The Use of Multiple Medications During Pregnancy Among an Ethnically Diverse Population in South-Eastern Melbourne: A Retrospective Analysis to Explore Potential Risks and Complications.

BACKGROUND AND OBJECTIVE: Medication use is increasing to treat both pre-existing and pregnancy-related medical conditions or complications. This study aims to investigate factors associated with multiple medication use during pregnancy, as well as any increased risk of pregnancy complications for women taking multiple medications. METHODS: A retrospective analysis of routinely collected medical records of singleton pregnant women was conducted in Southeast Melbourne, Australia, between 2016 and 2021. Self-reported medication use was recorded as part of routine medical care, starting from the first antenatal booking appointment and continuing for every subsequent antenatal appointment until birth. Multimorbidity was defined as having two or more medical conditions. Logistic regression was used to assess factors influencing multiple medication use (defined as taking two or more non-supplemental medications at any stage of pregnancy) and associations with pregnancy complications. RESULTS: Of 48,502 participants, 34.9% used one medication, while 11.7% used multiple medications. Women of older age (30-34, 35-39, and ≥  40 years), higher body mass index (25.0-29.9 kg/m2 and ≥  30 kg/m2), born in Australasia and Oceania, higher socioeconomic status, and multimorbidity were more likely to use multiple medications during pregnancy. Women taking multiple medications had a higher risk of preterm and caesarean deliveries, fetal death, and neonatal admissions to intensive care. Sensitivity analyses exploring different morbidity categories produced no changes to findings. CONCLUSIONS: Medication use during pregnancy is prevalent, with many pregnant mothers taking multiple medications. Given the rising maternal age, body mass index, and morbidities in pregnancy, the use of medications during pregnancy is increasing. Such use correlates with an increased chance of adverse pregnancy outcomes. In the context of limited trials on the safety and efficacy of medications in pregnancy, timely harnessing of the information available within routine medical records for post-marketing surveillance is important.

Adverse pregnancy outcomes and chronic hypertension in the era of prevention: A contemporary, retrospective cohort study using data from the National Inpatient Sample Database.

Objective Chronic hypertension is a known risk factor for the development of preeclampsia and obstetrical morbidity. However, recent risk estimates, particularly in the era of use of low-dose acetylsalicylic acid for preeclampsia prevention, are lacking. This study aimed to estimate the association between chronic hypertension and preeclampsia and other adverse pregnancy outcomes in a contemporary cohort of births spanning the period since the introduction of a low-dose acetylsalicylic acid protocol. The secondary outcome was to estimate trends in preeclampsia and preterm birth among patients with chronic hypertension during the study period. Study Design A retrospective, population-based cohort study was conducted using the National Inpatient Sample (NIS) Database to identify individuals discharged from hospitals in the United States following obstetrical delivery from 2014 to 2019. Pregnancies complicated by chronic hypertension were identified using ICD 9/10 codes. Multivariable logistic regression models were used to estimate the adjusted odds ratios (OR) for the association between chronic hypertension and adverse pregnancy outcomes compared to pregnancies not complicated by chronic hypertension. Temporal trends in preeclampsia and preterm birth among patients with chronic hypertension were estimated over the study period. Results Among 4,451,667 obstetrical delivery-related admissions, 139,556 (3.1%) included pregnancies complicated by chronic hypertension. Of these, 27,146 (19.4%) admissions included pregnancies with superimposed preeclampsia, compared to 222,351 (5.2%) of admissions that included pregnancies with preeclampsia without prior diagnosis of chronic hypertension. Pregnancies complicated by chronic hypertension were associated with 3.29 times the odds of preeclampsia compared to pregnancies without chronic hypertension (95% CI 3.22-3.36), but the odds of preeclampsia (p-value for linear trend <0.0001) and preterm birth (p-value for linear trend = 0.0001) in this subgroup decreased over the study period. Conclusion While the odds of preeclampsia are increased among pregnancies complicated by chronic hypertension, the odds of preeclampsia in this population have decreased over time.

Assessing Feeding Difficulties in Children Presenting with Non-IgE-Mediated Gastrointestinal Food Allergies-A Commonly Reported Problem.

