Distance In Newborns Research Articles

Prenatal exposure to common heavy metals is associated with anogenital distance in newborns

Prenatal exposure to common heavy metals is associated with anogenital distance in newborns

Association of prenatal exposure to heavy metal mixtures and anogenital distance in newborns

BACKGROUND AND AIMS: Although the association between prenatal exposure to multiple metals and newborns' anthropometrics has been extensively studied, little is known about the reproductive toxicity and the endocrine disturbance characteristics of these metals. Hence, this study aimed to investigate the associations between prenatal exposures to a wide scope of metals to newborn's anogenital distance, as a marker of endocrine disruptions. METHODS: We used data of 889 mother-infant pairs, from two major hospitals in Israel. Associations between eight metals (arsenic, cadmium, chromium, mercury, lead, nickel, selenium and thallium) detected in maternal urine samples from day of delivery to anogenital distance index (AGI) at birth were examined. Adjusted estimates were calculated separately for males and females, using single-exposure models, and weights-quantile sums (WQS) models accounting for metals mixtures. RESULTS: Females found more susceptible to prenatal metals exposure as their z-scaled anoclitoris distance index (AGIac) was positively associated to chromium (β = .158 [95%CI:.061–.256]), nickel (β = .083 [95%CI:.005–.161]) and thalium (β = .140 [95%CI:.022–.258]). Their Z-scaled anofourchette distance index was positively associated to nickel (β = .079 [95%CI:.001–.158]). Z-scaled anoscrotal distance index (AGIas) was the only measure found associated to exposure in the WQS models (β = -.329 [95%CI:-.629– -.030]) and was associated to nickel and selenium. In the single-exposure models, chromium found positively associated (β = .111 [95%CI:.017–.206]) to the Z-scored anoscrotal distance index (AGIas) among males. CONCLUSIONS: The results suggest prenatal exposure to chromium, nickel and thallium may be associated to alterations of females AGD, while chromium, nickel and selenium to changes in males AGD. Since AGD alterations could represent wider endocrine interruptions, the effects of these metals on biological and chemical mechanisms during the vulnerable period of pregnancy should be further investigated. KEYWORDS: Prenatal Exposure; Pregnancy; Anogenital-Distance; Metals; WQS

Maternal urinary levels of glyphosate during pregnancy and anogenital distance in newborns in a US multicenter pregnancy cohort.

Human exposure to glyphosate has become ubiquitous because of its increasing agricultural use. Recent studies suggest endocrine disrupting effects of glyphosate. Specifically, in our work in rodents, low-dose early-life exposure to Roundup® (glyphosate-based herbicide) lengthened anogenital distance (AGD) in male and female offspring. AGD is a marker of the prenatal hormone milieu in rodents and humans. The relationship between glyphosate exposure and AGD has not been studied in humans. We conducted a pilot study in 94 mother-infant pairs (45 female and 49 male) from The Infant Development and the Environment Study (TIDES). For each infant, two AGD measurements were collected after birth; the anopenile (AGD-AP) and anoscrotal (AGD-AS) distances for males, and anoclitoral (AGD-AC) and anofourchette distances (AGD-AF) for females. We measured levels of glyphosate and its degradation product aminomethylphosphonic acid (AMPA) in 2nd trimester maternal urine samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. We assessed the relationship between exposure and AGD using sex-stratified multivariable linear regression models. Glyphosate and AMPA were detected in 95% and 93% of the samples (median 0.22ng/mL and 0.14ng/mL, respectively). Their concentrations were moderately correlated (r=0.55, p=5.7×10-9). In female infants, high maternal urinary glyphosate (above the median) was associated with longer AGD-AC (β=1.48, 95%CI (-0.01, 3.0), p=0.05), but this was not significant after covariate adjustment. Increased AMPA was associated with longer AGD-AF (β=1.96, 95%CI (0.44, 3.5), p=0.01) after adjusting for infant size and age at AGD exam. No associations were detected in male offspring. These preliminary findings partially reproduce our previous results in rodents and suggest that glyphosate is a sex-specific endocrine disruptor with androgenic effects in humans. Given the increasing glyphosate exposures in the US population, larger studies should evaluate potential developmental effects on endocrine and reproductive systems.

