The safety of phthalate-containing medications used during pregnancy.

INTRODUCTION: Phthalates freely cross the placenta and have the potential to influence pregnancy outcomes, with evidence of an increased incidence of preterm birth, low birth weight, pregnancy loss, and gestational diabetes. There is no regulation of phthalate concentrations in medications, which is often found in enteric coatings. Ingestion of phthalate containing medication during pregnancy may result in materno-fetal harm. AREAS COVERED: Phthalate subtypes, sources of phthalate exposure, mechanisms of phthalate toxicity, associations between phthalate exposure and incidence of preterm birth, low birth weight, fetal growth, gestational diabetes, and placental development. EXPERT OPINION: There is robust evidence to link exposure to phthalates in medical products including preterm birth, gestational diabetes, pregnancy-induced hypertension, and miscarriage. Nevertheless, future studies need to address standardization to avoid the heterogeneity of current studies. In future, the use of naturally occurring biopolymers may be safer, and the role of vitamin D as an immune modulator also has promise.

Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis.

BACKGROUND: Bacterial vaginosis (BV) increases preterm delivery (PTD) risk, but treatment trials showed mixed results in preventing PTD. OBJECTIVES: Determine, using individual participant data (IPD), whether BV treatment during pregnancy reduced PTD or prolonged time-to-delivery. DATA SOURCES: Cochrane Systematic Review (2013), MEDLINE, EMBASE, journal searches, and searches (January 2013-September 2022) ("bacterial vaginosis AND pregnancy") of (i) clinicaltrials.gov; (ii) Cochrane Central Register of Controlled Trials; (iii) World Health Organization International Clinical Trials Registry Platform Portal; and (iv) Web of Science ("bacterial vaginosis"). STUDY SELECTION AND DATA EXTRACTION: Studies randomising asymptomatic pregnant individuals with BV to antibiotics or control, measuring delivery gestation. Extraction was from original data files. Bias risk was assessed using the Cochrane tool. Analysis used "one-step" logistic and Cox random effect models, adjusting gestation at randomisation and PTD history; heterogeneity by I2 . Subgroup analysis tested interactions with treatment. In sensitivity analyses, studies not providing IPD were incorporated by "multiple random-donor hot-deck" imputation, using IPD studies as donors. RESULTS: There were 121 references (96 studies) with 23 eligible trials (11,979 participants); 13 studies (6915 participants) provided IPD; 12 (6115) were incorporated. Results from 9 (4887 participants) not providing IPD were imputed. Odds ratios for PTD for metronidazole and clindamycin versus placebo were 1.00 (95% CI 0.84, 1.17), I2  = 62%, and 0.59 (95% CI 0.42, 0.82), I2  = 0 before; and 0.95 (95% CI 0.81, 1.11), I2  = 59%, and 0.90 (95% CI: 0.72, 1.12), I2  = 0, after imputation. Time-to-delivery did not differ from null with either treatment. Including imputed IPD, there was no evidence that either drug was more effective when administered earlier, or among those with a PTD history. CONCLUSIONS: Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation.

The contribution of bacteriophages to the aetiology and treatment of the bacterial vaginosis syndrome.

Bacteriophages are obligate intracellular viruses that parasitize bacteria, making use of the host biosynthetic machinery. Bacterial vaginosis (BV) causes serious adverse sequelae, such as sexually transmitted infections, seroconversion to HIV positivity, and preterm birth. The aetiology of BV is multifactorial, and the vaginal microbiota, the response to antibiotics, and the phenotypic outcomes differ between cases. The choice of antibiotics to treat BV depends on the clinician's personal experience, which contributes to the poor outcome of BV treatment and high recurrence rate. In this review, we classify BV into two subtypes based on whether or not the BV case is sexually associated (potentially phage-related). An appropriate antibiotic can be selected on the basis of this BV-typing to optimise the short- and long-term effects of treatment. Not all Lactobacillus spp. are helpful or protective and some may sequestrate metronidazole, which mitigates its therapeutic efficacy. Phages, used therapeutically, could contribute to eubiosis by sparing beneficial species of Lactobacilli. However, Lactobacilli have an important role in maintaining vaginal eubiosis, so conventional wisdom has been that treatment of BV may benefit from metronidazole that conserves lactobacilli rather than clindamycin, which destroys lactobacilli. Furthermore, if the quality and quantity of vaginal lactobacilli are compromised by phage colonisation, as in the sexually transmitted subtype, eradication of lactobacilli with clindamycin followed by replacement by probiotics may be better therapeutically than metronidazole and reduce recurrence rates. Accordingly, the subtype of BV may provide a more scientific approach to antibiotic selection, which is absent in current clinical guidelines. We provide support for the role of bacteriophages in the aetiology, recurrence or failure to cure BV following treatment, through parasitic colonisation of lactobacilli that may be sexually transmitted and may be enhanced by other risk factors like smoking, a factor associated with BV.

