Pen-Hua Su

Phthalate exposure in pregnant women and their children in central Taiwan

Phthalate exposure was found to be associated with endocrine disruption, respiratory effects, reproductive and developmental toxicity. The intensive use of plastics may be increasing the exposure to phthalates in Taiwanese population, particularly for young children. We studied phthalate metabolites in pregnant women and their newborns in a prospective cohort from a medical center in Central Taiwan. One hundred maternal urine samples and 30 paired cord blood and milk samples were randomly selected from all of participants (430 pregnant women). Eleven phthalate metabolites (MEHP, 5OH-MEHP, 2cx-MEHP, 5cx-MEPP, 5oxo-MEHP, MiBP, MnBP, MBzP, OH-MiNP, oxo-MiNP, and cx-MiNP) representing the exposure to five commonly used phthalates (DEHP, di-isobutyl phthalate (DiBP), DnBP, BBP, DiNP) were measured in urine of pregnant women, cord serum and breast milk after delivery, and in urine of their children. Exposure was estimated with excretion factors and correlation among metabolites of the same parent compound. Thirty and 59 urinary samples from 2 and 5 years-old children were randomly selected from 185 children successfully followed. Total urinary phthalate metabolite concentration (geometric mean, μg L⁻¹) was found to be higher in 2-years-olds (398.6) and 5-years-olds (333.7) than pregnant women (205.2). Metabolites in urine are mainly from DEHP. The proportion of DiNP metabolites was higher in children urine (4.39 and 8.31%, ages 2 and 5) than in adults (0.83%) (p<0.01). Compared to urinary levels, phthalate metabolite levels are low in cord blood (37.45) and milk (14.90). DEHP metabolite levels in womens urine and their corresponding cord blood are significantly correlated. Compared to other populations in the world, DEHP derived metabolites in maternal urine were higher, while phthalate metabolite levels in milk and cord blood were similar. The level of phthalate metabolites in milk and cord blood were comparable to those found in other populations. Further studies of health effects related to DEHP and DiNP exposure are necessary for the children.

Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants

Background : Patent ductus arteriosus (PDA) is commonly found in very low‐birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.

Herlyn-Werner-Wunderlich Syndrome Consisting of Uterine Didelphys, Obstructed Hemivagina and Ipsilateral Renal Agenesis in a Newborn

Herlyn-Werner-Wunderlich (HWW) syndrome is a rare variant of Müllerian duct anomalies consisting of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Patients with HWW syndrome are usually asymptomatic until menarche, when they present with acute lower abdominal pain. Here we report a case of a female newborn with right renal agenesis diagnosed during the pregnancy. The patient presented with a protruding mass over the vaginal introitus that was associated with an obstructed hemivagina and uterine didelphys.

Infant With In Utero Ketamine Exposure: Quantitative Measurement of Residual Dosage in Hair

BACKGROUND The drug ketamine is frequently abused for recreational use in Asia, but few studies in humans have focused on the effects of ketamine exposure during pregnancy on the health of neonates. Here, we report a neonate whose mother was suspected of ketamine abuse during pregnancy. The case was confirmed by testing hair samples of the neonate. METHODS Hair samples of the neonate were taken on the first day of referral. Levels of common drugs of abuse in Asia were measured in the hair sample by gas chromatography-mass spectrometry using our previously reported method with modifications. This method was developed and validated to simultaneously quantify levels of amphetamine, ketamine and opiate in human hair. RESULTS The neonate was a female baby, born full term, with a low birth weight of 2250 g. Very high levels of ketamine were detected in the neonates hair, even though the mother stated that she had stopped abusing ketamine during the early stage of pregnancy. The neonate suffered from general hypotonia; moderate cerebral dysfunction was found by electroencephalography. Fortunately, her hypotonia improved gradually within 21 days. CONCLUSION This is the first report of ketamine exposure during late pregnancy detected by hair testing. We noted several clinical features in this case, including the infant being small for gestational age, intrauterine growth retardation, remarkable hypotonia, and poor reflex responses. Although the mother denied the use of ketamine during the late stage of her pregnancy, significant amount of ketamine and norketamine was still found in hair samples (only 2 cm long and 25 mg) from the infant.

Efficacy of intermediate-dose oral erythromycin on very low birth weight infants with feeding intolerance.

