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Highlights • largest monocentric cohort study on metformin safety during the first trimester. • 336 pregnancies with metformin exposure and 1011 matched controls. • no increase in major birth defects and spontaneous abortions. • no distinct pattern of major birth defects. Abstract The aim of this study was to evaluate the risk of major birth defects and spontaneous abortion after metformin use during the first trimester of pregnancy. We conducted an observational cohort study comparing pregnancies with metformin treatment during the first trimester with non-exposed women matched for BMI and year of enrolment. Pregnancies were prospectively ascertained in the German Embryotox pharmacovigilance database between 2004 and 2014. The study sample included 336 pregnancies with metformin exposure for PCOS and fertility disorders (56.8%), diabetes (25.9%) and insulin resistance (14.9%) and 1011 matched controls. Independent of the treatment indication, neither the rate of major birth defects (OR adjusted 0.58, 95% CI 0.3–1.3) nor of spontaneous abortions (HR adjusted 0.95, 95% CI 0.6–1.5) was significantly increased among metformin exposed. Our study supports the evidence that metformin does not carry a developmental risk for the fetus when used during the first trimester. [ABSTRACT FROM AUTHOR]

Studies of the effects on pregnancy outcomes of in utero exposure to phthalates, contaminants that are widely present in the environment, have yielded conflicting results. In addition, the mode of assessment of exposure varies between studies. The aim of this review was therefore to establish a current state of knowledge of the phthalates and metabolites involved in unfavorable pregnancy outcomes. Extant data were analyzed to determine which biomarker is the best suited to assess the relation between in utero exposure to phthalates and pregnancy outcomes. This review of the literature was conducted using the database of PubMed. A search was made of studies investigating exposure to phthalates and the following birth outcomes: preterm birth (gestational age < 37 weeks), change in gestational age, change in body size at birth (birth weight, length, head circumference), anti-androgenic function, decreased anogenital distance, cryptorchidism, hypospadias and congenital malformation. The methodological approach adopted in each study was examined, in particular the methods used for exposure assessment (biomarkers and/or questionnaire). Thirty-five studies were included. Premature birth and decreased anogenital distance were the most commonly reported outcomes resulting from a moderate level of exposure to phthalates. The principal metabolites detected and involved were primary metabolites of di-2(ethylhexyl)-phthalate (DEHP) and di- n -butyl-phthalate (DnBP). No clear conclusion could be drawn with regard to gestational age at birth, body size at birth and congenital malformations. In epidemiological studies, maternal urine is the most suitable matrix to assess the association between in utero exposure to phthalates and pregnancy outcomes: in contrast to other matrices (cord blood, amniotic fluid, meconium and milk), sampling is easy, non-invasive and, can be repeated to assess exposure throughout pregnancy. Oxidative metabolites are the most relevant biomarkers since they are not prone to external contamination. Further epidemiological studies are required during pregnancy to i) determine the role of phthalates other than DEHP [currently replaced by various substitution products, in particular diisononyl-phthalate (DiNP)]; ii) establish the effect of phthalates on other outcomes (body size adjusted for gestational age, and congenital malformations); iii) determine the pathophysiological pathways; and iv) identify the most suitable time for biomarker determination of in utero exposure to phthalates. [ABSTRACT FROM AUTHOR]

Extensive research defines the impact of advanced maternal age on couples' fecundity and reproductive outcomes, but significantly less research has been focused on understanding the impact of advanced paternal age. Yet it is increasingly common for couples at advanced ages to conceive children. Limited research suggests that the importance of paternal age is significantly less than that of maternal age, but advanced age of the father is implicated in a variety of conditions affecting the offspring. This review examines three aspects of advanced paternal age: the potential problems with conception and pregnancy that couples with advanced paternal age may encounter, the concept of discussing a limit to paternal age in a clinical setting, and the risks of diseases associated with advanced paternal age. As paternal age increases, it presents no absolute barrier to conception, but it does present greater risks and complications. The current body of knowledge does not justify dissuading older men from trying to initiate a pregnancy, but the medical community must do a better job of communicating to couples the current understanding of the risks of conception with advanced paternal age. [ABSTRACT FROM AUTHOR]