Genital Mycoplasmas and Biomarkers of Inflammation and Their Association With Spontaneous Preterm Birth and Preterm Prelabor Rupture of Membranes: A Systematic Review and Meta-Analysis.

Genital mycoplasmas (GM), such as Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma parvum, and Ureaplasma urealyticum are commonly associated with spontaneous preterm labor (SPTL), spontaneous preterm birth (PTB), and preterm prelabor rupture of membranes (PPROM). This study determined the association between GM and such adverse pregnancy outcomes. We searched for studies published 1980-2019 in MEDLINE, EMBASE, and Web of Science. Studies were eligible when GM was detected during pregnancy. We included 93 and 51 studies in determining the prevalence and the inflammatory biomarkers associated with GM, respectively, using the "metafor" package within R. The protocol was registered with PROSPERO (registration no. CRD42016047297). Women with the studied adverse pregnancy outcomes had significantly higher odds of presence with GM compared to women who delivered at term. For PTB, the odds ratios were: M. hominis (OR: 2.25; CI: 1.35-3.75; I 2: 44%), M. genitalium (OR: 2.04; CIL 1.18-3.53; I 2: 20%), U. parvum (OR: 1.75; CI: 1.47-2.07; I 2: 0%), U. urealyticum (OR: 1.50; CI: 1.08-2.07; I 2: 58%). SPTL had significantly higher odds with M. hominis (OR: 1.96; CI: 1.19-3.23; I 2: 1%) or U. urealyticum (OR: 2.37; CI: 1.20-4.70; I 2: 76%) compared to women without SPTL. Women with PPROM had significantly higher odds with M. hominis (OR: 2.09; CI: 1.42-3.08; I 2: 0%) than women without PPROM. However, our subgroup analysis based on the diagnostic test and the sample used for detecting GM showed a higher prevalence of GM in maternal samples than in fetal samples. GM presence of the cervix and vagina was associated with lower odds of PTB and preterm labor (PTL). In contrast, GM presence in the AF, fetal membrane, and placenta was associated with increased odds of PTB and PTL. However, genital mycoplasmas may not elicit the massive inflammation required to trigger PTB. In conclusion, GM presence in the fetal tissues was associated with significantly increased odds of PTB and PTL.

Developing an algorithm for the diagnosis of abnormal vaginal discharge in a dutch clinical setting: a pilot study.

Abnormal vaginal discharge may be caused by bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis and/or aerobic vaginitis. For the development of a diagnostic algorithm, tree-based classification analysis was performed on symptoms, signs and bedside test results of 56 patients, and laboratory tests (culture, Nugent score, qPCRs) were compared. Amplicon sequencing of the 16S rRNA gene was used as reference test for bacterial vaginosis and aerobic vaginitis, culture for vulvovaginal candidiasis and qPCR for trichomoniasis. For bacterial vaginosis, the best diagnostic algorithm was to screen at the bedside with a pH and odour test and if positive, to confirm by qPCR (sensitivity 94%; specificity 97%) rather than Nugent score (sensitivity of 59%; specificity 97%; P = 0.031). The analysis for the other infections was less conclusive due to the low number of patients with these infections. For bacterial vaginosis, the developed algorithm is sensitive, specific, and reduces the need for laboratory tests in 50% of the patients.

Prevention of preterm birth: Proactive and reactive clinical practice-are we on the right track?

Preterm birth remains the major cause of death and disability among children under the age of five. In developing countries antenatal preterm birth prevention clinics are set up to provide cervical length surveillance and/or treatment modalities such as cerclage or progesterone for those women with identified risk factors such as previous cervical treatment or preterm birth. However, 85% of women have no risk factors for PTB and currently there is no biomarker to screen women early in pregnancy. Women will present unexpectedly in threatened preterm labour and we have no choice but to adopt a re-active approach to their care by using predication and preparation strategies such as fetal fibronectin, tocolytic therapy and steroids. Despite these strategies approximately 15-20% of these women will give birth preterm before 34 weeks. There is a urgent need to re-design primary, secondary and tertiary prevention strategies for spontaneous preterm labour (sPTL) in singleton pregnancies aimed at identifying and addressing key gaps in clinical practice and research.

Childhood inflammatory and metabolic disease following exposure to antibiotics in pregnancy, antenatally, intrapartum and neonatally.

