The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

Urinary Ferritin as a Noninvasive Means of Assessing Iron Status in Young Children.

BACKGROUND: Iron deficiency (ID) is the most common nutritional deficiency affecting young children. Serum ferritin concentration is the preferred biomarker for measuring iron status because it reflects iron stores; however, blood collection can be distressing for young children and can be logistically difficult. A noninvasive means to measure iron status would be attractive to either diagnose or screen for ID in young children. OBJECTIVES: This study aimed to determine the correlation between urinary and serum ferritin concentrations in young children; to determine whether correcting urinary ferritin for creatinine and specific gravity improves the correlation; and to determine a urine ferritin cut point to predict ID. METHODS: Validation study was conducted using paired serum and urine collected from 3-y-old children (n = 142) participating in a longitudinal birth cohort study: the ORIGINS project in Perth, Western Australia. We calculated the sensitivity, specificity, positive, and negative predictive values of urinary ferritin amount in identifying those with ID at the clinical cut point used by the World Health Organization (serum ferritin concentration of <12 ng/mL). RESULTS: Urine ferritin, corrected for creatinine, correlated moderately with serum ferritin [r = 0.53 (0.40-0.64)] and performed well in predicting those with ID (area under the curve: 0.85; 95% confidence interval: 0.75, 0.94). Urine ferritin <2.28 ng/mg creatinine was sensitive (86%) and specific (77%) in predicting ID and had a high negative predictive value of 97%; however, the positive predictive value was low (40%) owing to the low prevalence of ID in the sample (16%). CONCLUSIONS: Urine ferritin shows good diagnostic performance for ID. This noninvasive biomarker maybe a useful screening tool to exclude ID in healthy young children; however, further research is needed in other populations.

Concurrent use of hormonal long-acting reversible contraception by women of reproductive age dispensed teratogenic medications, Australia, 2013-2021: a retrospective cohort study.

OBJECTIVES: To examine patterns in the dispensing of category X medications (Therapeutic Goods Administration categorisation system for prescribing medicines in pregnancy) to women aged 15-49 years in Australia during 2008-2021, and patterns of concurrent use of hormonal long-acting reversible contraception (LARC) and other hormonal contraception. STUDY DESIGN: Retrospective cohort study; analysis of 10% random sample of national Pharmaceutical Benefits Scheme dispensing data. PARTICIPANTS, SETTING: Women aged 15-49 years dispensed category X medications, Australia, 1 January 2013 - 31 December 2021. MAIN OUTCOME MEASURES: Incident and prevalent dispensing of category X medications, by medication class, age group, and year; contraceptive overlap (proportions of women dispensed hormonal LARC or other hormonal contraception that overlapped the first dispensing of category X medications), by medication class. RESULTS: Among 15 627 women aged 15-49 years dispensed category X medications during 2013-2021, the prevalence of dispensing increased from 4.6 in 2013 to 8.7 per 1000 women aged 15-49 years in 2021; the largest increase was for the dispensing of dermatological agents, from 3.9 to 7.9 per 1000 women aged 15-49 years. LARC overlap was inferred for 2059 women at the time of first dispensing of category X medications (13.2%); 3441 had been dispensed any type of hormonal contraception (22.1%). The proportion with LARC overlap was smallest for those dispensed dermatological agents (1806 of 14 331 women, 12.6%); for this drug class, both LARC overlap (adjusted odds ratio [aOR], 0.17; 95% confidence interval [CI], 0.14-0.20) and any hormonal contraception overlap (aOR, 0.28; 95% CI, 0.25-0.32) were less likely for those aged 15-19 years than for women aged 25-29 years. CONCLUSIONS: Concurrent use of highly effective hormonal contraception at the time of first dispensing of category X medications is low in Australia, raising concerns about potential fetal harms during unintended pregnancies. Awareness of the importance of hormonal contraception and its uptake by women prescribed category X medications should be increased.

Oral immunotherapy using boiled peanuts for treating peanut allergy: An open-label, single-arm trial.