After kidney transplantation (KT), pregnancy is possible, although the risk of maternal and fetal complications is much higher than in the general population. Outcome of 22 pregnancies in 17 patients transplanted in the Gdańsk center in the period 1980–2012 was studied. Mean maternal age at pregnancy was 30 ± 5 (range, 23–39) years, interval between transplantation and conception 3.4 ± 2.5 (range, 0.6–11) years. Mean creatinine concentration before conception was 1.29 ± 0.36 (range, 0.8–2.45) mg/dL and was stable during 1 year preceding pregnancy (mean increase, 0.01 mg/dL). Nine of the 17 patients received 1 and 4 received ≥2 antihypertensive drugs, and 1 had proteinuria. Twelve of the 17 patients were primagravidas, 1 was pregnant 3 times, and 14 times. At the time of conception, 20 patients received CNI (14 cyclosporine, 6 tacrolimus), 15 antimetabolites (3 mycophenolate mofetil [MMF], 12 azathioprine), 1 mammalian target of rapamycin inhibitor (mTORi; sirolimus), and all prednisone. MMF and mTORi were discontinued before or during the 1st weeks of pregnancy. Maternal outcome: all survived the pregnancy. None experienced rejection or graft loss as a direct result of pregnancy. Maternal complications included edema (5/17), worsening of blood pressure control (5/17), and worsening (1/17) or new onset of proteinuria (2/17). Mean creatinine decrease during pregnancy was 0.06 mg/dL. Mean creatinine 1 year after pregnancy was 1.49 ± 0.53 mg/dL. There were 12 cesarean sections. Fetal outcomes: 17 live births (2 with serious congenital defects), 2 spontaneous and 1 induced abortion, 2 stillbirths. Mean pregnancy age and neonate birth weights were 35 ± 4 (range, 23–39) weeks and 2,552 ± 629 (range, 1,480–3,420) g, respectively. During mean 8.5 (range, 1–25) years of follow-up after pregnancy, 4/17 patients lost grafts. Grafts were lost in the 3rd to 7th years after pregnancy. We conclude that pregnancy does not exert a direct negative influence on patient and graft survivals; 68% of all pregnancies resulted in delivering healthy neonates. [ABSTRACT FROM AUTHOR]

The current body of literature concerning cervical conization and its effect on subsequent pregnancy outcome is conflicting. Depending on the type of conization procedure that is examined and the quality of the control group, the results and conclusions vary widely. Because treatment for cervical intraepithelial neoplasia is commonplace among women of reproductive age, it is imperative that practitioners have an understanding of the issues surrounding the treatment. Therefore, this review will summarize the published literature that addresses excisional procedures of the uterine cervix and the risk of preterm delivery in subsequent pregnancies and provide reasonable treatment recommendations for women with cervical abnormalities and a desire for future fertility. [ABSTRACT FROM AUTHOR]

Abstract: Toxic heavy metals are released to the environment constantly from unregulated electronic waste (e-waste) recycling in Guiyu, China, and thus may contribute to the elevation of lead and other heavy metals levels in placenta. We aimed to investigate concentrations of heavy metals, including lead (Pb), cadmium (Cd), chromium (Cr), and nickel (Ni) in placenta from Guiyu and compared them with those from a control area where no e-waste processing occurs. Two hundred and twenty human placentas were collected from Guiyu (n =101) and the control area (n =119). The placenta concentrations of Pb, Cd, Cr, and Ni (PCPb, PCCd, PCCr, and PCNi) were determined by graphite furnace atomic absorption spectrometry (GFAAS). Risk factors of high exposure and correlation with adverse pregnancy outcomes were analyzed using Spearman correlation analyses. PCPb from Guiyu ranged from 6.51 to 3465.16ng/g with a median of 301.43ng/g, whereas PCPb from the control area ranged from 4.53 to 3176.12ng/g with a median of 165.82ng/g (P =0.010). We also observed that in Guiyu, 41.6% of women (42/101) had PCPb>500ng/gwt (wet weight), compared with 24.4% of women (29/119) in the control area (P =0.006). No significant differences of PCCd and PCCr were found between the two groups. In contrast, PCNi was higher in samples from the control area (median 14.30, range 1.76–593.70ng/g) than in Guiyu samples (median 7.64, range 1.19–1108.99ng/g) (P =0.000), and a negative correlation between PCNi and gestational age was found in this study (P =0.017). Spearman correlation analyses showed that there was correlation between PCPb and residence in e-waste recycling area. Environmental pollution, resulted from unregulated e-waste recycling activities, may contribute to elevated PCPb in neonates born in Guiyu and threaten their health. [Copyright &y& Elsevier]