Anogenital Distance in Newborns with Hypospadias

Hypospadias is a very common congenital anomaly in which the urethra opens onto the ventral aspect of the penis rather than at the tip. It has an incidence of less than 1% of live male births. In humans, anogenital distance (AGD) is a sexually dimorphic measure of genital development. In this study, we intended to examine the association between AGD and hypospadias using a homogenous group of patients. The same investigator examined all male newborns in our hospital, and anthropometric measurements of the anogenital distance were recorded. All the measurements were made in millimeters (mm) with a sliding digital caliper (graduated in millimeters) used for measuring the distance between the base of the scrotum to the center of the anus; defined as AGD. During the period Jan 2015 to December 2019 (both inclusive), there were 28,426 (14,615 males and 13,811 females) full-term live births in our hospital. The gestational age of the newborns ranged from 37 to 42 weeks. The mean AGD was 21.06±5.57 (range 12.11 to 33.14) mm in newborns without hypospadias, 9.92±1.90 (range 8.0 – 13.9) in newborns with proximal hypospadias and 17.03±1.95 (range 14.0 to 19.9) mm with distal hypospadias. In humans, hypospadias is associated with reduced anogenital distance. AGD further decreases with the severity of hypospadias.

In Utero Glyphosate Exposure and Anogenital Distance in Newborns from The Infant Development and Environment Study (TIDES)

Background: Human exposure to glyphosate has become ubiquitous as its presence in the environment rises. Recent studies have described some endocrine disrupting effects of glyphosate. Specifically, in our work in rodents we observed an association between gestational exposure to low-dose glyphosate and Roundup® (a glyphosate-based herbicide) and longer anogenital distance (AGD), a marker of the prenatal hormone milieu, in male and female pups, suggesting an androgenic effect. In this pilot human study, we examined relation between in utero glyphosate exposure and newborn AGD. Methods: We measured glyphosate and its degradation product aminomethylphosphonic acid (AMPA) in 2nd trimester maternal urine from 100 pregnant women from the TIDES cohort (50 females and 50 males). Study staff obtained two measures of AGD; the anopenile and anoscrotal distances (males) and the anoclitoral and anofourchette distances (females). We used the median glyphosate and AMPA concentration to classify subjects into low and high exposure. The relation between exposure and AGD was evaluated using sex-stratified multivariable linear regression adjusted for age at exam, weight-for-length Z-scores, study center, gestational age, maternal age and urine collection time. Results: Glyphosate and AMPA concentrations were above the limits of detection in 95% and 93% of the samples, respectively. Glyphosate and AMPA urinary concentrations were highly correlated (r=0.57, P=7.6x10-10), with glyphosate levels (median, 0.23 ng/mL) higher than AMPA (median, 0.15 ng/mL). High (above median) glyphosate and AMPA were both statistically significantly (P<0.05) associated with increased AGD in females. In males, associations were also positive, but weaker and non-significant. Conclusion: These preliminary findings demonstrate measurable glyphosate exposure in the general population, and suggest a link between in utero glyphosate exposure and longer AGD particularly in females. Given the increasing glyphosate exposure in the US population and its potential role as an endocrine disruptor, this prevalent exposure warrants evaluation in larger studies.

The Endocrine Disruption of Prenatal Phthalate Exposure in Mother and Offspring.

Phthalates are a group of ubiquitous synthetic endocrine-disrupting chemicals. Fetal and neonatal periods are particularly susceptible to endocrine disorders, which prenatal exposure to phthalates causes. There is increasing evidence concerning the potential endocrine disrupting for phthalate exposure during pregnancy. This article aims to review the endocrine impairment and potential outcomes of prenatal phthalate exposure. Prenatal exposure phthalates would disrupt the levels of thyroid, sex hormone, and 25-hydroxyvitamin D in pregnant women or offspring, which results in preterm birth, preeclampsia, maternal glucose disorders, infant cryptorchidism, infant hypospadias, and shorter anogenital distance in newborns, as well as growth restriction not only in infants but also in early adolescence and childhood. The relationship of prenatal phthalate exposure with maternal and neonatal outcomes in human beings was often sex-specific associations. Because of the potentially harmful influence of prenatal phthalate exposure, steps should be taken to prevent or reduce phthalate exposure during pregnancy.