BACKGROUND Erythromycin is generally used as a prokinetic agent for the treatment of feeding intolerance in preterm infants; however, results from previous studies significantly vary due to different medication dosages, routes of administration, and therapy durations. The effectiveness and safety of intermediate-dose oral erythromycin in very low birth weight (VLBW) infants with feeding intolerance was examined in this study. METHODS Between November 2007 and August 2009, 45 VLBW infants with feeding intolerance, who were all at least 14 days old, were randomly allocated to a treatment group and administered 5mg/kg oral erythromycin every 6hours for 14 days (n=19). Another set of randomly selected infants was allocated to the control group, which was not administered erythromycin (n=26). RESULTS The number of days required to achieve full enteral feeding (36.5±7.4 vs. 54.7±23.3 days, respectively; p=0.01), the duration of parenteral nutrition (p<0.05), and the time required to achieve a body weight ≥2500g (p<0.05) were significantly shorter in the erythromycin group compared with the control group. The incidence of parenteral nutrition-associated cholestasis (PNAC) and necrotizing enterocolitis (NEC) ≥ stage II after 14 days of treatment were significantly lower (p<0.05) in the erythromycin group. No significant differences were observed in terms of the incidences of sepsis, bronchopulmonary dysplasia, or retinopathy of prematurity. No adverse effects were associated with erythromycin treatment. CONCLUSIONS Intermediate-dose oral erythromycin is effective and safe for the treatment of feeding intolerance in VLBW infants. The incidences of PNAC and ≥ stage II NEC were significant lower in the erythromycin group.

The effect of in utero exposure to dioxins and polychlorinated biphenyls on reproductive development in eight year-old children☆ , ☆☆

We have previously reported on the effects of in utero exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) on thyroid function and growth hormone concentrations at birth and in two and five year-old children. Herein, we present our most recent follow-up examination findings for the same cohort of children at eight-years of age. A total of 56 children (23 boys, 33 girls) were examined. Bone age (BA), hormone concentrations, and indicators of reproductive development including Tanner, breast, genital, and armpit stages were assessed. Estradiol concentrations were significantly lower in children exposed to higher levels than median of PCDD/Fs+PCBs TEQ compared to the children exposed to levels lesser than median (P=0.003). Girls exposed to higher levels than median of indicator PCBs had a significantly greater proportion in genital stage 1 and shorter fundi and uteri lengths, as compared to those exposed to low levels (P=0.025 and P<0.05, respectively). There was a significant negative relationship between estradiol concentrations and PCDD/Fs+PCB exposure level (P=0.005). After adjusting for BA, there was a significant association between fundus length and indicator PCB exposure level (P=0.034). Exposure to both high levels of ΣPCDD/Fs+PCBs TEQ and high levels of total PCBs was associated with decreased fundus length (P=0.016) and uterus length (P=0.016). In utero exposure to high levels of PCDD/Fs and PCBs may result in lower estradiol concentrations in eight year-old children and impaired reproductive development in girls.

Growth and Thyroid Function in Children With In Utero Exposure to Dioxin: A 5-Year Follow-Up Study

Because placental polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) levels are associated with decreased free thyroxine (FT4) and thyroid stimulating hormone (TSH) in neonates, we assessed development by gender and maternal PCDD/Fs exposure at years 2 and 5 in 92 mother and newborn pairs. RIA quantified thyroid, sex, and growth hormones. Of 200 subjects followed up from November 2000, 136 and 149 were observed at year 2 and year 5, respectively. PCDD/Fs exposure levels were low (n = 35) or high (n = 35) in 70 subjects at year 2, low (n = 21) or high (n = 20) in 41 at year 5. Height, weight, BMI, and head circumference were significantly higher in males, chest girth significantly higher in females at year 2. Significantly, more girls had higher bone age (BA) and chronological age (CA) at both times. Height, weight, FT4 × TSH, and transthyretin (TTR) at year 2; and height, triiodothyronine, and IGF-1 at year 5 differed significantly by PCDD/Fs level. In females, height, weight, CA, BA, and thyroid hormones differed significantly at year 2. In males, FT4 × TSH at year 2 and IGF-1 at year 5 were significantly higher in the high PCDD/Fs group. In utero exposure to PCDD/Fs differentially affects growth and hormone levels in male and female preschool children.

Exposure to di(2-ethylhexyl) phthalate in premature neonates in a neonatal intensive care unit in Taiwan.