Abstract: Objective: We conducted a meta-analysis of all published data in order to evaluate the risk for birth defects, stillbirths, preterm births and low birth weight following exposure to quinolones in the first trimester of pregnancy. Study design: Medline, Embase, Scopus, Biological Abstracts and Proquest Thesis Dissertation databases were searched. Other papers and abstracts were located from the retrieved articles’ references, meeting booklets, internet web sites and books on teratology. Results: Five studies met the inclusion criteria. The summary odds ratio for all the included studies was 1.05 (95% CI 0.90–1.22) for major malformations, 2.6 (95% CI 0.36–18.67) for stillbirths, 1.15 (95% CI 0.69–1.91) for preterm births and 0.73 (95% CI 0.30–1.79) for low birth weight. In an additional analysis including only fluoroquinolones (nalidixic acid was removed), the summary odds ratio for major malformations remained non-significant (1.11, 95% CI 0.57–2.15). Conclusions: The use of quinolones during the first trimester of pregnancy does not appear to represent an increased risk for major malformations recognized after birth, stillbirths, preterm births or low birth weight. [Copyright &y& Elsevier]

Objective: To define specific features of follow-up in pregnant women with gastric banding in order to evaluate obstetrical outcomes and gastric banding related complications. Materials and methods: A systematic review of observational and case-control studies, as well as case reports to discuss pregnant women follow-up. Results: Seven articles were retained. Doctors manage differently gastric banding. With gastric banding, there is a better maternal weight gain control and less hypertension and diabetic complications. We found four gastric banding related complications. Discussion and conclusion: Gastric banding is well tolerated during pregnancy and can be safely recommended to obese women of childbearing age. [Copyright &y& Elsevier]

Introduction: The albumin:creatinine ratio (ACr) is the newest of available methods of proteinuria assessment in pregnancy. Published cut-offs for detection of ⩾0.3g/d proteinuria vary from 2mg/mmol to 8mg/mmol. Up to 20% of women have an elevated ACr in pregnancy but normal outcome. In addition, it is our impression that the urine albumin component of the ACr is frequently below the detection limit of the assay. Objectives: To evaluate the frequency with which a measurable ACr can be obtained in a high-risk outpatient maternity population. Methods: In this prospective cohort study, consecutive inpatients or outpatients (attending primarily morning high-risk maternity clinics) were evaluated at a tertiary care facility. Random midstream urine samples were obtained as part of normal clinical care. In the hospital laboratory, urinary albumin was measured using an immunoturbidimetric method, and urinary creatinine by an enzymatic method, both on an automated analyser (Vitros® 5,1 FS or Vitros® 5600, Ortho-Clinical Diagnostics, Rochester NY). ACr was calculated for samples with measurable urine albumin, and for samples with albumin below the assay range, ACr was calculated using the assay cut-off for albumin of 6.00mg/L. Results: One hundred and sixty women (81.9% outpatients) were screened at one/more antenatal visits, providing a total of 233 urine samples for analysis. 68 (29.2%) urine samples were dilute (i.e., had urinary creatinine <3mM); only 13 (19.1%) of these had measurable urinary albumin for calculation of the ACr. Overall, 117/233 samples (50.2%) had measurable urine albumin that could be used to calculate the ACr. 76 (65.0%) had ACr >2mg/mmol and 34 (29.1%) had ACr >8mg/mmol. For the 116/233 (49.8%) samples with urine albumin below the assay detection limit, ACr was calculated using 6.00mg/L as the value for urine albumin. All of the 55 dilute samples had an ACr >2mg/mmol and 3 (2.6%) had an ACr >8mg/mmol. If dilute samples were excluded, none of the remaining 61 samples had an ACr value >2mg/mmol. Conclusion: Among a population of pregnant women attending primarily morning high-risk maternity clinics, urine is often dilute and urine albumin is often below the assay detection limit. This combination may result in uninterpretable ACr values if an ACr cut-off of 2mg/mmol is used as the decision limit for proteinuria ⩾0.3g/d. ACr may be best performed on first voided (concentrated) urine if ACr is used to assess proteinuria in pregnancy. [Copyright &y& Elsevier]