BACKGROUND: Peanut allergy affects 1%-3% of children in Western countries. Boiling peanuts has been demonstrated to result in a hypoallergenic product that may provide a safer way of inducing desensitization in peanut-allergic patients by first inducing tolerance to boiled peanut. We aimed to assess the efficacy and safety of oral immunotherapy (OIT) using sequential doses of boiled peanuts followed by roasted peanuts for treating peanut allergy in children. METHODS: In this open-label, phase 2, single-arm clinical trial, children aged 6-18 years with a positive history of peanut allergy and positive peanut skin prick test ≥ 8 mm and/or peanut-specific IgE ≥ 15 kU/L at screening underwent OIT involving sequential up-dosing with 12-hour boiled peanut for 12 weeks, 2-hour boiled peanut for 20 weeks and roasted peanut for 20 weeks, to a target maintenance dose of 12 roasted peanuts daily. PRIMARY OUTCOME: proportion of children passing open-label oral food challenge involving cumulative administration of 12 roasted peanuts (12 g peanuts; approximately 3000 mg peanut protein) 6-8 weeks after reaching the target maintenance dose. Secondary outcomes included treatment-related adverse events and use of medications for treating allergy symptoms. RESULTS: Between 1 July 2017 and 22 June 2018, 70 participants were enrolled and commenced OIT. Desensitization was successfully induced in 56 of 70 (80%) participants. Withdrawal due to treatment-related adverse events was infrequent (n = 3). Treatment-related adverse events were reported in 43 (61%) participants, corresponding to a rate of 6.58 per 1000 OIT doses. Medication use associated with treatment-related adverse events was infrequent, with rescue epinephrine use reported by three (4%) participants (0.05 per 1000 doses). CONCLUSION: Oral immunotherapy using boiled followed by roasted peanuts represents a pragmatic approach that appears effective in inducing desensitization and is associated with a favourable safety profile.

Pharmacoepidemiology and costs of medications dispensed during pregnancy: A retrospective population-based study.

OBJECTIVE: To describe the pharmacoepidemiology and costs associated with medications dispensed during pregnancy. DESIGN: Pharmacoepidemiological study and cost analysis. SETTING: Queensland, Australia. POPULATION: All women who gave birth in Queensland between January 2013 and June 2018. METHODS: We used a whole-of-population linked administrative dataset, Maternity1000, to describe medications approved for public subsidy that were dispensed to 255 408 pregnant women. We describe the volume of medications dispensed and their associated costs from a Government and patient perspective. MAIN OUTCOME MEASURES: Prevalence of medication use; proportion of total dispensings; total medication costs in AUD 2020/21 ($1AUD = $0.67USD/£0.55GBP in December 2022). RESULTS: During pregnancy, 61% (95% CI 60.96-61.29%) of women were dispensed at least one medication approved for public subsidy. The mean number of items dispensed per pregnancy increased from 2.14 (95% CI 2.11-2.17) in 2013 to 2.47 (95% CI 2.44-2.51) in 2017; an increase of 15%. Furthermore, mean Government cost per dispensing increased by 41% from $21.60 (95% CI $20.99-$22.20) in 2013 to $30.44 (95% CI $29.38-$31.49) in 2017. These factors influenced the 53% increase in total Government expenditure observed for medication use during pregnancy between 2013 and 2017 ($2,834,227 versus $4,324,377); a disproportionate rise compared with the 17% rise in women's total out-of-pocket expenses observed over the same timeframe ($1,880,961 versus $2,204,415). CONCLUSIONS: Prevalence of medication use in pregnancy is rising and is associated with disproportionate and rapidly escalating cost implications for the Government.

Dispensing of psychotropic medications to Australian children and adolescents before and during the COVID-19 pandemic, 2013-2021: a retrospective cohort study.

