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ABSTRACTIntroductionPhthalates 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 CoveredPhthalate 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 OpinionThere 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.

ABSTRACTIntroduction: 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.

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 β2-agonists (mainly ritodrine, terbutaline, salbutamol and fenoterol). Maternal safety concerns have reduced the use of β2-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.

ABSTRACTIntroduction: Preterm birth is the major cause of neonatal mortality and morbidity worldwide and a huge cost burden on healthcare. Between 22 and 26 completed weeks of gestation, for every day that delivery is delayed, survival increases by 3%.Areas covered: Following a systematic review of the literature, we have provided an overview of the use of tocolytics for the prevention of preterm birth and have examined the fetal and maternal adverse effects of the various tocolytic agents currently in use.Expert opinion: No tocolytic currently in use was developed specifically to treat preterm labour so most have multi-organ side effects. β2-agonists are relatively safe for the fetus but have rare and potentially serious maternal adverse effects. In contrast, prostaglandin synthetase inhibitors have potentially serious side effects for the fetus and neonate but have mild maternal gastrointestinal side effects. In Europe, the choice of first line therapy is either atosiban or nifedipine. The evidence base for atosiban is much more robust than for nifedipine. While their efficacy is similar, atosiban has placebo level side effects and is safer than nifedipine but is much more expensive.

ABSTRACTMillions of doses of HPV vaccine have been administered globally. Inadvertent administration of HPV vaccine during pregnancy occurs given that the main recipients of the vaccine are fertile young women, who might be unaware of their pregnancy at the time of their vaccination. To investigate the subject of HPV vaccine and pregnancy , the databases of PubMed and Embase were searched to find the relevant literature published in English within the last 10 y. Most of the evidence pertaining to fetal adverse events following HPV vaccination relates to spontaneous miscarriage. None of the relevant studies found any significantly increased rate of spontaneous abortion in the overall analyses. There was no indication of other HPV vaccine-associated adverse events in pregnancy or immediately post-conception.

Introduction:The extent of antibiotic use in pregnancy remains unknown but may occur in > 40% of pregnant women for various indications, at different gestational ages from different sources.Areas covered:Antibiotic resistance, alterations to the neonatal immune system causing allergy, asthma and atopic disease in later life and teratogenicity.Expert opinion:Although teratogenesis is not a major concern, it is important, and ignorance and complacency cast a long shadow. Robust evidence exists to guide clinicians in their choice of a safe agent with respect to teratogenicity. Antibiotic resistance is a major safety concern, and together with decreased research and development of new antibiotic agents, it has required legal initiatives to encourage Big Pharma to search for safe alternatives. New information from culture-independent, molecular-based techniques has resulted in a greater understanding of the adverse effects of antepartum/intrapartum antibiotics on the maternal vaginal microbiome and the neonatal gut microbiome. As this might adversely affect the development of the immature immune system and lead to asthma, allergy and atopic disease in later life, new research merits support in scrutinizing the safety of antibiotic use in pregnancy.

Introduction:Preterm birth is the major cause of perinatal mortality and morbidity in high-income countries. The etiology of preterm birth is multifactorial but there is overwhelming evidence to implicate infection as a major cause. Abnormal genital tract flora in early pregnancy is predictive of preterm birth so it is logical to consider the use of antibiotics for the prevention of preterm birth.Areas covered:Infection and antibiotics in the etiology, prediction and prevention of preterm birth.Expert opinion:Antibiotics for the prevention of preterm birth have addressed different risk groups, diagnostic methods, degrees of abnormal flora, antibiotic dose regimens, routes of administration, host susceptibilities, host response, gestational age at time of treatment, outcome parameters and definitions of success and outcomes. To address this confusion, a number of systematic reviews/meta-analyses have been conducted but none has simultaneously addressed the optimal choice of agent, patient and timing of intervention. We conclude that inappropriate antibiotics used in inappropriate women at inappropriately late gestations do not reduce preterm birth. Conversely, a focused systematic review/meta-analysis, which targeted the use of clindamycin before 22 weeks gestation, in women with objective evidence of abnormal genital tract flora, demonstrated that clindamycin produced a significant decrease in late miscarriage and preterm birth.

Vitamin D status (which is involved in glucose homeostasis) is related to gestational diabetes mellitus (GDM). GDM is characterized by increased resistance to and impaired secretion of insulin and results in higher risk of adverse pregnancy outcomes including operative delivery, macrosomia, shoulder dystocia and neonatal hypoglycemia. Women with GDM and their babies are at increased risk for developing type II diabetes.