Do stressful life events during pregnancy modify associations between phthalates and anogenital distance in newborns?

Anogenital distance (AGD) has been used as a marker of fetal androgen action to identify endocrine disrupting chemicals. A US study (TIDES) has reported that the association between some phthalates and reduced AGD in males was only apparent in sons of mothers reporting no stressful life events (SLEs) during pregnancy. The objective of the current study was to examine the potential modifying effect of SLEs and their subjective impact on associations between prenatal phthalates and AGD. First trimester urines from the MIREC Study were analysed for phthalate metabolites and AGD was measured in neonates. Post-delivery, the women answered questions on SLEs during the pregnancy. Women reporting 1 or more SLEs during pregnancy were considered a “higher stressor” group, whereas women reporting no SLEs or who reported a SLE that was perceived as not at all stressful were considered a “lower stressor” group. Multivariable linear regression models were fit stratified by stressor group.Maternal stressor, AGD and phthalates results were available for 153 females and 147 males. A summary measure of androgen-disrupting phthalates (Σ AD) was associated with significantly longer AGDs in females from the higher stressor group. These effect sizes were increased when the perceived impact was restricted to moderately or very much stressful. In males, all phthalates were associated with longer anopenile distance (APD), regardless of stressor group; however, higher Σ AD was associated with significantly longer APD in the lower stressor group. In contrast to the TIDES study, we did not observe shorter AGDs in male infants prenatally exposed to di-(2-ethylhexyl) phthalates, regardless of maternal stressor level.In conclusion, we were unable to replicate the findings of the TIDES study, but did find some evidence that prenatal SLEs may modify associations between phthalates and female AGD. Further research with other populations and measures of prenatal stress may shed more light on whether prenatal stress is an important effect modifier of associations between phthalates (or other chemicals) and anogenital distance.

First trimester phthalate exposure and anogenital distance in newborns.

Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (β, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 (-2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical. Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest.

The Establishment of a Birth Cohort in Israel: the Environmental Health Fund Cohort Study.

Background: Brominated flame retardants and phthalates are ubiquitous contaminants in western populations. Exposure characterizations in pregnant women and associations with various outcomes in the offspring have been studied in several populations, including the US. These compounds have not been studied in pregnant women in Israel, where the population is multi-ethnic, and the routes of exposure and associations with outcomes may differ by ethnic group. Aims: The Environmental Health Fund Pregnancy (EHF) Cohort Study was developed to assess exposure to brominated flame retardants and phthalates in pregnant women in two hospitals in central Israel and to examine the associations between these contaminants and (a) pregnancy complications, (b) newborn anthropometrics, (c) ano-genital distance in newborns and (d) maternal and infant thyroid function. We are establishing an analytical laboratory to measure these compounds and establishing a bio-repository of maternal, paternal, and umbilical cord serum, maternal and paternal urine, meconium, and breast milk for future studies. Methods: The anticipated population characteristics of the EHF cohort will be described. Results from preliminary studies of the reliability of the anthropometrics and ano-genital distance measures will be given. The extensive questionnaires given to both parents will be described. We will also discuss establishment of the analytical chemistry laboratory and provide preliminary quality control data. Finally, we will describe the development of the biorepository. Conclusions: The EHF cohort will be an important resource for pregnancy studies of a wide range of contaminants in Israel. Ancillary studies will include evaluations of the associations between a wide range of social variables, and the interaction between social and environmental contaminants and outcomes. We anticipate instituting follow up studies of the children beginning at age 6 months and welcome collaborations.