Many guidelines have been published to help diagnose food allergies, which have included feeding difficulties as a presenting symptom (particularly for non-IgE-mediated gastrointestinal allergies). This study aimed to investigate the prevalence of feeding difficulties in children with non-IgE-mediated gastrointestinal allergies and the association of such difficulties with symptoms and food elimination. An observational study was performed at Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Children aged 4 weeks to 16 years without non-allergic co-morbidities who improved on an elimination diet using a previously published Likert scale symptom score were included. This study recruited 131 children, and 114 (87%) parents completed the questionnaire on feeding difficulties. Feeding difficulties were present in 61 (53.5%) of the 114 children. The most common feeding difficulties were regular meal refusals (26.9%), extended mealtimes (26.7%), and problems with gagging on textured foods (26.5%). Most children (40/61) had ≥2 reported feeding difficulties, and eight had ≥4. Children with feeding difficulties had higher rates of constipation and vomiting: 60.7% (37/61) vs. 35.8% (19/53), p = 0.008 and 63.9% (39/61) vs. 41.5% (22/53), p = 0.017, respectively. Logistic regression analysis demonstrated an association between having feeding difficulties, the age of the child, and the initial symptom score. Gender and the number of foods excluded in the elimination diet were not significantly associated with feeding difficulties. This study found that feeding difficulties are common in children with non-IgE-mediated gastrointestinal allergies, but there is a paucity of food allergy specific tools for establishing feeding difficulties, which requires further research in the long-term and consensus in the short term amongst healthcare professions as to which tool is the best for food allergic children.

Machine Learning Algorithms Versus Classical Regression Models in Pre-Eclampsia Prediction: A Systematic Review.

PURPOSE OF REVIEW: Machine learning (ML) approaches are an emerging alternative for healthcare risk prediction. We aimed to synthesise the literature on ML and classical regression studies exploring potential prognostic factors and to compare prediction performance for pre-eclampsia. RECENT FINDINGS: From 9382 studies retrieved, 82 were included. Sixty-six publications exclusively reported eighty-four classical regression models to predict variable timing of onset of pre-eclampsia. Another six publications reported purely ML algorithms, whilst another 10 publications reported ML algorithms and classical regression models in the same sample with 8 of 10 findings that ML algorithms outperformed classical regression models. The most frequent prognostic factors were age, pre-pregnancy body mass index, chronic medical conditions, parity, prior history of pre-eclampsia, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and pregnancy-associated plasma protein A. Top performing ML algorithms were random forest (area under the curve (AUC) = 0.94, 95% confidence interval (CI) 0.91-0.96) and extreme gradient boosting (AUC = 0.92, 95% CI 0.90-0.94). The competing risk model had similar performance (AUC = 0.92, 95% CI 0.91-0.92) compared with a neural network. Calibration performance was not reported in the majority of publications. ML algorithms had better performance compared to classical regression models in pre-eclampsia prediction. Random forest and boosting-type algorithms had the best prediction performance. Further research should focus on comparing ML algorithms to classical regression models using the same samples and evaluation metrics to gain insight into their performance. External validation of ML algorithms is warranted to gain insights into their generalisability.

Prevention of preeclampsia.

Preeclampsia is a relatively common pregnancy complication and constitutes a major cause of morbidity and mortality for mothers and children worldwide. It disproportionally affects low-resource countries. Appropriate identification of individuals at increased risk and prevention of the disease and its complications remain healthcare and research priorities, and the investigation of potential interventions to prevent preeclampsia has driven much of the obstetric research in recent decades. In this article, we review the scientific literature on the topic, highlighting established benefits and remaining questions regarding different non-pharmacological and pharmacological strategies, including exercise, the timing of birth, aspirin and calcium use, among others, as well as potential novel therapies under investigation.

Inpatient versus outpatient management of prenatally diagnosed vasa praevia: A systematic review and meta-analysis.

OBJECTIVE: Vasa praevia is a serious pregnancy complication that is potentially life-threatening for the fetus. The possible benefits of prophylactic hospital admission of asymptomatic women diagnosed with vasa praevia antenatally remain unclear. This study aims to compare the pregnancy outcomes of inpatient versus outpatient management in women with a prenatal diagnosis of vasa praevia. METHODS: A systematic search of four electronic databases was conducted and two reviewers independently screened studies for eligibility. The inclusion criteria incorporated studies with prenatally diagnosed vasa praevia, a distinction on whether women were managed as inpatients and/or outpatients and where perinatal mortality was recorded as an outcome. The primary outcome of the study was perinatal mortality with additional outcomes of perinatal morbidity, need for emergency caesarean and antenatal steroid administration. Reporting of the results followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: The search produced 2,300 studies with ten of these studies included in the qualitative synthesis and four included in the quantitative analysis. There was no significant difference in perinatal mortality (OR 1.12, 95 % CI 0.10-12.07, p = 0.93, I2 = 0 %) or morbidity between women managed as inpatients or outpatients. The prophylactic inpatient group had higher rates of earlier gestational delivery and antenatal corticosteroid administration (OR 10.78, 95 % CI 1.07-108.74, p = 0.04, I2 = 82 %), but lower rates of emergency caesareans (OR 0.35, 95 % CI 0.17-0.72, p = 0.004, I2 = 0 %). CONCLUSION: There were no significant differences in perinatal mortality or morbidity rates observed between inpatient and outpatient management of asymptomatic women with antenatally diagnosed vasa praevia. However, outpatient management is associated with prolonged gestation, a decrease in antenatal corticosteroid administration, and higher odds of emergency caesarean. Outpatient management of prenatally diagnosed vasa praevia seems appropriate for carefully selected asymptomatic women.

