Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine.

BACKGROUND: Since the urinary concentration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a reliable biomarker of exposure to tobacco smoke, we developed a relatively simple high-throughput chromatographic method to quantify total urinary NNAL concentrations in the general population. METHODS: The high-throughput analytical method was developed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) to identify and quantify total urinary NNAL concentrations in 10 non-smokers and 15 otherwise healthy smokers. RESULTS: Loss of nitric oxide at m/z 30 was found to be the predominant mass transitioned, and therefore was used as the SIM transition to quantify both NNAL and NNAL-methyl-d3 in urine. The analytical method did not require sample derivatization. Standard curves for total NNAL concentrations were linear between 20 and 1500 pg/mL, with coefficients of determination >0.95. Precision and accuracy ranged from 2.2% to 8.6% (CV) and from -5.6% to 10.9% (percent error), respectively. The lowest limit of quantification was 6.7 pg/mL, and 2.0 pg/mL the lowest limit of detection (LLOD). Total urinary NNAL concentrations in non-smoker subjects were

Dose-response and time-response analysis of total fatty acid ethyl esters in meconium as a biomarker of prenatal alcohol exposure.

OBJECTIVES: Little is known on how the dose and timing of exposure co-influence the cumulative concentration of fatty acid ethyl esters (FAEEs) in meconium. The objective of the study was to assess the cumulative concentration of FAEEs in meconium as a biomarker of light, moderate, or heavy prenatal alcohol exposure occurring at either first, second, or third trimesters of pregnancy. METHODS: History of prenatal alcohol exposure was obtained in the 34th week of gestation from 294 pregnant women. Meconium was collected from their babies within the first 6 to 12 h after birth and examined for the presence of nine FAEEs. RESULTS: No significant differences were identified between the cumulative levels of FAEEs in the meconium from the babies born to abstainers and those born to mothers with history of light-to-moderate prenatal alcohol exposure during their pregnancy. CONCLUSIONS: Light-to-moderate prenatal alcohol exposure cannot be reliably predicted by the cumulative FAEE concentrations in meconium of exposed babies. A cumulative FAEE level of >10 nmol/g would be required to consider that prenatal alcohol exposure during the second to third trimesters occurred at risky levels in the absence of reliable maternal history of ethanol exposure.

Fetal and neonatal outcomes in women reporting ingestion of licorice (Glycyrrhiza uralensis) during pregnancy.

Maternal intake of licorice from dietary sources has been associated with adverse maternal and fetal outcomes. We prospectively studied the outcome of 185 singleton pregnancies who took over-the-counter or naturopathic formulations containing licorice during their pregnancy, and 370 age-matched singleton pregnant controls that were not exposed to any potential teratogen. The indication in 56.8% of the women taking licorice was for cough and cold control, with the maximum dose of 2104 mg/day and exposure occurring between the 4th day and 25th week of gestation. The rate of stillbirths was marginally higher among women who took licorice than those who did not (OR = 7.9; 95% CI 0.9-71.5; p = 0.048), and significantly higher when compared to the general population in the Republic of Korea (OR = 13.3; 95% CI 4.9-35.8; p < 0.001). Other fetal outcomes assessed in the study were similar between the two study groups, e.g., the OR of major malformations was 3.9 (95% CI 0.4-43.5; p = 0.27). In conclusion, the present study suggests that licorice is not a major teratogen. However, whether licorice may increase the risk of stillbirths requires careful consideration in further studies with a larger sample size.

Pregnancy outcome of women inadvertently exposed to ribostamycin during early pregnancy: a prospective cohort study.

