suture (Group 3) (adjusted RR 2.17; 95% CI 1.05, 4.45; p = 0.035). There was no significant difference in risk of wound infection for absorbable vs non-absorbable sutures in women who did not undergo fascia closure. CONCLUSION: The combination of subcutaneous fascia closure and skin closure with an absorbable suture may be associated with an increased risk of reported wound infection after caesarean section. TRIAL REGISTRATION: Prospectively registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12608000143325 , on the 20th March, 2008.

Aspirin (single dose) for perineal pain in the early postpartum period.

BACKGROUND: Perineal trauma, due to spontaneous tears, surgical incision (episiotomy), or in association with operative vaginal birth, is common after vaginal birth, and is often associated with postpartum perineal pain. Birth over an intact perineum may also lead to perineal pain. There are adverse health consequences associated with perineal pain for the women and their babies in the short- and long-term, and the pain may interfere with newborn care and the establishment of breastfeeding. Aspirin has been used in the management of postpartum perineal pain, and its effectiveness and safety should be assessed. This is an update of the review, last published in 2017. OBJECTIVES: To determine the effects of a single dose of aspirin (acetylsalicylic acid), including at different doses, in the relief of acute postpartum perineal pain. SEARCH METHODS: For this update, we searched the Cochrane Pregnancy and Childbirth's Trials Register (4 October 2019), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (4 October 2019) and screened reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), assessing single dose aspirin compared with placebo, no treatment, a different dose of aspirin, or single dose paracetamol or acetaminophen, for women with perineal pain in the early postpartum period. We planned to include cluster-RCTs, but none were identified. We excluded quasi-RCTs and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included RCTs. Data were checked for accuracy. The certainty of the evidence for the main comparison (aspirin versus placebo) was assessed using the GRADE approach. MAIN RESULTS: We included 17 RCTs, 16 of which randomised 1132 women to aspirin or placebo; one RCT did not report numbers of women. Two RCTs (of 16) did not contribute data to meta-analyses. All women had perineal pain post-episiotomy, and were not breastfeeding. Studies were published between 1967 and 1997, and the risk of bias was often unclear, due to poor reporting. We included four comparisons: aspirin versus placebo (15 RCTs); 300 mg versus 600 mg aspirin (1 RCT); 600 mg versus 1200 mg aspirin (2 RCTs); and 300 mg versus 1200 mg aspirin (1 RCT). Aspirin versus placebo Aspirin may result in more women reporting adequate pain relief four to eight hours after administration compared with placebo (risk ratio (RR) 2.03, 95% confidence interval (CI) 1.69 to 2.42; 13 RCTs, 1001 women; low-certainty evidence). It is uncertain whether aspirin compared with placebo has an effect on the need for additional pain relief (RR 0.25, 95% CI 0.17 to 0.37; 10 RCTs, 744 women; very low-certainty evidence), or maternal adverse effects (RR 1.08, 95% CI 0.57 to 2.06; 14 RCTs, 1067 women; very low-certainty evidence), four to eight hours after administration. Analyses based on dose did not reveal any clear subgroup differences. 300 mg versus 600 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 600 mg aspirin has an effect on adequate pain relief (RR 0.82, 95% CI 0.36 to 1.86; 1 RCT, 81 women) or the need for additional pain relief (RR 0.68, 95% CI 0.12 to 3.88; 1 RCT, 81 women). There were no maternal adverse effects in either aspirin group. 600 mg versus 1200 mg aspirin It is uncertain whether over four to eight hours after administration, 600 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.85, 95% CI 0.52 to 1.39; 2 RCTs, 121 women), the need for additional pain relief (RR 1.32, 95% CI 0.30 to 5.68; 2 RCTs, 121 women), or maternal adverse effects (RR 3.00, 95% CI 0.13 to 69.52; 2 RCTs, 121 women). 300 mg versus 1200 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.62, 95% CI 0.29 to 1.32; 1 RCT, 80 women) or need for additional pain relief (RR 2.00, 95% CI 0.19 to 21.18; 1 RCT, 80 women). There were no maternal adverse effects in either aspirin group. None of the included RCTs reported on neonatal adverse effects. No RCTs reported on secondary review outcomes of: prolonged hospitalisation due to perineal pain; re-hospitalisation due to perineal pain; fully breastfeeding at discharge; mixed feeding at discharge; fully breastfeeding at six weeks; mixed feeding at six weeks; perineal pain at six weeks; maternal views; or maternal postpartum depression. AUTHORS' CONCLUSIONS: Single dose aspirin may increase adequate pain relief in women with perineal pain post-episiotomy compared with placebo. It is uncertain whether aspirin has an effect on the need for additional analgesia, or on maternal adverse effects, compared with placebo. We downgraded the certainty of the evidence because of study limitations (risk of bias), imprecision, and publication bias. Aspirin may be considered for use in non-breastfeeding women with post-episiotomy perineal pain. Included RCTs excluded breastfeeding women, so there was no evidence to assess the effects of aspirin on neonatal adverse effects or breastfeeding. Future RCTs should be designed to ensure low risk of bias, and address gaps in the evidence, such as the secondary outcomes established for this review. Current research has focused on women with post-episiotomy pain; future RCTs could be extended to include women with perineal pain associated with spontaneous tears or operative birth.