Introduction:Nausea and vomiting in pregnancy remains the most common cause of hospitalization in the first half of pregnancy. Although the exact cause is largely unknown, an interaction of genetic, biological and psychological factors is plausible. An endocrine trigger for hyperemesis has been linked with both ovarian and placental hormones, but this association requires further clarification. The use of type-3 serotonin receptor antagonists is increasing but as yet there are no convincing data to demonstrate their superiority over the other antiemetics.Areas covered:A computerized search was conducted using PubMed, Embase, Cinahl, Lilacs, ISI Web of Science, the Cochrane Central Register of Controlled Trials (all from inception or 1960 to October 2010), and Research Registries of ongoing trials. The key words used were nausea, vomiting, emesis, hyperemesis gravidarum, morning sickness, pregnancy, pregnancy complications, treatment, efficacy, effectiveness, antiemetics, safety and teratogenesis.Expert opinion:The precise mechanism underlying hyperemesis gravidarum remains unclear, but appears to be multifactorial. As yet there is no evidence that any antiemetic class is superior to another with respect to effectiveness.

Background: Preterm birth is the major cause of perinatal mortality and morbidity in the developed world. Objective: The aim of this study was to establish the importance of preterm birth and the huge healthcare costs involved and review the pathophysiology of preterm labor and the use of antepartum glucocorticoids, which are the main reason why tocolytics are used to prevent or delay preterm birth. The study also reviewed the range of tocolytics available, their mode of action and the evidence for their efficacy and fetomaternal safety. Methods: An extensive review of the literature using well-recognized and accepted scientific search engines was employed. Results/conclusions: The perfect tocolytic does not exist. The evidence to support the use of magnesium sulfate as a tocolytic is poor. The use of β-agonists is decreasing worldwide as clinicians move to nifedipine or atosiban, which are as effective but much safer. Although nifedipine is cheaper than atosiban and can be administered orally, the evidence to support atosiban is much superior to that of nifedipine and there have been recent safety concerns over nifedipine.

Preterm birth is the major cause of neonatal mortality and morbidity in the developed world. The perfect tocolytic that is uniformly effective with complete fetomaternal safety does not exist. Tocolytic agents differ in cost, utero-specificity, safety, efficacy and whether they are licensed for use. The main three agents that are used worldwide are -agonists, Ca2+channel blockers and vasopressin/oxytocin receptor antagonists. -Agonists are gradually being phased out of use and are being replaced by either nifedipine or atosiban. The evidence base for atosiban is strong but the evidence is of poor quality for nifedipine. The balance of evidence indicates that atosiban is as effective as nifedipine and more effective than -agonists and is significantly safer than both. Atosiban was developed specifically to treat preterm labor, so the cost is higher than nifedipine or ritodrine. However, the cost of a course of atosiban (∼ £200) should not only be considered in comparison with other tocolytic agents but to other medical budgets (e.g., oncology, fertility, cardiology and psychiatry) and to the huge healthcare costs associated with the morbidity and mortality caused by preterm birth. Atosiban is a new advance in the management of spontaneous preterm labor.

Preterm birth (PTB) is the main cause of neonatal mortality and morbidity in the developed world. Historically, the approach for the prevention of PTB has been reactive rather than proactive. With the introduction of new screening tests and a greater emphasis on prevention rather than treatment, a number of new approaches have been introduced that show promise. Progesterone, which is responsible for myometrial quiescence in pregnancy and is used in women with a previous history of PTB, is associated with a significant reduction in the incidence of PTB and low birth weight. Infection is an important cause of PTB in ≤ 40% of women. The appropriate antibiotics administered early in pregnancy to women with abnormal genital tract flora have been associated with a 40 – 60% reduction in the incidence of PTB. Although there has been debate regarding the benefits of nutritional supplementation for the prevention of many complications of pregnancy, recent evidence suggests that fish oil supplementation can be shown to reduce the incidence of PTB in women at risk of PTB. Although these three proactive, preventative approaches show promise, further research is needed to establish the best agent, the optimum gestational age at commencement and cessation, the ideal candidate patient to achieve a response and the long-term feto–maternal benefits and/or side effects.

Objective: To develop a technique that would permit the identfication of dendritic cells (DC) in small volumes of preterm neonatal cord blood in order to investigate neonatal immune response in relation to infection and preterm labor.Methods: We used three-color flow cytometry and a fixed quantity of fluorospheres to determine absolute cell numbers. Four red cell lysis techniques, sample dilution, time delay experiments, and a comparison with traditional Ficoll cell separation techniques were performed. Absolute numbers of DC recovered using each technique were calculated and compared.Results: With increasing time delay, there was a statistically significant reduction in the numbers of leukocytes in adult blood. In contrast, there was a significant increase in leukocytes in umbilical cord blood. Sample dilution did not significantly affect the total number of leukocytes or DC. The use of the reagent Optilyse B (Immunotech, Oxford, UK) combined with an additional washing step produced the best discrimination of all populations based on light scatter properties. For the same blood sample, antibody labeling of whole blood resulted in a greater recovery of DC when compared to prior cell purfication using a Ficoll density gradient.Conclusion: Using traditional Ficoll cell separation, cell manipulation requires large volumes of blood and leads to cell loss and alteration in phenotype. We have validated a novel method using small volumes of whole blood, diluted if necessary, and using red cell lysis to enable analysis of small volumes of preterm neonatal cord blood. This may permit further analysis of the contribution of the fetal immune response in the development of spontaneous preterm labor and preterm birth due to infection.