Background: It is unclear whether a neonatal or a fetal growth standard is a better predictor of adverse in-hospital newborn infant outcomes.Objective: We aimed to evaluate and compare the power of birthweight for gestational age to predict adverse neonatal outcomes using neonatal and fetal growth charts. Gestational age-specific birthweight was examined either as a percentile score or as a binary indicator for birthweight <10th percentile (small for gestational age) with the use of 3 fetal growth charts (National Institute of Child Health and Human Development, World Health Organization, and Intergrowth-21st) and 1 neonatal sex-specific birthweight chart.Study Design: Inborn singleton infants from 2006-2014 with gestational age between 22 and 29 weeks and who were enrolled at 1 of the 852 US centers that were participating in the Vermont Oxford Network were studied. Outcomes included death, necrotizing enterocolitis, severe intraventricular hemorrhage, severe retinopathy of prematurity, and chronic lung disease. Receiver operating characteristic curve analysis was used to assess the predictive power of birthweight for gestational age, either as a score or as a small-for-gestational-age indicator, with the use of the 4 charts. We also examined the relative risks of the outcomes by comparing small-for-gestational-age and non-small-for-gestational-age infants with the use of the 4 charts.Results: The percentage of small-for-gestational-age newborn infants ranged from 25.9-29.7% when with used the fetal growth charts. In contrast, the percentage was 10% when we used the neonatal charts. The areas under the receiver operating characteristic curves were similar across the 4 classification methods and were all <0.60, which suggests a poor predictive power. Small-for-gestational-age status, as classified by the neonatal chart, showed stronger associations with death, necrotizing enterocolitis, severe retinopathy of prematurity, and chronic lung disease, compared with those associations that were based on the other classification methods.Conclusion: Neither the neonatal nor the fetal growth charts are predictive of adverse infant in-hospital outcomes. In contrast to fetal charts, the use of the neonatal charts results in stronger associations between small-for-gestational-age and adverse outcomes. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to describe the risk of adverse obstetric and neonatal outcome after bariatric surgery. Study Design: Nationwide register-based matched cohort study of singleton deliveries after bariatric surgery during 2004-2010. Data were extracted from The Danish National Patient Registry and The Medical Birth Register. Each woman with bariatric surgery (exposed) was individually matched with 4 women without bariatric surgery (unexposed) on body mass index, age, parity, and date of delivery. Continuous variables were analyzed with the paired t test and binary outcomes were analyzed by logistic regression. Results: We identified 339 women with a singleton delivery after bariatric surgery (84.4% gastric bypass). They were matched to 1277 unexposed women. Infants in the exposed group had shorter mean gestational age (274 vs 278 days; P < .001), lower mean birthweight (3312 vs 3585 g; P < .001), lower risk of being large for gestational age (adjusted odds ratio, 0.31; 95% confidence interval, 0.15–0.65), and higher risk of being small for gestational age (SGA) (adjusted odds ratio, 2.29; 95% confidence interval, 1.32–3.96) compared with infants in the unexposed group. No statistically significant difference was found between the groups regarding the risk of gestational diabetes mellitus, preeclampsia, labor induction, cesarean section, postpartum hemorrhage, Apgar score less than 7, admission to neonatal intensive care unit or perinatal death. Conclusion: Infants born after maternal bariatric surgery have lower birthweight, lower gestational age, 3.3-times lower risk of large for gestational age, and 2.3-times higher risk of SGA than infants born by a matched group of women without bariatric surgery. The impact on SGA was even higher in the subgroup with gastric bypass. [ABSTRACT FROM AUTHOR]