The effect of maternal obesity on fetal biometry, body composition, and growth velocity.

Introduction: The aim of this secondary analysis was to investigate the relationship between maternal body mass index (BMI) and fetal biometry, body composition, and velocity measurements at 28 and 36 weeks gestation.Materials and methods: The current analysis involves 911 overweight or obese women who were randomized to the Standard Care group of the LIMIT randomized trial.Results: The fetus of women with Class 3 obesity (BMI ≥ 40.0) showed the greatest increase in all biometry z-scores, abdominal area (AA), and abdominal fat mass (AFM) compared with women classified as overweight (BMI 25.0-29.9). In women with Class 3 obesity, AA velocity was increased by 0.035 cm2 (0.004, 0.066, p = .029) and the z-score velocity was increased by 0.238 (0.022, 0.453, p = .03). Estimated fetal weight (EFW) velocity for women with Class 3 obesity was higher than that of overweight women by 2.028 g per day (0.861, 3.196, p<.001) and the z-score velocity was also higher by 0.441 per day (0.196, 0.687, p < .001).Conclusions: Maternal obesity is associated with an increase in fetal abdominal circumference, AFM and area along with EFW velocity over time. Women with Class 3 obesity (BMI ≥ 40.0) may represent a higher risk group for perpetuating the intergenerational transmission of obesity to their offspring.

Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy.

BACKGROUND: Multiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe. Since publication of this new review in Issue 10, 2017, we have now moved one study (El-Refaie 2016) from included to studies awaiting classification, pending clarification about the study data. OBJECTIVES: To assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi-randomised or cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence. MAIN RESULTS: We included 16 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4548 women. The risk of bias for the majority of included studies was low, with the exception of three studies that had inadequate blinding, or significant loss to follow-up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM progesterone versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low-quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by dose There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.90, 95% CI 0.66 to 1.23; women = 1503; studies = 5; I2 = 36%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.53, 95% CI 0.79 to 2.97; women = 1345; studies = 3; low-quality evidence); infant birthweight less than 2500 g (average RR 0.95, 95% CI 0.84 to 1.07; infants = 2640; studies = 3; I2 = 66%, moderate-quality evidence)). No childhood outcomes were reported in the trials. For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (8%) (RR 0.92, 95% CI 0.86 to 0.98; women = 1919; studies = 5; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.70, 95% CI 0.52 to 0.94; infants = 2695; studies = 4). AUTHORS' CONCLUSIONS: Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes. Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).

Intravenous or oral iron for treating iron deficiency anaemia during pregnancy: systematic review and meta-analysis.