OBJECTIVE: To determine longitudinal patterns of dispensing of antidepressant, anxiolytic, antipsychotic, psychostimulant, and hypnotic/sedative medications to children and adolescents in Australia during 2013-2021. DESIGN: Retrospective cohort study; analysis of 10% random sample of Pharmaceutical Benefits Scheme (PBS) dispensing data. PARTICIPANTS, SETTING: People aged 18 years or younger dispensed PBS-subsidised psychotropic medications in Australia, 2013-2021. MAIN OUTCOME MEASURES: Population prevalence of dispensing of psychotropic medications to children and adolescents, by psychotropic class, gender, and age group (0-6, 7-12, 13-18 years). RESULTS: The overall prevalence of psychotropic dispensing to children and adolescents was 33.8 per 1000 boys and 25.2 per 1000 girls in 2013, and 60.0 per 1000 boys and 48.3 per 1000 girls in 2021. The prevalence of psychotropic polypharmacy was 5.4 per 1000 boys and 3.7 per 1000 girls in 2013, and 10.4 per 1000 boys and 8.3 per 1000 girls in 2021. Prevalent dispensing during 2021 was highest for psychostimulants (boys, 44.0 per 1000; girls, 17.4 per 1000) and antidepressants (boys, 20.4 per 1000; girls, 33.8 per 1000). During 2021, the prevalence of dispensing was higher than predicted by extrapolation of 2013-2019 data for many classes, including antidepressants (boys: +6.1%; 95% CI, 1.1-11.1%; girls: +22.2%; 95% CI, 17.4-26.9%), and psychostimulants (boys: +14.5%; 95% CI, 8.0-21.1%; girls: +27.7%; 95% CI, 18.9-36.6%). The increases were greatest for girls aged 13-18 years (antidepressants: +20.3%; 95% CI, 16.9-23.7%; psychostimulants: +39.0%; 95% CI, 27.9-50.0%). CONCLUSIONS: The prevalence of both psychotropic dispensing and psychotropic polypharmacy for children and adolescents were twice as high in 2021 as in 2013. The reasons and appropriateness of the marked increases in psychotropic dispensing during the COVID-19 pandemic, particularly to adolescent girls, should be investigated.

Online platforms for prescription and supply of hormonal contraception in Australia: a mapping review.

Online platforms have emerged as a convenient way for individuals to access contraception. However, the extent to which such services exist in Australia and how they operate is currently unknown. We aimed to identify Australian online contraception platforms and evaluate the services they provide to determine the degree to which they may facilitate equitable access to contraception. We conducted an internet search to identify online contraception platforms operating in Australia. Data were extracted from each of the platforms relating to operating policies, services provided and associated payment processes, as well as prescribing and screening processes for assessing user suitability. As of July 2022, eight online contraception platforms operating within Australia were identified. All platforms offered oral contraception, with two also offering the vaginal ring, and one emergency oral contraception. None of the platforms provided access to long-acting reversible contraception. Significant variability existed in product and membership costs across platforms, with only one platform providing access to subsidised medicines. Five platforms restricted services to those already using oral contraception. Overall, online questionnaires were deemed to be adequately screening for important contraindications to using oral contraception. While online contraception platforms may be a valuable option for some individuals who face access barriers and are willing to pay out-of-pocket for to have their contraception sent straight to their home, they do not necessarily ensure that individuals can access their contraceptive method of choice or address recognised financial and structural barriers to contraceptive care.