Objective: Neonates are exposed to high levels of di(2ethylhexyl) phthalate through numerous medical procedures in the neonatal intensive care unit. Our aim was to assess the contribution of specific medical devices to the di(2-ethylhexyl) phthalate exposure of neonates. Design: Prospective. Setting: University hospital. Patients: We recruited 32 premature neonates, 20 with very low birth weight (<1500 g) and 12 with low birth weight (<2500 g), and 31 controls at a neonatal intensive care unit from a medical center in central Taiwan. Interventions: Interventions were based on a clinical need and used standard materials and devices, including endotracheal tubes, continuous positive airway pressure, oxygen hood, intravenous injection, intralipid injection, blood transfusion, orogastric tubes, nasogastric tubes, umbilical venous catheterization, umbilical arterial catheterization, chest tube, and isolate. Measurements and Main Results: We recorded the medical procedures of each subject, collected their urine samples, and determined the urinary concentration of three metabolites of di(2-ethylhexyl) phthalate using reversed-phase highperformance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. Median levels of di(2-ethylhexyl) phthalate metabolites in premature neonates treated with an endotracheal tube and orogastric tube or nasogastric tube were significantly higher than those not treated with an endotracheal tube, orogastric tube, or nasogastric tube. Median levels of di(2-ethylhexyl) phthalate metabolites in premature neonates treated with intravenous injection were ≥2-fold higher than those of healthy controls who received intravenous injections (p = .01). Median levels of three di(2-ethylhexyl) phthalate metabolites were similar in verylowbirth-weight and lowbirthweight neonates. Conclusions: These data suggest that polyvinyl chloride-containing devices are the major defining factor in di(2-ethylhexyl) phthalate exposure levels in neonates in the neonatal intensive care unit. We urge the use of polyvinyl chloride-free or alternative materials in medical devices, especially for endotracheal tubes, orogastric tubes, nasogastric tubes, and intravenous tubing in the neonatal intensive care unit. The health effects of high di(2-ethylhexyl) phthalate exposure on premature neonates in the neonatal intensive care unit is worthy of further investigation.

Fetal and Childhood Exposure to Phthalate Diesters and Cognitive Function in Children Up to 12 Years of Age: Taiwanese Maternal and Infant Cohort Study

Few studies have examined the association between environmental phthalate exposure and children’s neurocognitive development. This longitudinal study examined cognitive function in relation to pre-and postnatal phthalate exposure in children 2–12 years old. We recruited 430 pregnant women in their third trimester in Taichung, Taiwan from 2001–2002. A total of 110, 79, 76, and 73 children were followed up at ages 2, 5, 8, and 11, respectively. We evaluated the children’s cognitive function at four different time points using the Bayley and Wechsler tests for assessing neurocognitive functions and intelligence (IQ). Urine samples were collected from mothers during pregnancy and from children at each follow-up visit. They were analyzed for seven metabolite concentrations of widely used phthalate esters. These esters included monomethyl phthalate, monoethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, and three metabolites of di(2-ethylhexyl) phthalate, namely, mono-2-ethylhexyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. We constructed a linear mixed model to examine the relationships between the phthalate metabolite concentrations and the Bayley and IQ scores. We found significant inverse associations between the children’s levels of urinary mono(2-ethyl-5-oxohexyl) phthalate and the sum of the three metabolites of di(2-ethylhexyl) phthalate and their IQ scores (β = -1.818; 95% CI: -3.061, -0.574, p = 0.004 for mono(2-ethyl-5-oxohexyl) phthalate; β = -1.575; 95% CI: -3.037, -0.113, p = 0.035 for the sum of the three metabolites) after controlling for maternal phthalate levels and potential confounders. We did not observe significant associations between maternal phthalate exposure and the children’s IQ scores. Children’s but not prenatal phthalate exposure was associated with decreased cognitive development in the young children. Large-scale prospective cohort studies are needed to confirm these findings in the future.

Common Etiologies of Neonatal Pleural Effusion

BACKGROUND Pleural effusion is rare and includes several disease entities in the neonatal period. The aim of this study was to investigate the etiology, management, and outcome of neonatal pleural effusions. METHODS We retrospectively collected all neonates who were admitted to the neonatal intensive care unit of Chung Shan Medical University Hospital, Taichung, Taiwan, with discharge diagnosis of pleural effusion, chylothorax, hydrothorax, hemothorax, and empyema, from January 1999 to December 2009. The characteristics, etiology, management, and outcome were analyzed. RESULTS There were 21 patients identified, 16 males (76%) and 5 females (24%). Eight patients (38%) had primary and 13 patients (62%) had secondary etiologies. The etiologies included four parapneumonic effusions or empyema (19%); nine chylothorax (42.8%) with four congenital and five iatrogenic after thoracic surgery; three percutaneously inserted central venous catheter extravasation (14%); one umbilical venous catheter extravasation (4.7%); three hydrops fetalis (14%); and one congestive heart failure (4.7%). Fifteen patients (71%) needed chest tube placement. Conservative management with complete cessation of enteral feedings and use of total parenteral nutrition followed with infant formula containing medium-chain triglyceride was successful in six of the patients (67%) with chylothorax. There were two patients (22%) with chylothorax who received somatostatin administration; one was successful and the other one failed. Thoracic duct ligation was performed uneventfully in two patients with acquired chylothorax. There were three mortalities (14.3%) in this study, which were related to causes other than pleural effusion. CONCLUSIONS Pleural effusions in the neonatal stage may result from chylothorax, hydrops fetalis, extravasation of percutaneously inserted central venous catheter, parapneumonic effusion, congestive heart failure, or other less frequently occurring conditions. Diagnostic chest tap is required for subsequent management. Good outcome is the rule except in hydrops fetalis, which carries high mortality rate.