OBJECTIVES: To compare the effects on perinatal maternal and neonatal outcomes of intravenous and oral iron therapy as first-line treatment of iron deficiency anaemia (IDA) in pregnant women. STUDY DESIGN: A meta-analysis, applying fixed and random effects models, of randomised controlled trials (RCTs) that compared the effects of intravenous and oral iron therapy for pregnant women with IDA. DATA SOURCES: MEDLINE, EMBASE, Scopus, Cochrane Register of Controlled Trials, Web of Science; bibliographies of identified articles. DATA SYNTHESIS: Fifteen eligible studies with a total of 1938 participants were identified. Each was at high risk of bias in at least one domain; ten were undertaken in low or middle income countries. Evidence (from nine RCTs) that intravenous iron was superior to oral iron in reducing the need for blood transfusion at delivery was low quality (Peto odds ratio, 0.19 [95% CI, 0.05-0.78]; number needed to treat, 95 [95% CI, 81-348]). Evidence that intravenous iron was superior to oral iron in increasing neonatal birthweight (eight RCTs: mean difference, 58 g; 95% CI, 4-112 g) or reducing the rate of breastfeeding cessation within 24 months of delivery (one RCT: hazard ratio, 0.70; 95% CI, 0.50-0.99) was of low or very low quality. While intravenous iron treatment was superior to oral iron for improving maternal haematological parameters at delivery, their effects on neonatal haematological parameters were similar. CONCLUSIONS: There is no strong evidence that first-line therapy with intravenous iron is superior to oral administration for treating IDA in pregnant women. The few identified differences in outcomes were small in magnitude and from studies at high risk of bias. REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019120652.

Nutrition During Pregnancy, Lactation and Early Childhood and its Implications for Maternal and Long-Term Child Health: The Early Nutrition Project Recommendations.

BACKGROUND: A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). METHODS: Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. FINDINGS: Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. INTERPRETATION: We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases.

Awareness of Listeriosis and Methylmercury toxicity public health recommendations and diet during pregnancy.

BACKGROUND: Awareness of Listeriosis and Methylmercury toxicity recommendations are associated with decreased intake of high-risk foods. Whether awareness of the recommendations affect dietary quality of pregnant women in Australian is unknown. AIM: To evaluate awareness of Listeriosis and Methylmercury toxicity recommendations during pregnancy and its impact on dietary quality. METHODS: Pregnant women (n=81) were recruited from antenatal clinics. Awareness of Listeriosis and Methylmercury toxicity recommendations and high-risk foods consumption were assessed via questionnaire at 10-23 weeks gestation. Diet quality was measured using the 2005 Healthy Eating Index using a validated food frequency questionnaire at 10-23 and 34-36 weeks gestation. FINDINGS: A higher proportion of women were aware of Methylmercury toxicity compared with Listeriosis recommendations (75.3 vs. 59.2%, p<0.001). The proportion of women who decreased or avoided consumption of certain high-risk Listeriosis foods were higher in those who were aware compared with those who were unaware of Listeriosis recommendations [raw fish (96.0 vs 69.2%, p=0.046), soft-serve ice cream (93.9 vs 58.3%, p=0.004) and alfalfa/bean sprouts (68.7 vs 28.5%, p=0.006)]. A large proportion of women (96.8%) met recommendations for limiting consumption of high Methylmercury fish. There was no difference in the change in dietary quality over pregnancy regardless of women's awareness of the recommendations. DISCUSSION AND CONCLUSIONS: Awareness of Listeriosis and Methylmercury toxicity recommendations has little impact on dietary quality of pregnant women in this small study. Further research in a large representative population of pregnant women is needed to confirm our findings and to optimise dietary quality during pregnancy.

Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial.