Objective: TO develop a technique that would permit the identification of dendritic cells (DC) in small volumes of preterm neonatal cord blood in order to investigate neonatal immune response in relation to infection and preterm labor. Methods: We used three-color flow cytometry and a fixed quantity of fluorospheres to determine absolute cell numbers. Four red cell lysis techniques, sample dilution, time delay experiments, and a comparison with traditional Ficoll cell separation techniques were performed. Absolute numbers of DC recovered using each technique were calculated and compared. Results: With increasing time delay, there was a statistically significant reduction in the numbers of leukocytes in adult blood. In contrast, there was a significant increase in leukocytes in umbilical cord blood. Sample dilution did not significantly affect the total number of leukocytes or DC. The use of the reagent Optilyse B (Immunotech, Oxford, UK) combined with an additional washing step produced the best discrimination of all populations based on light scatter properties. For the same blood sample, antibody labeling of whole blood resulted in a greater recovery of DC when compared to prior cell purification using a Ficoll density gradient. Conclusion: Using traditional Ficoll cell separation, cell manipulation requires large volumes of blood and leads to cell loss and alteration in phenotype. We have validated a novel method using small volumes of whole blood, diluted if necessary, and using red cell lysis to enable analysis of small volumes of preterm neonatal cord blood. This may permit further analysis of the contribution of the fetal immune response in the development of spontaneous preterm labor and preterm birth due to infection.

Preterm birth is the major cause of neonatal mortality and morbidity. Infection is a major cause of preterm labour. Abnormal genital tract flora in early pregnancy is predictive of preterm labour. Antibiotics may be of help in preventing preterm birth.

To determine whether intravaginal clindamycin cream reduces the incidence of abnormal pregnancy outcome in women with abnormal vaginal microbial flora graded as intermediate or BV and to investigate the effect of the antibiotic on vaginal microbial flora. A prospective cohort study of pregnant women in an antenatal clinic of a district general hospital. The subjects were 268 women who had abnormal vaginal microbial flora at first clinic visit by examination of a Gram-stained vaginal smear and 34 women with a normal vaginal flora. Two hundred and thirty-seven women were evaluable. Women with abnormal Gram-stained smears (graded as II or III) on clinic recall were randomised to receive treatment (intravaginal clindamycin cream) or placebo and followed to assess outcome of pregnancy, vaginal flora, and detection of Mycoplasma hominis and Ureaplasma urealyticum after treatment. Abnormal outcomes of pregnancy were not significantly different in treated and placebo groups by Chi square (P = 0.2). However, women with grade III flora responded better to clindamycin than women with grade II flora by numbers of abnormal outcomes (P = 0.03) and return to normal vaginal flora (P = 0.01) (logistic regression analysis model). This may be due to differences in vaginal bacterial species in these grades. Women whose abnormal vaginal flora had spontaneously returned to normal on follow-up and were therefore not treated (revertants) had as many abnormal outcomes as placebos suggesting that damage by abnormal bacterial species occurred early in pregnancy. Gram-stain screening distinguishing grade II from grade III flora may be helpful in prescribing treatment other than clindamycin for women with grade II flora. Earlier diagnosis and treatment may be more effective in preventing an abnormal outcome, possibly as soon as pregnancy is diagnosed or even offered as a pre-conception screen. Infect. Dis. Obstet. Gynecol. 8:158–165, 2000. © 2000 Wiley-Liss, Inc.

OBJECTIVE:s To determine if the risks of perinatal mortality and antepartum stillbirth associated with post term birth increase earlier during pregnancy in South Asian and black women than in white women, and to investigate differences in the factors associated with antepartum stillbirth between the racial groups. Design Prospective study using logistic regression analysis. Setting 15 maternity units in northwest London from 1988 to 2000. Participants 197 061 nulliparous women self reported as white, South Asian, or black, who delivered a single baby weighing at least 500 g at 24-43 completed weeks' gestation. MAIN OUTCOME MEASURES: Gestation specific perinatal mortality, antepartum stillbirth rates, and independent factors for antepartum stillbirth by racial groups. RESULTS: The crude gestation specific perinatal mortality patterns for the three racial groups differed (P<0.001). The perinatal mortality rate among black women was lower than among white women before 32 weeks but was higher thereafter. Perinatal mortality was highest among South Asian women at all gestational ages and increased the fastest at term. After adjusting for the confounders of antepartum stillbirth (placental abruption, congenital abnormality, low birth weight, birth weight <10th centile, meconium passage, fever, maternal body mass index ≥30, and maternal age ≥30), the excess mortality among black women after 32 weeks was not significant. After adjusting for confounding, South Asian women still had a significantly higher risk of antepartum stillbirth (odds ratio 1.8, 95% confidence interval 1.2 to 2.7). CONCLUSIONS: The risk of perinatal mortality increased earlier in gestation among South Asian women than among white women. The most important factor associated with antepartum stillbirth among white women was placental abruption, but among South Asian and black women it was birth weight below 2000 g.