Preterm Birth: Screening and Prediction.

Preterm birth (PTB) affects approximately 10% of births globally each year and is the most significant direct cause of neonatal death and of long-term disability worldwide. Early identification of women at high risk of PTB is important, given the availability of evidence-based, effective screening modalities, which facilitate decision-making on preventative strategies, particularly transvaginal sonographic cervical length (CL) measurement. There is growing evidence that combining CL with quantitative fetal fibronectin (qfFN) and maternal risk factors in the extensively peer-reviewed and validated QUanititative Innovation in Predicting Preterm birth (QUiPP) application can aid both the triage of patients who present as emergencies with symptoms of preterm labor and high-risk asymptomatic women attending PTB surveillance clinics. The QUiPP app risk of delivery thus supports shared decision-making with patients on the need for increased outpatient surveillance, in-patient treatment for preterm labor or simply reassurance for those unlikely to deliver preterm. Effective triage of patients at preterm gestations is an obstetric clinical priority as correctly timed administration of antenatal corticosteroids will maximise their neonatal benefits. This review explores the predictive capacity of existing predictive tests for PTB in both singleton and multiple pregnancies, including the QUiPP app v.2. and discusses promising new research areas, which aim to predict PTB through cervical stiffness and elastography measurements, metabolomics, extracellular vesicles and artificial intelligence.

Ophthalmic artery Doppler in the complementary diagnosis of preeclampsia: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the accuracy of different parameters of the ophthalmic artery Doppler (OAD) in the complementary diagnosis of preeclampsia (PE). METHODS: This meta-analysis adhered to the PRISMA guidelines. To investigate the mean difference in OAD values, peak systolic velocity (PSV), end-diastolic velocity (EDV), second systolic velocity peak (P2), resistance index (RI), pulsatility index (PI), and peak ratio (PR), between PE cases (overall and according to severity) and controls, random-effects meta-analyses were conducted for each Doppler parameter, with overall PE and mild and severe PE subgroups. Diagnostic performance and heterogeneity were evaluated with summary receiver operating characteristic (sROC) curves and 95% confidence intervals obtained with bivariate models. RESULTS: Eight studies stratified the results into mild and severe or late and early PE, involving 1,425 pregnant women. PR and P2 had better diagnostic performance than the other indexes, with the PR of AUsROC at 0.885, the sensitivity of 84%, and specificity of 92%, with a low false-positive rate of 0.08 and the P2 with AUsROC of 0.926, the sensitivity of 85% and specificity of 88%. RI, PI, and EDV showed good performance and consistency across studies but lower AUsROC values of 0.833, 0.794, and 0.772, respectively. CONCLUSION: Ophthalmic artery Doppler is a complementary tool with good performance for the diagnosis of overall and severe preeclampsia, with high and best sensitivity and specificity when using PR and P2 parameters.

Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps.

Pre-eclampsia (PE) is a complex multisystem disease of pregnancy that is becoming increasingly recognized as a state of angiogenic imbalance characterized by low concentrations of placental growth factor (PlGF) and elevated soluble fms-like tyrosine kinase (sFlt-1). PlGF is a protein highly expressed by the placenta with vasculogenic and angiogenic properties, which has a central role in spiral artery remodeling and the development of a low-resistance placental capillary network. PlGF concentrations are significantly lower in women with preterm PE, and these reduced levels have been shown to precede the clinical onset of disease. Subsequently, the clinical utility of maternal serum PlGF has been extensively studied in singleton gestations from as early as 11 to 13 weeks' gestation, utilizing a validated multimarker prediction model, which performs superiorly to the National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) guidelines in the detection of preterm PE. There is extensive research highlighting the role of PlGF-based testing utilizing commercially available assays in accelerating the diagnosis of PE in symptomatic women over 20 weeks' gestation and predicting time-to-delivery, allowing individualized risk stratification and appropriate antenatal surveillance to be determined. "Real-world" data has shown that interpretation of PlGF-based test results can aid clinicians in improving maternal outcomes and a growing body of evidence has implied a role for sFlt-1/PlGF in the prognostication of adverse pregnancy and perinatal events. Subsequently, PlGF-based testing is increasingly being implemented into obstetric practice and is advocated by NICE. This literature review aims to provide healthcare professionals with an understanding of the role of angiogenic biomarkers in PE and discuss the evidence for PlGF-based screening and triage. Prospective studies are warranted to explore if its implementation significantly improves perinatal outcomes, explore the value of repeat PlGF testing, and its use in multiple pregnancies.