No information is currently available on the safety of the aminoglycoside ribostamycin in pregnancy. We aimed to study the pregnancy outcome of women inadvertently exposed to ribostamycin during the first trimester of pregnancy. In a prospective cohort study, 102 women inadvertently exposed to ribostamycin during the first trimester of pregnancy and an age- and gravidity-matched control group, were enrolled. Study outcomes were gestational age at birth, major and minor malformations, and birth weight. Fetal outcomes were evaluated in 85 women inadvertently exposed to ribostamycin during the first-trimester of pregnancy and in 170 control subjects. Newborns were clinically examined at birth by a neonatologist and by imaging studies if any suspicious abnormalities were noted. There were 4/85 (4.9%) babies born with major malformations in the exposed group and 3/170 (1.8%) in the control group (P=0.7). Gestational age at delivery, rate of minor anomalies, rate of preterm births, and birth weight were not different between groups. In conclusion, similar to what is reported for other aminoglycoside, exposure to ribostamycin during the first-trimester of pregnancy does not appear to increase the risk of adverse fetal outcomes.

A pilot study of nalbuphine versus tramadol administered through continuous intravenous infusion for postoperative pain control in children.

Nalbuphine and tramadol are potent analgesic drugs. Our aim was to preliminarily assess and compare the efficacy and safety of nalbuphine and tramadol for postoperative analgesia in children. In a double-blind design, 24 ASA 1-3 children aged 1 to 10 years undergoing a scheduled surgical procedure were randomly allocated to receive either an intravenous bolus dose of nalbuphine 100 microg/kg immediately before the end of surgery followed by an infusion of 0.2 microg/kg/min for 72 hrs., or an intravenous bolus dose of tramadol 1000 microg/kg followed by an infusion of 2.0 microg/kg/min for 72 hrs. Postoperative pain control and drug-related adverse events were recorded. Three children who received nalbuphine required an extra bolus dose within the 12 hrs. of post-surgery versus one child in the tramadol group. A similar number of patients in both groups required an increment in the infusion rate within the 72 post-surgery hours. Sedation was observed in 2 children in the nalbuphine group and in 1 child in the tramadol group. Four children presented vomiting with tramadol and two with nalbuphine. Cardiovascular parameters remained within the normal ranges in both groups. In conclusion, the bolus/infusion regimen of tramadol evaluated in this study appears to have better postoperative analgesic efficacy than the bolus/infusion regimen of nalbuphine. These preliminary results require further confirmation by studies with a sample size enough to clearly identify differences in their efficacy as well as in the rate of adverse events secondary to the administration of each of them.

Obstetric and fetal outcomes in dystocic and eutocic sows to an injection of exogenous oxytocin during farrowing.

Sixty hybrid Yorkshire-Landrace penned sows, 30 with eutocic farrowing and 30 experiencing a dystocic parturition, were studied to evaluate the obstetric and neonatal outcomes to low doses of oxytocin administered at advanced stages of parturition. Animals in each group were randomly subdivided into 2 subgroups: 15 eutocic and 15 dystocic sows received oxytocin 0.083 IU/kg (equivalent to 1 IU/12 kg body weight), administered intramuscularly after the delivery of the 5th piglet; the other 15 eutocic and 15 dystocic sows received saline solution intramuscularly at the same time. Oxytocin decreased the number of intrapartum deaths by approximately 50% (P = 0.002). No piglet was born dead from the saline- and oxytocin-treated eutocic sows. The highest viability score was observed among piglets born to eutocic sows treated with oxytocin. In summary, this dose schedule would help to decrease the number of stillbirths in both eutocic and dystocic farrowing sows.

Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia.

OBJECTIVE: Our goal was to determine whether sildenafil increased fetal weight and favored fetal tolerance to induced asphyxia at birth in guinea pigs. STUDY DESIGN: Twenty guinea pigs were randomly allocated to placebo (n = 10) or sildenafil 50 microg/kg (n = 5) or 500 microg/kg (n = 5), starting from day 35 of gestation to delivery. Fetuses were delivered by cesarean section. Fetal asphyxia was induced by clamping the umbilical cord at birth for 5 minutes. RESULTS: Sildenafil protected the pups against induced asphyxia at birth in a dose-dependent manner (eg, partial pressure (tension) of carbon dioxide levels were 75.9 +/- 19.3, 66.9 +/- 18.8, and 54.8 +/- 13.0 in the control and low- and high-dose sildenafil groups, respectively). The high-dose sildenafil group of piglets gained 1.5 times more body weight. CONCLUSION: In guinea pigs, low doses of sildenafil administered from day 35 to the end of gestation favored fetal tolerability to induced intrapartum asphyxia. High doses of sildenafil increased fetal weight.