Incidence, antibiotic treatment and outcomes of lactational mastitis: Findings from The Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Mastitis is a common and distressing maternal postpartum condition, but the relationship between mastitis timing and antibiotic treatment and breastfeeding outcomes and postnatal mental health is unclear. OBJECTIVES: To describe the incidence of mastitis and treatment with antibiotics in first 6 months postpartum, and to investigate the impact of mastitis timing and antibiotic treatment on breastfeeding practices and postnatal mental health. METHODS: This study is based on 79,985 mother-infant dyads in the Norwegian Mother, Father and Child Cohort Study (MoBa). Women were classified according to self-reported mastitis within first month ('early') or 1-6 months ('later') postpartum and antibiotic treatment. Breastfeeding outcomes included predominant or any breastfeeding and abrupt breastfeeding cessation until 6 months postpartum. Maternal mental health was assessed by self-report at 6 months postpartum. RESULTS: The incidence of mastitis was 18.8%, with 36.8% reporting treatment with antibiotics. Women reporting early mastitis were less likely to report predominant breastfeeding (adjustedd relative risk [aRR] 0.92, 95% confidence interval [CI] 0.86, 0.99) and any breastfeeding for 6 months (aRR 0.97, 95% CI 0.96, 0.98) than women who did not report mastitis, and more likely to report abrupt breastfeeding cessation (aRR 1.37, 95% CI 1.23, 1.53). Late-onset mastitis was not associated with poorer breastfeeding outcomes. Among women reporting mastitis, the risk of abrupt breastfeeding cessation was higher in those also reporting antibiotic use. Mastitis was associated with an increased risk of mental health problems postpartum which was highest among those reporting no antibiotic use (aRR 1.29, 95% CI 1.18, 1.41), in contrast to those also reporting antibiotic use (aRR 1.08, 95% CI 0.96, 1.22). CONCLUSIONS: Lactational mastitis and its associated treatment with antibiotics are common. Early (<1 month postpartum) mastitis appears to be a modest risk factor for suboptimal breastfeeding outcomes. In addition, mastitis is associated with poorer mental health.

Perinatal antidepressant use and breastfeeding outcomes: Findings from the Norwegian Mother, Father and Child Cohort Study.

INTRODUCTION: Antidepressant use is common in the perinatal period, but there are concerns that it can negatively impact on breastfeeding outcomes. The aim of this study was to examine the effects of perinatal antidepressant use on breastfeeding initiation and duration. MATERIAL AND METHODS: This was a retrospective analysis of 80 882 mother-infant dyads in the Norwegian Mother, Father and Child Cohort Study (MoBa). Women were first classified according to self-reported mental disorders and timing of antidepressant use before and/or after gestational week 28 (i.e., early-mid-gestation and/or late-gestation use). We subsequently classified women according to self-reported mental disorders and antidepressant use postpartum and whether antidepressants were continued from late gestation or were new/restarted. Breastfeeding outcomes included breastfeeding initiation as well as predominant or any breastfeeding and abrupt breastfeeding discontinuation until 6 months. RESULTS: Late-gestation antidepressant use was associated with a reduced likelihood of breastfeeding initiation (adjusted relative risk [aRR] 0.93; 95% confidence interval [CI] 0.90-0.97) but not predominant (aRR 0.96; 95% CI 0.67-1.39) or any (aRR 1.00; 95% CI 0.93-1.07) breastfeeding at 6 months compared with unexposed women with mental disorders. When examined according to postnatal antidepressant use, no differences in predominant (aRR 0.94; 95% CI 0.60-1.48) or any breastfeeding (aRR 0.99; 95% CI 0.91-1.07) at 6 months were evident among women who continued antidepressant use from late gestation into the postpartum period compared with unexposed women with mental disorders. In contrast, new/restarted antidepressant use postpartum was associated with a reduced likelihood of predominant (aRR 0.37; 95% CI 0.22-0.61) and any (aRR 0.49; 95% CI 0.42-0.56) breastfeeding at 6 months, as well as increased risk of abrupt breastfeeding discontinuation (aRR 2.64; 95% CI 2.07-3.37) compared with the unexposed women with mental disorders. CONCLUSIONS: A complex relation exists between depression, antidepressant use, and breastfeeding outcomes. Antidepressant use in late pregnancy was associated with a reduced likelihood of breastfeeding initiation but not breastfeeding duration or exclusivity. In contrast, initiating or restarting antidepressants postpartum was associated with poorer breastfeeding outcomes. Overall, women taking antidepressants and women with a mental disorder may benefit from additional education and support to improve breastfeeding rates and promote maternal and infant health and wellbeing.