The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis.

BACKGROUND: The performance of cell-free DNA (cfDNA) screening for microscopic copy number variants (CNVs) is unclear. OBJECTIVES: This was a systematic review and meta-analysis to investigate the sensitivity, specificity and positive predictive value (PPV) of cfDNA screening for CNVs. SEARCH STRATEGY: Articles published in EMBASE, PubMed or Web of Science before November 2022 were screened for inclusion. This protocol was registered with PROSPERO (23 March 2021, CRD42021250849) prior to initiation. SELECTION CRITERIA: Articles published in English, detailing diagnostic outcomes for at least 10 high-risk CNV results with cfDNA were considered for inclusion. DATA COLLECTION AND ANALYSIS: The PPV was calculated and pooled with random-effects models for double-arcsine transformed proportions, using cases with diagnostic confirmation. Overall sensitivity, specificity and a summary receiver-operating characteristics (ROC) curve were calculated using bivariate models. The risk of bias was assessed using QUADAS-2. MAIN RESULTS: In all, 63 articles were included in the final analysis, detailing 1 591 459 cfDNA results. The pooled PPV was 37.5% (95% confidence interval [CI] 30.6-44.8), with substantial statistical heterogeneity (I2  = 93.9%). Bivariate meta-analysis estimated sensitivity and specificity to be 77.4% (95% CI 65.7-86.0) and 99.4% (95% CI 98.0-99.8), respectively, with an area under the summary ROC curve of 0.947 (95% CI 0.776-0.984). CONCLUSIONS: Approximately one-third of women who screen high-risk for CNVs with cfDNA will have an affected fetus. This value is of importance for screening counselling.

Performance of a risk factor-based approach in the detection of small for gestational age neonates: A cohort study.

BACKGROUND: Antenatal detection of fetal growth restriction allows the opportunity to increase surveillance and initiate intervention to prevent adverse outcomes. Detection of small for gestational age (SGA) fetuses with risk factor screening and selective ultrasonography is the standard of care in Australia, but evidence regarding performance is lacking. AIMS: To evaluate the diagnostic performance of a risk factor-based screening approach in detection of SGA neonates. MATERIALS AND METHODS: Retrospective cohort study conducted in a metropolitan maternity service, including all consecutive singleton deliveries over 20 weeks gestation from July 2016 to December 2017, and excluding terminations of pregnancy. An SGA neonate was defined by birthweight below the tenth percentile according to Australian reference ranges. Antenatally detected SGA cases were defined by estimated fetal weight or abdominal circumference below the tenth percentile for gestational age, or abnormal symphysio-fundal height. The diagnostic accuracy of the screening protocol was calculated using detection rates and false-positive rates. RESULTS: There were 13 384 singleton pregnancies included. There were 1330 infants (10.0%) who were SGA at birth. Antenatal detection rate of SGA neonates was 39.6% (95% confidence interval (CI) 37.0-42.3%), with a false-positive rate of 10.2% (95% CI 9.6-10.7%). There were 10 266 pregnancies (77.0%) which had at least one risk factor for an SGA infant. Of these, 6650 (64.8%) underwent at least one fetal growth ultrasound after 24 weeks gestation. CONCLUSIONS: Antenatal recognition of poor fetal growth is suboptimal using our current screening protocol. Three-quarters of pregnancies demonstrated risk factors for delivering an SGA infant, but growth ultrasonography may be underutilised.

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances.

OBJECTIVE: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. METHOD: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. RESULTS: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%-10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%-30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%-16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). CONCLUSION: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

Predictors for insulin use in gestational diabetes mellitus.