Evaluation of the intercanine distance in newborns with cleft lip and palate using 3D digital casts.

ObjectiveThe purpose of this present study was to compare, by means of 3D digital casts, the anterior transverse dimension of the dental arch of newborns with and without cleft lip and palate.Material and MethodsThe sample was composed of ninety-four children aged from 3 to 9 months divided into three study groups: Group I - children without craniofacial deformities (control group); Group II - children with unilateral cleft lip and palate; Group III - children with bilateral cleft lip and palate. Impressions were executed before lip and palate repair in patients with clefts. Dental casts were digitized using a 3D scanner linked to a computer. Measurements of the intercanine distance were measured on the digital casts. Intergroup comparisons were performed using ANOVA (p<0.05).ResultsThe results showed a mean of 36.5 mm for unilateral cleft lip and palate group, 34.8 mm for bilateral cleft lip and palate group and 27.52 mm for the control group. There was a statistically significant difference between the control group and both groups of patients with cleft lip and palate. There was no statistically significant difference between complete unilateral and bilateral cleft lip and palate groups.ConclusionsPatients with complete cleft lip and palate were born with an increased anterior dimension of the maxillary dental arch compared to non cleft patients.

Maternal diet, prenatal exposure to dioxins and other persistent organic pollutants and anogenital distance in children

We investigated the potential endocrine disruptive effect of prenatal exposure to persistent organic pollutants (POPs) through maternal diet, by measuring anogenital distance in newborns and young children. We included 231 mothers and their newborns measured at birth from the Rhea study in Crete, Greece and the Hmar study in Barcelona, Spain and 476 mothers and their children measured between 1 and 2years from the Rhea study. We used food frequency questionnaires to assess maternal diet and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX®) and other POPs in maternal samples. We defined a “high-fat diet” score, as a prenatal exposure estimate, that incorporated intakes of red meat, processed meat, fatty fish, seafood, eggs and high-fat dairy products during pregnancy. Increasing maternal “high-fat diet” score was related to increasing dioxin-like activity and serum concentrations of lipophilic persistent organic pollutants in maternal blood. An inverse dose–response association was found between “high-fat diet” score and anoscrotal distance in newborn males. The highest tertile of the maternal score was associated with −4.2mm (95% CI −6.6 to −1.8) reduction in anoscrotal distance of newborn males, compared to the lowest tertile. A weak positive association was found between the “high-fat diet” score and anofourchetal distance in newborn females. In young children we found no association between maternal “high-fat diet” score and anogenital distances. In conclusion, maternal high-fat diet may be linked to high prenatal exposure to persistent organic pollutants and endocrine disruptive effects, resulting to phenotypic alterations of the reproductive system.

In Utero Exposure to Dioxins and Dioxin-like Compounds and Anogenital Distance in Newborns and Infants

Background: Anogenital distance in animals is used as a measure of fetal androgen action. Prenatal exposure to dioxins and dioxin-like compounds in rodents causes reproductive changes in male offspring and decreases anogenital distance.Objective: We assessed whether in utero exposure to dioxins and dioxin-like compounds adversely influences anogenital distance in newborns and young children (median age, 16 months; range, 1–31 months).Methods: We measured anogenital distance among participants of the “Rhea” mother–child cohort study in Crete and the Hospital del Mar (HMAR) cohort in Barcelona. Anogenital distance (AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), and penis width (PW) were measured in 119 newborn and 239 young boys; anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette) were measured in 118 newborn and 223 young girls. We estimated plasma dioxin-like activity in maternal blood samples collected at delivery with the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX®) bioassay.Results: Anogenital distances were sexually dimorphic, being longer in males than females. Plasma dioxin-like activity was negatively associated with AGD in male newborns. The estimated change in AGD per 10 pg CALUX®–toxic equivalent/g lipid increase was –0.44 mm (95% CI: –0.80, –0.08) after adjusting for confounders. Negative but smaller and nonsignificant associations were observed for AGD in young boys. No associations were found in girls.Conclusions: Male infants may be susceptible to endocrine-disrupting effects of dioxins. Our findings are consistent with the experimental animal evidence used by the Food and Agriculture Organization/World Health Organization to set recommendations for human dioxin intake.