Hemorrhoids in pregnancy.

QUESTION: One of my patients is in the third trimester of her first pregnancy. She has recently experienced spotting during her bowel movements. She has hemorrhoids. What medications are safe? ANSWER: The treatment is mainly symptomatic for most patients. Most forms of the condition can be treated by increasing fibre content in the diet, administering stool softeners, increasing liquid intake, and training in toilet habits. Although none of the topical antihemorrhoidal agents commonly used have been assessed for safety in pregnancy, it is unlikely that the constituent parts (anesthetic, corticosteroids, and anti-inflammatory agents) will harm the third-trimester infant. In most women, most symptoms of the condition will resolve spontaneously soon after giving birth.

Accidental poisoning with "Chinese chalk".

We present a 1.5-year old, 11 kg, female infant with a history of bronchial hyper-responsiveness who accidentally ingested half of a "Chinese chalk". A day later, the infant showed vomiting, cough, fever, drowsiness, and irritability and her clinical conditions progressively worsened. She was admitted to the emergency department with cough, respiratory distress, and hepatomegaly. It has been reported that the chalk may contain deltamethrin and cypermethrin. The patient was successfully treated with supportive therapy. This report identifies "Chinese chalk" as a potential source of accidental poisoning in children and should be considered as part of the differential diagnoses in the emergency rooms since poisoning with these compounds may be misdiagnosed as organophosphate poisoning due to the presentation of similar symptoms.

Cefepime/clindamycin vs. ceftriaxone/clindamycin for the empiric treatment of poisoned patients with aspiration pneumonia.

Different antimicrobial treatments have proved to be effective in patients with aspiration pneumonia. However, resistant bacterial strains are commonly observed in hospital settings challenging the empirical treatment of these patients. In this study, we aimed to compare the efficacy of cefepime/clindamycin and ceftriaxone/clindamycin for empiric therapy of poisoned patients with aspiration pneumonia. In an open, randomized, prospective design, 140 consecutive patients aged more than 13 years, with radiographic signs of infiltration in chest radiography and dullness on percussion or pulmonary rales or ronchi in combination with at least two of the following clinical criteria were considered as eligible: fever > or = 37 degrees C (axillary), or hypothermia < 35 degrees C (axillary) and leukocytosis (> 10 cells/mm3), or leukopenia (< 3,000 cells/mm3), a left-shift of > 10%, or purulent sputum or secretion from trachea or bronchi. Participants received intravenously either ceftriaxone 1 g q12 h and clindamycin 900 mg q8 h (group 1) or cefepime 1 g q12 h and clindamycin 900 mg q8 h (group 2). On day 5 of treatment, the number of improved/cured patients was not different between groups (OR 0.86; 95% CI 0.24 to 2.90) nor at 14 days of the study (OR 0.66; 95% CI 0.12 to 3.29). Six patients died in group 1 and 5 in group 2 (RR 0.83; 95% CI 0.28 to 2.46). In conclusion, efficacy of empiric treatment of poisoned patients with aspiration pneumonia with ceftriaxone/clindamycin was comparable to treatment with cefepime/clindamycin.

Is prenatal childbirth preparation effective in decreasing adverse maternal and neonatal response to labor? A nested case-control study.