Relative importance of metabolic syndrome components for developing gestational diabetes.

PURPOSE: To assess the independent and joint contribution of the individual components of metabolic syndrome, and known risk factors for gestational diabetes (GDM), on risk of GDM. METHODS: Two thousand nine hundred and fifteen women from Australia and New Zealand, who participated in The Screening for Pregnancy Endpoints Study (SCOPE), were included. Using the SCOPE clinical data set and biomarkers obtained at 14-16 weeks' gestation, a logistic regression model was fitted to the binary outcome GDM, with individual metabolic syndrome components (waist circumference, blood pressure, glucose, HDL-C, triglycerides), recruitment site, and other established factors associated with GDM. Hierarchical partitioning was used to assess the relative contribution of each variable. RESULTS: Of the 2915 women, 103 women (3.5%) developed GDM. The deviance explained by the logistic regression model containing all variables was 18.65% and the AUC was 0.809. Seventy percent of the independent effect was accounted for by metabolic syndrome components. The highest independent relative contribution to GDM was circulating triglycerides (17 ± 3%), followed by waist circumference (13 ± 3%). Glucose and maternal BMI contributed 12 ± 2% and 12 ± 3%, respectively. The remaining factors had an independent relative contribution of < 10%. CONCLUSION: Triglyceride concentrations had the highest independent relative importance for risk of GDM. Increased focus for lowering triglycerides as an important risk factor for GDM is warranted.

Early medical abortion services provided in Australian primary care.

OBJECTIVES: To examine primary care provision of early medical abortion services in Australia. DESIGN: Cross-sectional study; analysis of Pharmaceutical Benefits Scheme (PBS) dispensing data. SETTING, PARTICIPANTS: Women of child-bearing age (15-54 years), Australia, 2015-2019. MAIN OUTCOME MEASURES: Age-standardised rates of MS-2 Step prescriptions dispensed by year for 2015-2019, and age-standardised rates by state, remoteness area, and level 3 statistical areas (SA3s) for 2019. Numbers and proportions of SA3s in which MS-2 Step was not prescribed by a GP or dispensed by a community pharmacy during 2019 (unweighted and weighted by number of women of reproductive age), by state and remoteness area. RESULTS: During 2015-2019, 91 643 PBS prescriptions for MS-2 Step were dispensed; the national age-standardised rate increased from 1.63 in 2015 to 3.79 prescriptions per 1000 women aged 15-54 years in 2019. In 2019, rates were higher in outer regional Australia (6.53 prescriptions per 1000 women aged 15-54 years) and remote Australia (6.02 per 1000) than in major cities (3.30 per 1000). However, about 30% of women in Australia lived in SA3s in which MS-2 Step had not been prescribed by a GP during 2019, including about 50% of those in remote Australia. CONCLUSIONS: The rate of early medical abortion is greater among women in remote, outer regional, and inner regional Australia than in major cities, but a considerable proportion of women live in areas in which MS-2 Step was not locally prescribed or dispensed during 2019. Supporting GPs in the delivery of early medical abortion services locally should be a focus of health policy.

Pregnant women report being denied medications to treat severe nausea and vomiting of pregnancy or hyperemesis gravidarum - findings from an Australian online survey.

We conducted an online survey of 249 Australian women who currently or previously experienced severe nausea and vomiting of pregnancy (NVP) or hyperemesis gravidarum (HG) and examined their experiences in being denied medications during pregnancy. One in four women reported being denied medications for NVP/HG, which most commonly involved doxylamine and encounters with community pharmacists. Women's experiences reflected that lack of awareness of guidelines and unfavourable risk-benefit assessments appeared to be key barriers to facilitating medication access. Approaches towards identifying and effectively addressing barriers to the provision of effective treatments for severe NVP and HG are urgently needed.

Changes in use of hormonal long-acting reversible contraceptive methods in Australia between 2006 and 2018: A population-based study.