Background: There are concerns that the use of antibiotics before, during or immediately after pregnancy may have adverse effects on the neonatal gut microbiome and adversely affect the development of the infant immune system, leading to the development of childhood allergy, asthma, atopic disease and obesity. Methods: In this narrative review, we have explored a number of hypotheses, including the "Barker hypothesis", the "hygiene hypothesis", the link between inflammation and metabolic disease, and the influence of the neonatal gut microbiota on the development of the immune system in infants. Results: We found evidence to link the use of antibiotics before, during or immediately after pregnancy with an increased risk of childhood allergy, asthma, atopy and obesity. Conclusions: Although we found robust evidence to link antibiotic use in pregnancy with obesity and an "allergic triad" of asthma, eczema and hay fever, care must be taken when interpreting the findings because of the lack of adjustment for confounding variables in published studies. These may be (i) whether or not the mother had the same outcome variable (for example, asthma) as the infant, for which the mother may have received the antibiotics; (ii) the indication, timing or number of antibiotic courses given; (iii) the use of broad-spectrum or narrow-range antibiotics; (iv) the dose-dependent nature of the effector; and (v) the class of antibiotics used.

Recent advances in cultivation-independent molecular-based techniques for the characterization of vaginal eubiosis and dysbiosis.

"The bacterial vaginosis syndrome" has significant adverse effects for women and babies, including preterm birth and increased risk of acquisition of sexually transmitted infections and HIV. Currently, the gold standard for diagnosis is Gram stain microscopy of vaginal secretions, which is not readily available, is somewhat subjective, and does not differentiate between the likely different subtypes of vaginal dysbioses that may have different etiologies, microbiology, responses to antibiotics, and phenotypic outcomes. With new information from molecular-based, cultivation-independent studies, there is increasing interest in the use of molecular techniques for the diagnosis of bacterial vaginosis. We reviewed the current evidence on and the rationale behind the use of molecular techniques for the diagnosis of bacterial vaginosis. We found a number of commercially available molecular diagnostic tests, a few of which have US Food and Drug Administration (FDA) and/or Conformité Européenne in vitro diagnostic (CE-IVD) approval, and we have compared their performance with respect to sensitivities and specificities. Molecular-based tests have the advantage of objectivity, quantification, detection of fastidious organisms, and validity for self-obtained vaginal swabs. The performance of the molecular tests against standard microscopy is impressive, but further education of users on interpretation is needed. Bacterial vaginosis is the major cause of vaginal dysbiosis and should be recognized for the threat it is to women's genital tract health. Quantitative assessment of microbial abundance, the diversity of other organisms present, specific primers for gene sequence regions, and clades and biovars of target microbes should be recognized and incorporated into future molecular diagnostic tests to better differentiate between vaginal eubiosis and dysbiosis.

The influence of the vaginal microbiota on preterm birth: A systematic review and recommendations for a minimum dataset for future research.

OBJECTIVE: This systematic review aims to identify, critically appraise and summarize the results of studies examining the relationship between the vaginal microbiota and preterm birth (PTB). METHODS: We searched the electronic databases Medline, EMBASE and the Cochrane Controlled Register of Trials for studies in any language reporting on vaginal microbiota and PTB published from 1990 to November 29th, 2017. We included any study that performed lower genital tract microbiota assessment in asymptomatic pregnant women and reported on spontaneous preterm birth, with either intact or ruptured membranes. RESULTS: The search strategy yielded 2171 unique citations, of which nine studies were eligible for inclusion in this review. In six studies an association was found between the composition of the vaginal microbiota and PTB, but findings differed between subgroups, ethnicities and degree of risk of PTB. In three studies no association was found. Two of these studies found a significant difference in richness and Shannon diversity between term and PTB. CONCLUSIONS: We have demonstrated that there is a paucity of molecular based, culture-independent studies that analyse the relationship between the vaginal microbiota and PTB as an outcome. The heterogeneity precluded a meta-analysis. Studies provide contradictory evidence and the quality of the clinical information in the studies is poor. To improve quality of future studies we have provided a database of essential and desirable items of quality that are method and topic specific.

Spontaneous preterm labour that leads to preterm birth: An update and personal reflection.

OBJECTIVE: The objective was to provide an update of progress made over time (including personal reflection) of our attempts to reduce the mortality and morbidity associated with spontaneous preterm labour that leads to preterm birth. METHODS: An experienced and evidence based approach was taken to provide an overview of progress made over a generation (∼40 years) in our understanding of spontaneous preterm labour. RESULTS: It is evident that we have made significant progress in our understanding of the aetiology, the measurement of the burden, the basic science, systems biology and mechanical pathways of the preterm parturition syndrome. We have better ways of predicting, preventing and managing spontaneous preterm labour than existed a generation ago. CONCLUSIONS: The profile of spontaneous preterm labour that leads to preterm birth, thanks to organisations such as the March of Dimes, WHO and PREBIC is much more evident than before. However, while we have come a long way, we must not be complacent, and clinicians and basic scientists must continue to work in harmony, while recruiting and encouraging young investigators to join the effort to improve survival and handicap in what is one of the Great Obstetric Syndromes.