852 Under Agarose Migration Assay - a Method to Study Graded Chemotactic Activity of Leukocytes in Newborn Infants

Background: Preterm newborn infants are at risk of developing chronic inflammation and tissue injury in their lungs and CNS due to prolonged and exaggerated accumulation of leukocytes.Aim: To study migration of leukocytes from newborn infants with a modified under agarose cell migration assay.Methods: Blood was collected from healthy adults (n=9) and from healthy, term newborn infants (umbilical cord; caesarean section; spinal anaesthesia; n=9). Isolated leukocytes were added to outer wells and chemoattractants to central wells. Gels were incubated for 2 hours whereby only polymorphonuclear (PMN) leukocytes migrated. Dose responses of intermediate (n=4; IL-8) and end-target (n=5; fMLP) chemoattractants were tested on PMN.Results: Similar dose response curves of PMN migration to gradients of IL-8 and fMLP were observed in newborn infants as in adults, but with less PMN migrating with newborns than with adults. The PMN leukocyte migration per distance in newborns was 80% of adults with IL-8, and >90% of adults with fMLP. There was a high linear correlation between the number of PMN and the distance of migration irrespective of chemoattractant studied (IL-8: r=0.85 and r=0.65 respectively for newborns and adults; p< 0.001 for both) (fMLP: r=0.76 and r=0.87; p< 0.001). The pattern of migration differed between fMLP and IL-8.Conclusion: Similar graded chemotaxis of PMN was observed with under agarose cell migration assay in newborn infants as in adults, making this an attractive method for functional clinical studies of leukocytes in newborn infants during different stages of maturity and disease.

In Utero Exposure to the Antiandrogen 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) in Relation to Anogenital Distance in Male Newborns from Chiapas, Mexico

The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is still used for disease control in some areas, resulting in high levels of human exposure. The main degradation product of DDT is 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), an antiandrogen. In animal experiments, in utero exposure to DDE decreases anogenital distance in male offspring. In these models, anogenital distance serves as a measure of fetal androgen action. The authors designed the present study to examine the hypothesis that in utero exposure to DDE decreases anogenital distance in newborn human males. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-2003 in Chiapas, México, where DDT had recently been used for malaria control. Measurements of anogenital distance and penile dimensions were taken, and a sample of the mother's blood was drawn. In this population, the range of serum DDE levels was large (0.8-398 microg/liter). The authors, using two-sided tests, found no evidence that exposure in utero to DDE was related to reduced androgen action as reflected by anogenital distance or penile dimensions at birth. If DDE has important antiandrogenic action in humans, it may be manifest only at higher levels of exposure or via effects on other outcomes.

Management of Chronic Pain In Children

Pain relief has received considerable attention in recent years, but pain in neonates and children has been underreported, undertreated, and misunderstood. Several reviews have dealt with the recognition and treatment of acute pain, but much less has been written about chronic pain in children. Here we will address general considerations of pain management in children and specific chronic and recurrent pain syndromes of childhood. Developmental Considerations The perception of pain includes both a sensory component, involving neural pathway activation in response to noxious stimuli, and an affective/cognitive response, involving several behavioral aspects. Cutaneous sensory perception has been reported in the perioral area of human fetuses as early as the seventh week of gestation and spreads to include cutaneous and mucosal surfaces by the twentieth week. Incomplete myelinization of nerve fibers and immature synaptic connections have been thought to indicate a lack of maturity in the neonatal nervous system, but this phenomenon merely implies a slower conduction velocity, with much shorter traveling distance in newborns. Development of the fetal neocortex begins during the eighth week of gestation; by 20 weeks, each cortex has a full complement of neurons. Sensory pathways required for pain transmission can be traced from receptors in the skin to sensory areas in the cerebral cortex of infants. Functional development of the cerebral cortex is suggested by specific features of both the fetal and the neonatal electroencephalogram.