BACKGROUND: Maternal overweight and obesity are associated with well recognised pregnancy complications. Antenatal dietary and lifestyle interventions have a modest effect on gestational weight gain without affecting pregnancy outcomes. We aimed to assess the effects on maternal and infant outcomes of antenatal metformin given in addition to dietary and lifestyle advice among overweight and obese pregnant women. METHODS: GRoW was a multicentre, randomised, double-blind, placebo-controlled trial in which pregnant women at 10-20 weeks' gestation with a BMI of 25 kg/m2 or higher were recruited from three public maternity units in Adelaide, SA, Australia. Women were randomly assigned (1:1) via a computer-generated schedule to receive either metformin (to a maximum dose of 2000 mg per day) or matching placebo. Participants, their antenatal care providers, and research staff (including outcome assessors) were masked to treatment allocation. All women received an antenatal dietary and lifestyle intervention. The primary outcome was the proportion of infants with birthweight greater than 4000 g. Secondary outcomes included measures of maternal weight gain, maternal diet and physical activity, maternal pregnancy and birth outcomes, maternal quality of life and emotional wellbeing, and infant birth outcomes. Outcomes were analysed on an intention-to-treat basis (including all randomly assigned women who did not withdraw consent to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks' gestation, or a stillbirth). The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612001277831. FINDINGS: Of 524 women who were randomly assigned between May, 28 2013 and April 26, 2016, 514 were included in outcome analyses (256 in the metformin group and 258 in the placebo group). Median gestational age at trial entry was 16·29 weeks (IQR 14·43-18·00) and median BMI was 32·32 kg/m2 (28·90-37·10); 167 (32%) participants were overweight and 347 (68%) were obese. There was no significant difference in the proportion of infants with birthweight greater than 4000 g (40 [16%] with metformin vs 37 [14%] with placebo; adjusted risk ratio [aRR] 0·97, 95% CI 0·65 to 1·47; p=0·899). Women receiving metformin had lower average weekly gestational weight gain (adjusted mean difference -0·08 kg, 95% CI -0·14 to -0·02; p=0·007) and were more likely to have gestational weight gain below recommendations (aRR 1·46, 95% CI 1·10 to 1·94; p=0·008). Total gestational weight gain, pregnancy and birth outcomes, maternal diet and physical activity, and maternal quality of life and emotional wellbeing did not differ significantly between groups. Similar numbers of women in both treatment groups (76% [159/208] in the metformin group and 73% [144/196] in the placebo group) reported side-effects including nausea, diarrhoea, and vomiting. Two stillbirths (placebo group) and one neonatal death (metformin group) occurred; none of the perinatal deaths were determined to be attributable to participation in the trial. INTERPRETATION: For pregnant women who are overweight or obese, metformin given in addition to dietary and lifestyle advice initiated at 10-20 weeks' gestation does not improve pregnancy and birth outcomes. FUNDING: Australian National Health and Medical Research Council.

The multidisciplinary management of placenta accreta spectrum (PAS) within a single tertiary centre: A ten-year experience.

INTRODUCTION: Placenta accreta spectrum (PAS) covers a spectrum of placental adherence abnormalities: placenta accreta, increta and percreta. PAS is associated with significant maternal morbidity and mortality. Studies have shown the importance of multidisciplinary teamwork in the management of PAS. AIM: This study was designed to describe the maternal and neonatal morbidity and mortality associated with PAS in our centre over a ten-year period. METHODS: A retrospective cohort study was conducted of pregnancies complicated by PAS between February 2006 and January 2016 at Flinders Medical Centre (FMC), South Australia. Electronic and medical records were examined to obtain patient demographics, antenatal and surgical, findings and postnatal outcomes. RESULTS: There were 67 PAS cases with an overall incidence of 2.3 per 1000 deliveries. Three cases were excluded due to incomplete information. Of the remaining 64 cases, 56 women were antenatally diagnosed. Sixty cases were confirmed to be invasive at delivery; 28 accreta (superficial) and 32 increta/percreta (deep) cases. The four cases with no invasion at delivery were suspected antenatally to have PAS. The median (Q1, Q3) number of caesarean sections in this cohort was 2 (1, 3). Deep invasion is significantly associated with increased bleeding, intensive care unit admission, surgical complications and an extended postpartum stay. CONCLUSION: The incidence of PAS at FMC is high as it is the state's tertiary referral centre. While PAS is associated with increased morbidity, thorough perioperative planning by a multidisciplinary team is crucial for excellent patient outcomes.

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes.

BACKGROUND: There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional strategies are required.Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy and reduce the risk of known adverse pregnancy outcomes. OBJECTIVES: To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including adverse effects of treatment and costs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (11 October 2017), and reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing.All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care.Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence).Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment.Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.

Correction: Gestational Dietary Protein Is Associated with Sex Specific Decrease in Blood Flow, Fetal Heart Growth and Post-Natal Blood Pressure of Progeny.

[This corrects the article DOI: 10.1371/journal.pone.0125694.].