BACKGROUND: Long-acting reversible contraceptives (LARCs) are promoted internationally as a key strategy for reducing unintended pregnancy and abortion rates. AIMS: To examine trends in use of hormonal LARCs among reproductive-aged women in Australia between 2006 and 2018 and explore trends according to age groups and state/territory of dispensing. MATERIALS AND METHODS: Retrospective population-based study using Pharmaceutical Benefits Scheme (PBS) dispensing claims of a 10% random sample of females aged 15-44. We investigated rates and annual trends in dispensing claims of etonorgestrel implant and levonorgestrel intrauterine systems (IUS). RESULTS: Between 2006 and 2018, annual PBS claims for LARCs increased approximately two-fold from 21.7 to 41.5 per 1000 women, with a plateau observed from 2015 onward. Absolute rate increases were similar for the implant (9.0/1000) and IUS (10.8/1000), with increases observed across all age groups and states/territories. Overall dispensing rates varied by two-fold according to state/territory of dispensing and four-fold according to age groups. Rate increases for the implant were highest among the 15-19 and 20-24 age groups, while rate increases for the IUS were highest among the 35-39 and 40-44 age groups. It is estimated that in 2018, 10.8% of women aged 15-44 were using a LARC; 4.5% for the implant and 6.3% for the IUS. CONCLUSIONS: Rates of hormonal LARC use have doubled over the past decade. Investigating underlying reasons for the large observed differences in rates of use according to age and state/territory could help further improve uptake for these most effective methods of contraception.

Maternal folate, one-carbon metabolism and pregnancy outcomes.

Single nucleotide polymorphisms and pre- and peri-conception folic acid (FA) supplementation and dietary data were used to identify one-carbon metabolic factors associated with pregnancy outcomes in 3196 nulliparous women. In 325 participants, we also measured circulating folate, vitamin B12 and homocysteine. Pregnancy outcomes included preeclampsia (PE), gestational hypertension (GHT), small for gestational age (SGA), spontaneous preterm birth (sPTB) and gestational diabetes mellitus (GDM). Study findings show that maternal genotype MTHFR A1298C(CC) was associated with increased risk for PE, whereas TCN2 C766G(GG) had a reduced risk for sPTB. Paternal MTHFR A1298C(CC) and MTHFD1 G1958A(AA) genotypes were associated with reduced risk for sPTB, whereas MTHFR C677T(CT) genotype had an increased risk for GHT. FA supplementation was associated with higher serum folate and vitamin B12 concentrations, reduced uterine artery resistance index and increased birth weight. Women who supplemented with <800 µg daily FA at 15-week gestation had a higher incidence of PE (10.3%) compared with women who did not supplement (6.1%) or who supplemented with ≥800 µg (5.4%) (P < .0001). Higher serum folate levels were found in women who later developed GDM compared with women with uncomplicated pregnancies (Mean ± SD: 37.6 ± 8 nmol L-1 vs. 31.9 ± 11.2, P = .007). Fast food consumption was associated with increased risk for developing GDM, whereas low consumption of green leafy vegetables and fruit were independent risk factors for SGA and GDM and sPTB and SGA, respectively. In conclusion, maternal and paternal genotypes, together with maternal circulating folate and homocysteine concentrations, and pre- and early-pregnancy dietary factors, are independent risk factors for pregnancy complications.

The deleterious effects of cannabis during pregnancy on neonatal outcomes.

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

Relief of pain due to uterine cramping/involution after birth.