Safety and Efficacy of Tocolytics for the Treatment of Spontaneous Preterm Labour.

BACKGROUND: Preterm birth is the major cause of perinatal mortality and morbidity worldwide. Attempts to reduce the burden may be proactive using biochemical or biophysical prediction and preventative measures. If these efforts fail, then the approach may have to be reactive using tocolytics to inhibit spontaneous preterm labour. OBJECTIVE: We have reviewed the evidence concerning the safety and efficacy of various classes of tocolytic agents. RESULTS: The evidence to support the use of magnesium sulfate or nitric oxide donors as a tocolytic is poor. Compared to placebo or no treatment, there is evidence to support the efficacy of calcium channel blockers (mainly nifedipine), prostaglandin synthetase inhibitors (mainly indomethacin and sulindac), oxytocin receptor antagonists (mainly atosiban) and ß2-agonists (mainly ritodrine, terbutaline, salbutamol and fenoterol). Maternal safety concerns have reduced the use of ß2-agonists. Fetal safety and gestational age restrictions have largely condemned prostaglandin synthetase inhibitors to second-line therapy. First-line therapy in Europe and other parts of the world outside the USA and Australia is limited to calcium channel blockers and oxytocin receptor antagonists. With respect to efficacy, atosiban and nifedipine are similar, but the robustness of the evidence favours atosiban. With respect to safety, atosiban is clearly the safest tocolytic as there are fetomaternal concerns with nifedipine, particularly in high daily doses. CONCLUSION: The perfect tocolytic that is uniformly effective and safe does not exist. Cost, licensing and informed consent are considerations involved in the choice. Efforts continue to develop and introduce other or better agents, including novel compounds such as progesterone, PGF2α antagonists and statins.

Comparison of Amsel criteria, Nugent score, culture and two CE-IVD marked quantitative real-time PCRs with microbiota analysis for the diagnosis of bacterial vaginosis.

Bacterial vaginosis (BV) is a common gynaecological condition. Diagnosis of BV is typically based on Amsel criteria, Nugent score and/or bacterial culture. In this study, these conventional methods and two CE-IVD marked quantitative real-time (q)PCR assays were compared with microbiota analysis for the diagnosis of BV. Eighty women were evaluated for BV during two sequential hospital visits by Amsel criteria, Nugent score, culture, the AmpliSens® Florocenosis/Bacterial vaginosis-FRT PCR kit (InterLabService, Moscow, Russia), and the BD MAX™ Vaginal Panel (BD Diagnostics, MD, USA). Microbiota analysis based on amplicon sequencing of the 16S ribosomal RNA gene was used as reference test. The microbiota profile of 36/115 (31%) included cases was associated with BV. Based on microbiota analysis, the sensitivity of detecting BV was 38.9% for culture, 61.15% for Amsel criteria, 63.9% for Nugent score and the BD MAX assay, and 80.6% for the AmpliSens assay, while the specificity of all methods was ≥ 92.4%. Microbiota profiles of the cases with discrepant results between microbiota analysis and the diagnostic methods were variable. All five diagnostic methods missed BV positive cases with a relatively high abundance of the genus Alloscardovia, Bifidobacterium, or Dialister, which were categorised as unspecified dysbiosis by the AmpliSens assay. Compared to Amsel criteria, Nugent score, culture, and the BD MAX assay, the AmpliSens assay was most in agreement with microbiota analysis, indicating that currently, the AmpliSens assay may be the best diagnostic method available to diagnose BV in a routine clinical setting.

The role of antimicrobial treatment during pregnancy on the neonatal gut microbiome and the development of atopy, asthma, allergy and obesity in childhood.

INTRODUCTION: The use of antibiotics prenatally, during pregnancy, or neonatally may have adverse effects on the neonatal gut microbiome, and adversely affect the development of the infant immune system, leading to childhood atopy, asthma, allergy and obesity. AREAS COVERED: Vaginal eubiosis and dysbiosis from molecular-based, cultivation-independent techniques, and how this affects the neonatal gut microbiome and early development of the immune system, the association between maternal antibiotics and the beneficial role of vitamin D in the development of atopy, asthma, allergy and obesity, efforts to reduce the use of antibiotics in pregnancy and therapeutic interventions such as vaginal 'seeding', probiotics, breastfeeding and neonatal dietary supplementation. EXPERT OPINION: Currently available research gives insufficient attention to confounding variables. There remains uncertainty as to whether it is relevant that the mother suffered from the same condition as the purported infant outcome variable, for which she may have received antibiotics. In most studies, there is a lack of control for the number of antibiotic courses administered, the timing of use, the use of broad spectrum or narrow range antibiotics, the indication for antibiotics, the dose-dependent nature of the effect, the class of antibiotics used, or a varying degree of risk.