Sophrology, based on a combination of Western relaxation therapy and Eastern yoga and meditation might decrease maternal stress during labor. This study aimed to evaluate whether prenatal sophrologic childbirth preparation may decrease maternal and neonatal adverse response associated with delivery. In a nested case-control study, 69 nulliparous, singleton pregnant women who underwent an educational course of sophrologic childbirth preparation were compared to 69 nulliparous, singleton, age- and gestational age-matched pregnant women who did not receive any childbirth preparation. All babies were vaginally delivered. Groups were not different (P > 0.05) in the number of neonates born with meconium-stained amniotic fluid as well as in the number of babies with Apgar score < or = 7 at 1 and 5 minutes after birth. Duration of labor was not different between groups. The number of women requiring oxytocin and delivering babies with low pH blood levels tended to be lower in the group undergoing sophrologic childbirth preparation, i.e. 58.0% vs 72.5% (P = 0.07) and 1.4% vs 10.9% (P = 0.06), respectively. In conclusion, we were unable to confirm that prenatal sophrologic childbirth preparation has a definitive role in decreasing adverse maternal and fetal response to pain or in shortening labor. Prospective cohort studies with a larger sample size or randomized trials may help to clarify this gap.

Angiotensin II receptor blockers in pregnancy: a case report and systematic review of the literature.

OBJECTIVE: To describe the case of a woman exposed to angiotensin-II receptor blockers (ARBs) in the preconceptional period and to systematically review the literature on the safety of these drugs when used by pregnant women. METHODS: The case was identified at the Korean Motherisk Program (Seoul). For the systematic review, we searched the PubMed for case reports, case series, and post-marketing surveys. RESULTS: A hypertensive woman was exposed to irbesartan prior to conception. The embryo had delayed development of upper and lower extremities and decreased digital groove. A karyotype identified a 45,XO Turner syndrome. The patient had a spontaneous abortion. Including the case reported here, 64 published cases were identified in total; 57.8% had favorable and 42.2% had unfavorable outcomes. Duration of treatment during pregnancy among women who had adverse fetal outcomes was 26.3 +/- 10.5 weeks (mean +/- SD), compared with 17.3 +/- 11.6 weeks in those who had favorable outcomes (p = 0.04). CONCLUSIONS: Exposure to ARBs for a period longer than the first trimester of pregnancy appears to be associated with a high risk for adverse fetal outcomes.

Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding.

OBJECTIVE: To assess the fetal outcome of three hypertensive women exposed to amlodipine. 5 mg/day, in the first trimester of pregnancy. CASE 1: The patient was treated with amlodipine until 7 weeks of gestation. She was also exposed to levosulpiride, aluminum hydroxide gel, magnesium carbonate, and Ginkgo biloba. At 38(+3) weeks of pregnancy, she delivered a 3750 g healthy female baby, and restarted taking amlodipine, 5 mg/day, while exclusively breastfeeding her daughter. At three months of age, the infant was healthy. CASE 2: The patient was treated with amlodipine from 2(+2) to 3(+4) weeks of pregnancy. Her treatment was modified to atenolol until the week 6(+4 weeks), when she declined any antihypertensive treatment. At 39(+4) weeks of pregnancy, the patient delivered a 2600 g baby. At 20 months old, the baby presented with intellectual delay and weakness in the left arm and hand grasp. These neurological alterations were not attributed to her exposure to amlodipine early in utero. CASE 3: The patient was treated with amlodipine from 7(+6) to 12 weeks of pregnancy. She was also taking sucralfate and lorazepam. At 12 weeks of amenorrhea, ultrasound revealed a 15.3 mm, single fetal pole in the gestational sac without cardiac activity. She underwent dilatation and evacuation of a dead embryo. CONCLUSION: As reported with other calcium-channel blockers, amlodipine does not appear to be teratogenic and it appears to be compatible with breastfeeding.

A study of piglets born by spontaneous parturition under uncontrolled conditions: could this be a naturalistic model for the study of intrapartum asphyxia?