Introduction: High prevalence of pre-pregnancy weight excess, as well as evidence of increased risk of maternal and perinatal complications associated with nutritional states have been observed lately. Considering the possible ethnic and environmental influences few studies have assessed this risk in pregnant Brazilian women. Objectives: This study aimed at determining the prevalence of pre-pregnancy weight excess (overweight and obesity) and its association with maternal and perinatal complications in a Brazilian women population. Methods: We conducted a prospective cross-sectional study with 3,300 women who had birth care at the Asa Sul Regional Hospital of Brasília – Federal District (FD), from October 2009 to May 2010. Nutritional status was determined by body mass index (BMI), according to WHO criteria (2000): Low weight (BMI<18.5kg/m2), Normal weight (BMI between 18.5 and 24.9kg/m2), Weight excess (BMI⩾25kg/m2), Overweight (BMI between 25 and 29.9kg/m2) and obesity (BMI⩾30kg/m2). The outcome variables were: pre-clinical complications such as chronic hypertension and diabetes, manifestation of gestational hypertension/preeclampsia, pregnancy duration and resolution as well as perinatal outcomes. The association among these variables was assessed using chi-square (Pearson) and Fisher’s exact test. Results were considered significant when p <0.05. Results: In this population, weight excess before pregnancy had a prevalence of 27.2%, being 19.7% and 7.5% of pregnant women presenting, respectively, overweight and obesity. The prevalence of normal weight was 64.6% and low weight was 8.3%. Comparing the weight excess (BMI⩾25kg/m2) group with the normal weight group it was observed predominant hypertension (23% vs. 10%) and diabetes (10.1% vs. 3.6%), prolonged pregnancy (14.4% vs. 10.7%) and cesarean section rate (58.1% vs. 47.2%) in the weight excess group. Newborn weight equal to or greater than 4,000 g (9.5% vs. 4.5%) as well as fetal macrosomia (14.6% vs. 7.4%) also predominated in weight excess group. The comparison among the groups normal weight, overweight and obesity showed predominance of hypertension, diabetes cesarean section rate, newborns weight and fetal macrosomia in the obesity group. Conclusion: In the population analyzed, the prevalence of pre-pregnancy weight excess, particularly obesity, was high and associated with maternal and perinatal complications. Weight excess pre-pregnancy should be considered a risk to the pregnancy, demanding different obstetric care. Efforts should be made so that, in the pre-pregnancy period, women’s weight can be as close to the normal weight as possible. [Copyright &y& Elsevier]

Introduction: NO-donors reduce the impedance in uteroplacental vessels. Consequently Lees et al. pilot study demonstrated that transdermal nitroglycerin positively influences pregnancy outcome within a high-risk collective. Furthermore the NO-donor pentaerythriltetranitrate additionally expresses cell stabilizing effects in endothelial cells. Objectives: Hypothesizing an effect on endothelial health and uterine perfusion in pregnancies presented with pathological uterine perfusion at 20weeks of gestation we performed a randomized, prospective, and placebo-controlled, double-blind study implemented with the aim to investigate whether the oral NO-donor Pentalong® (PETN) is suitable as a prophylactic drug in abnormal placentation. Methods: We included 111 pregnancies presenting with abnormal placental perfusion (bilateral notch or mean RI >0.7) between the 19th and 24thweek of gestation (w.o.g.). Further risk factors (high-risk group: history of HELLP/preeclampsia/IUGR/IUFD/placental abruption, type I diabetes mellitus, hypertension, thrombosis/thrombophilia) were identified in 78 study participants. Fifty-four women received PETN 57 received placebo. Doppler velocimetry measurements of uteroplacental and fetal vessels and fetal growth scans were monitored biweekly with primary endpoints being the occurrence of preeclampsia, IUGR and/or premature birth. Results: Within the first week of intake, PETN improved uteroplacental perfusion significantly in comparison to placebo (mean PI 1.26±0.36 vs. 1.49±0.44; p< 0.01). Overall frequency of premature birth <32nd w.o.g.(4 vs. 12), IUGR <10th percentile (15 vs. 29) and preeclampsia (11 vs. 14) were reduced. Although reduction in preeclampsia was comparably low in those 25 patients developing preeclampsia the outcome was markedly improved in the PETN study group by reducing the frequency of IUGR (4 vs. 10), diagnosis of preeclampsia before 32 w.o.g. (3 vs. 7) and premature birth before 32 w.o.g. (1 vs. 6). Furthermore 4 fetal losses occurred in the study group all in the placebo group. Conclusion: NO-donors constitute an interesting option in the prophylaxis of adverse pregnancy outcome related to abnormal placentation. [Copyright &y& Elsevier]

Objective: This population-based study aimed to assess the relation between herpangina and adverse pregnancy outcomes: low birthweight (LBW), small for gestational age (SGA), and preterm delivery. Study Design: A total of 242 pregnant women who had singleton births and who visited ambulatory care centers for the treatment of herpangina were assessed, together with 1936 matched women as a comparison group. Conditional logistic regression analyses were performed to examine the risk of LBW, preterm birth, and SGA for mothers with herpangina and unaffected mothers. Results: Compared with pregnant women without herpangina, herpangina was associated with a 2.29- (95% confidence interval [CI], 1.42–3.69), 1.67- (95% CI, 1.04–2.68), and 1.63-fold (95% CI, 1.14–2.33) increased risk of having LBW, preterm, and SGA infants, respectively, after adjusting for family income and maternal and infant characteristics. Conclusion: Our findings highlight a significant potential risk posed by herpangina, a usually mild disease, among pregnant women. [Copyright &y& Elsevier]