OBJECTIVES: Gestational diabetes mellitus (GDM) affects about 15% of pregnancies in Australia, with approximately 30% of those diagnosed with GDM requiring insulin therapy. There are several established risk factors for developing GDM, however limited studies show how these can be used to predict need for insulin treatment. The aim of this study is to identify predictors of insulin therapy in women diagnosed with GDM once an oral glucose tolerance test (OGTT) is performed during pregnancy. STUDY DESIGN: This is a retrospective cohort study of women with singleton pregnancies complicated by GDM between 2016 and 2017 at a single, large health network in Melbourne, Australia. Data were obtained from hospital record and pathology result systems. Univariable and multivariable logistic regression models were fit to the data to obtain crude and adjusted odds ratios. RESULTS: Of 2,048 women diagnosed with GDM, 647 (31.6%) required insulin therapy. Positive predictors included in the final multivariable model after backwards, stepwise elimination were an elevated fasting result on an OGTT (adjusted odds ratio (AOR) 2.93 [95% CI 2.34-3.66]), previous birth weight greater than 90th% (AOR 2.04 [95% CI 1.412.94]), previous diagnosis of GDM (AOR 1.68 [95% CI 1.28-2.21]), being born in the South Asian region (AOR 1.58 [95% CI 1.27-1.98]), the 2hr OGTT result (AOR 1.14 [95% CI 1.05-1.24]), body mass index (BMI; AOR 1.13 [95% CI 1.04-1.23]) and age (AOR 1.03 [95% CI 1.00-1.05]) The final predictive model had an area under the receiver-operating characteristics (ROC) curve of 0.744 (95% CI 0.720-0.767). CONCLUSIONS: This study highlights the possible predictors of insulin use, informing counselling for women who are newly diagnosed with gestational diabetes.

Ultrasound findings and detection of fetal abnormalities before 11 weeks of gestation.

OBJECTIVE: To determine the proportion of major fetal structural abnormalities that can be detected before 11 gestational weeks. METHODS: We conducted a retrospective study of individual patient files at a tertiary provider of obstetric and gynecological ultrasound in Melbourne, Australia. All women who had a pre-cell-free DNA ultrasound with a crown-rump length of less than 45 mm and had one or more ultrasounds at a later gestation were included in the analysis. The primary outcome was the incidence of a fetal structural abnormality. RESULTS: A total of 3333 cases were included in the final analysis. Overall, 316 fetuses (9.5%) had a structural abnormality detected at any point throughout gestation, of which 86 were major structural abnormalities (2.6%). Sixteen fetal abnormalities were detected before 11 weeks of gestation, including 15 major abnormalities (17.4% of the major anomalies). All major fetal abnormalities detected before 11 gestational weeks were confirmed at later ultrasound examinations or the pregnancy did not continue (in four cases due to termination of pregnancy and in one case spontaneous miscarriage before first trimester morphology ultrasound). CONCLUSION: Detection of fetal abnormalities is possible before 11 weeks of gestation. Early suspicion is more likely in cases of major structural abnormalities.

Business as usual during the COVID-19 pandemic? Reflections on state-wide trends in maternity telehealth consultations during lockdown in Victoria and New South Wales.

COVID-19 has resulted in unprecedented changes to maternity care across Australia. This study aims to analyse trends in maternity consultations and the uptake of telehealth in Victoria and New South Wales (NSW) since the first restrictions to reduce COVID-19 transmission were implemented. From March 2020 to April 2021, a higher proportion of antenatal care consultations was delivered via telehealth in Victoria compared to NSW (13.8% vs 7.4%, P < 0.0001). Uptake of telehealth and a shift from in-person care has been a major contributor to maintaining pregnancy care during pandemic restrictions. However, further research is required to understand women's perspectives and health outcomes.

Perspectives on administration of COVID-19 vaccine to pregnant and lactating women: a challenge for low- and middle-income countries.

Women who are in the pregnancy-puerperal cycle or are lactating have been deliberately excluded from participating in COVID-19 vaccine clinical trials that aimed to evaluate either the efficacy of the vaccines in inducing the formation of neutralizing antibodies or the investigational products' safety profile. The exclusion of pregnant and lactating women from such studies certainly and inequitably denies these women access to COVID-19 vaccines, since these products have become increasingly available to nonpregnant people and even to those who are pregnant and are in high-income settings. In this clinical opinion article, we discuss some aspects of the prolonged pandemic, the emergence of viral variants, the risks of severe complications of COVID-19 in pregnant women, and the disproportionate impact of the above on low- and middle-income countries. We argue that the decision to receive the COVID-19 vaccine should be a joint decision between the pregnant or lactating women and the healthcare providers, while considering the available data on vaccine efficacy, safety, the risks of SARS-CoV-2 infection in pregnant women, and the women's individual risks for infection and serious illness. The various types of vaccines that are already in use and their safety, effectiveness, and the potential risks and benefits of their administration to pregnant or lactating women are also reviewed.