In order to evaluate how spontaneously born piglets could be a suitable model for the study of intrapartum hypoxia, 230 newborn piglets were studied. Out them, 8.3% (n = 19) died intrapartum, 21.7% (n = 50) were born with moderate-to-severe intrapartum hypoxia, and 70% (n = 161) were born with mild or no evidence of intrapartum distress. Piglets born without any evidence of intrapartum asphyxia weighed approximately 240 g lower than those born with intrapartum hypoxia and intrapartum-dead piglets (P<0.0001). The viability score was approximately 3 units lower and the latency to contact the udder was two times longer in the piglets surviving intrapartum hypoxia than in controls (P <0.0001). In comparison with the control group, metabolic acidosis was most severe among intrapartum-dead piglets followed by piglets surviving intrapartum asphyxia (P =0.002). According to a multiple linear regression analysis, pCO2 and lactate blood levels, and birth weight were identified as explanatory variables of viability score (r: 0.78; P <0.001). Viability score, K+ and lactate blood levels, and birth weight were identified as explanatory variables of latency to contact the udder (r: 0.80; P <0.001). In conclusion, the spontaneously-born asphyxiated piglet could be considered as a naturalistic model for the study of intrapartum asphyxia. Histopathologic and more rigorous functional and behavioral evaluations are still required to further characterize the model. (www.actabiomedica.it)

Obstetric and neonatal outcomes to recombinant porcine somatotropin administered in the last third of pregnancy to primiparous sows.

This study aimed to investigate whether the administration of recombinant porcine somatotropin (rpST) late in gestation is associated with increased rates of obstetric and neonatal complications in primiparous sows. From days 80 to 114 of gestational age, 20 primiparous sows were randomly assigned to receive an intramuscular injection of either saline or 6 mg rpST/day. Throughout pregnancy, sows were fed 2.5 to 3 kg/day of a corn-soybean diet (14 MJ ME/kg). Of 111 piglets born to control sows and 109 piglets born to treated sows, 8.1% and 17.4% piglets respectively died intrapartum (P=0.04). Glucose blood levels in sows and live-born piglets in the rpST-treated group were significantly higher than in their corresponding controls. Birth weight of live-born piglets in the treated group was 1.4 +/- 0.1 kg versus 1.3 +/- 0.1 kg in the control group (P<0.0001). Birth weight of piglets born dead was also higher in the former than in the latter group (P<0.0001). No evidence of teratogenicity was observed in either of the groups. In conclusion, rpST administration in late pregnancy to primparous sows increased the rate of neonatal deaths and was associated with higher blood glucose levels in both sows and piglets.

Fetal outcome following roxithromycin exposure in early pregnancy.

OBJECTIVE: Because very little information exists on the fetal safety of roxithromycin, we aimed to extend the knowledge on fetal outcome in pregnant women who were exposed to roxithromycin in early pregnancy. METHODS: Twenty pregnant women inadvertently exposed to roxithromycin during early pregnancy were identified and prospectively followed-up. For comparison, 170 pregnant women matched by age and gravidity, not being exposed to any potential teratogenic agent during pregnancy, were recruited as controls. All gestations were confirmed by ultrasound examination, and participants were followed-up until delivery. Newborns were examined by a neonatologist. RESULTS: Of 20 pregnant women exposed to roxithromycin during early pregnancy, information was obtained from 17 cases. The median dose of roxithromycin to which pregnant women were exposed was 300 mg/day (range 300-450 mg/day) and exposure occurred at a mean of 4.0 (range 2.8-17.6) weeks. Mean gestational age at delivery was 39.2 weeks in the exposed group and 39.4 in the controls (p = 0.6). Birth weight of babies exposed in utero to roxithromycin was not different to controls. We did not observe any major malformation in the exposed group whereas three (1.8%) occurred in the control group. CONCLUSIONS: . Despite the limitations of the study due to the small sample size, roxithromycin appears not to be a major teratogen.

A randomized trial comparing laryngeal mask airway to endotracheal tube in children undergoing upper gastrointestinal endoscopy.