BACKGROUND: Women may experience differing types of pain and discomfort following birth, including cramping pain (often called after-birth pain) associated with uterine involution, where the uterus contracts to reduce blood loss and return the uterus to its non-pregnant size. This is an update of a review first published in 2011. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological pain relief/analgesia for the relief of after-birth pains following vaginal birth. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (31 October 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing two different types of analgesia or analgesia versus placebo or analgesia versus no treatment, for the relief of after-birth pains following vaginal birth. Types of analgesia included pharmacological and non-pharmacological. Quasi-randomised trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted 'Risk of bias' assessment, extracted data and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this update, we include 28 studies (involving 2749 women). The evidence identified in this review comes from middle- to high-income countries. Generally the trials were at low risk of selection bias, performance bias and attrition bias, but some trials were at high risk of bias due to selective reporting and lack of blinding. Our GRADE certainty of evidence assessments ranged from moderate to very low certainty, with downgrading decisions based on study limitations, imprecision, and (for one comparison) indirectness. Most studies reported our primary outcome of adequate pain relief as reported by the women. No studies reported data relating to neonatal adverse events, duration of hospital stay, or breastfeeding rates. Almost half of the included studies (11/28) excluded breastfeeding women from participating, making the evidence less generalisable to a broader group of women. Non-steroidal anti-inflammatory drugs (NSAIDs) compared to placebo NSAIDs are probably better than placebo for adequate pain relief as reported by the women (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.45 to 1.91; 11 studies, 946 women; moderate-certainty evidence). NSAIDs may reduce the need for additional pain relief compared to placebo (RR 0.15, 95% CI 0.07 to 0.33; 4 studies, 375 women; low-certainty evidence). There may be a similar risk of maternal adverse events (RR 1.05, 95% CI 0.78 to 1.41; 9 studies, 598 women; low-certainty evidence). NSAIDs compared to opioids NSAIDs are probably better than opioids for adequate pain relief as reported by the women (RR 1.33, 95% CI 1.13 to 1.57; 5 studies, 560 women; moderate-certainty evidence) and may reduce the risk of maternal adverse events (RR 0.62, 95% CI 0.43 to 0.89; 3 studies, 255 women; low-certainty evidence). NSAIDs may be better than opioids for the need for additional pain relief, but the wide CIs include the possibility that the two classes of drugs are similarly effective or that opioids are better (RR 0.37, 95% CI 0.12 to 1.12; 2 studies, 232 women; low-certainty evidence). Opioids compared to placebo Opioids may be better than placebo for adequate pain relief as reported by the women (RR 1.26, 95% CI 0.99 to 1.61; 5 studies, 299 women; low-certainty evidence). Opioids may reduce the need for additional pain relief compared to placebo (RR 0.48, 95% CI 0.28 to 0.82; 3 studies, 273 women; low-certainty evidence). Opioids may increase the risk of maternal adverse events compared with placebo, although the certainty of evidence is low (RR 1.59, 95% CI 0.99 to 2.55; 3 studies, 188 women; low-certainty evidence). Paracetamol compared to placebo Very low-certainty evidence means we are uncertain if paracetamol is better than placebo for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events (2 studies, 123 women). Paracetamol compared to NSAIDs Very low-certainty evidence means we are uncertain if there are any differences between paracetamol and NSAIDs for adequate pain relief as reported by the women, or the risk of maternal adverse events. No data were reported about the need for additional pain relief comparing paracetamol and NSAIDs (2 studies, 112 women). NSAIDs compared to herbal analgesia We are uncertain if there are any differences between NSAIDs and herbal analgesia for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events, because the certainty of evidence is very low (4 studies, 394 women). Transcutaneous nerve stimulation (TENS) compared to no TENS Very low-certainty evidence means we are uncertain if TENS is better than no TENS for adequate pain relief as reported by the women. No other data were reported comparing TENS with no TENS (1 study, 32 women). AUTHORS' CONCLUSIONS: NSAIDs may be better than placebo and are probably better than opioids at relieving pain from uterine cramping/involution following vaginal birth. NSAIDs and paracetamol may be as effective as each other, whereas opioids may be more effective than placebo. Due to low-certainty evidence, we are uncertain about the effectiveness of other forms of pain relief. Future trials should recruit adequate numbers of women and ensure greater generalisability by including breastfeeding women. In addition, further research is required, including a survey of postpartum women to describe appropriately their experience of uterine cramping and involution. We identified nine ongoing studies, which may help to increase the level of certainty of the evidence around pain relief due to uterine cramping in future updates of this review.

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.

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

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

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

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

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