Although the efficacy of laryngeal mask airway (LMA) has been demonstrated for securing patency of the airway in children, it has not yet been compared to endotracheal tube (ET) in this population. This study aimed to compare the safety and efficacy of LMA vs. ET in children undergoing elective diagnostic upper gastrointestinal endoscopies. Sixty ASA I-III patients were randomly allocated to ET (Group I) or LMA (Group II). A set of cardiovascular and respiratory parameters were obtained before, during and after the endoscopic procedure. The recovery time and the time to discharge were also registered. The cardiovascular and respiratory parameters evaluated in the study varied across the different evaluation periods. However, they remained within physiological ranges and were not different between groups. The median (range) recovery time was 4 (2-10) min and the time to discharge was 58 (36-88) min in the ET group and 3 (1-7) min and 50 (35-67) min in the LMA group (P > 0.10), respectively. In a 16 month-old, 80 cm and 10 kg girl, we failed to secure the patency of the airway with LMA. In conclusion, the LMA was as effective and safe as ET for securing the airway of children undergoing diagnostic upper endoscopies. However, the 3% failure rate occurred with LMA.

Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumors: report of 2 cases.

Bleomycin plus etoposide and cisplatin seem to be a promising alternative for women with ovarian cancer. We are reporting two cases with favorable pregnancy outcome after exposure to these chemotherapeutic agents at the second and third trimesters of pregnancy. A pregnant woman with a stage Ic yolk-sac tumor underwent a right oophorectomy with omentectomy, and received five cycles of bleomycin, etoposide and cisplatin from the 22nd week of pregnancy until delivery. The second case was a pregnant woman with a stage Ia immature teratoma who underwent right salpingo-oophorectomy and received two cycles of bleomycin, etoposide and cisplatin starting at 30th week of pregnancy. The two patients did not have any evidence of recurrence of ovarian cancer for 6 and 2 years, respectively. Their babies did not have any evidence of minor or major malformations, and showed normal neurological development at 6 and 2 years of follow-up, respectively.

Oral misoprostol and uterine rupture in the first trimester of pregnancy: a case report.

We are reporting the case of a woman with 8 weeks of amenorrhea who orally received a single dose of misoprostol 400 microg at midnight for ripening of cervix before uterine evacuation of an intrauterine gestational sac containing a single fetus (6.3 weeks of gestation) without cardiac activity. The patient had severe abdominal pain an hour later. Her blood pressure was 70/40 mmHg and her abdomen was slightly distended with direct and rebound tenderness. A transvaginal ultrasonography showed a 3-cm depth of a free fluid collection in the rectouterine pouch. Her hemoglobin and hematocrit levels were of 6.5 g/dL and 18.4%, respectively. A rupture of 1.5 cm at the left uterine horn with a protruding gestational sac was identified by laparoscopy. The gestational sac was removed and hemoperitoneal collection were successfully drained. The site of uterine rupture was primarily sutured and postoperative course was satisfactory. In summary, misoprostol administered in the first trimester of pregnancy may produce uterine rupture.

Dose minimization study of oxytocin in early labor in sows: uterine activity and fetal outcome.

Two hundred sows were randomly assigned to intramuscularly receive 0.9% NaCl (group 1) or oxytocin 0.083, 0.11 or 0.17 IU/kg (groups 2, 3 and 4, respectively) immediately after the expulsion of the first piglet. The overall duration of labor was decreased in a dose-dependent relationship. Time interval between piglets was decreased approximately 5 min in groups 3 and 4 while sows in these groups exhibited approximately 10-20 contractions x 10 births more than controls (P<0.005). Duration and intensity of uterine contractions also showed a positive dose-response relationship. As an indicative of fetal distress, approximately 2.5 times more meconium-stained piglets were born to sows receiving the higher doses of oxytocin, but in the lowest dose significantly decreased. Oxytocin 0.083 IU/kg significant decreased the mortality rate of piglets [OR 0.49 (95%CI, 0.26-0.92)]. In conclusion, we recommend the intramuscular administration of the lowest possible dose of oxytocin, which still decreases the duration of labor in sows.