Waveform analysis of the fetal ECG in labor in patients with intrahepatic cholestasis of pregnancy.

AIM: Intrahepatic cholestasis of pregnancy (ICP) is reported to be associated with an increased risk of sudden fetal death. The possible mechanism is thought to be cardiac arrhythmia. Prolonged QT interval of the electrocardiogram (ECG) is associated with arrhytmogenic events. The aim of the study was to compare the fetal ECG QT interval during labor in pregnancies complicated with ICP to healthy controls. METHODS: The fetal ECG and QT interval was reviewed retrospectively. The intrapartum QT interval was measured in 61 fetuses born to mothers with ICP and in a control group of similar size. The corrected QT interval (QTc) was calculated using Bazett's formula: QT/√RR. The occurrence of ST segment depression was also included in the analysis. RESULTS: The groups were similar regarding to maternal age, parity, BMI, gestational age and smoking habits. The rate of labor induction was significantly higher in ICP patients (P < 0.001). The QTc at the beginning and the end of recording was analyzed and there were no significant differences in these values between the ICP patients and healthy controls (P = 0.467). Most ICP patients used ursodeoxycholic acid (UDCA) for mediation. We analyzed separately patients who had elevated liver enzymes before labor. No significant differences in the QTc were noted in these patients either. Nor were there any significant ST depressions in ICP patients. CONCLUSIONS: The etiology of adverse perinatal outcome and even sudden fetal death in ICP is still controversial. No differences in QTc intervals and ST waveforms during labor were found in our study material.

Gut Microbiota Richness and Composition and Dietary Intake of Overweight Pregnant Women Are Related to Serum Zonulin Concentration, a Marker for Intestinal Permeability.

BACKGROUND: Increased intestinal permeability may precede adverse metabolic conditions. The extent to which the composition of the gut microbiota and diet contribute to intestinal permeability during pregnancy is unknown. OBJECTIVE: The aim was to investigate whether the gut microbiota and diet differ according to serum zonulin concentration, a marker of intestinal permeability, in overweight pregnant women. METHODS: This cross-sectional study included 100 overweight women [mean age: 29 y; median body mass index (in kg/m(2)): 30] in early pregnancy (<17 wk of gestation; median: 13 wk). Serum zonulin (primary outcome) was determined by using ELISA, gut microbiota by 16S ribosomal RNA sequencing, and dietary intake of macro- and micronutrients from 3-d food diaries. The Mann-Whitney U test was used for pairwise comparisons and linear regression and Spearman's nonparametric correlations for relations between serum zonulin and other outcome variables. RESULTS: Women were divided into "low" (<46.4 ng/mL) and "high" (≥46.4 ng/mL) serum zonulin groups on the basis of the median concentration of zonulin (46.4 ng/mL). The richness of the gut microbiota (Chao 1, observed species and phylogenetic diversity) was higher in the low zonulin group than in the high zonulin group (P = 0.01). The abundances of Bacteroidaceae and Veillonellaceae, Bacteroides and Blautia, and Blautia sp. were lower and of Faecalibacterium and Faecalibacterium prausnitzii higher (P < 0.05) in the low zonulin group than in the high zonulin group. Dietary quantitative intakes of n-3 (ω-3) polyunsaturated fatty acids (PUFAs), fiber, and a range of vitamins and minerals were higher (P < 0.05) in women in the low zonulin group than those in the high zonulin group. CONCLUSIONS: The richness and composition of the gut microbiota and the intake of n-3 PUFAs, fiber, and a range of vitamins and minerals in overweight pregnant women are associated with serum zonulin concentration. Modification of the gut microbiota and diet may beneficially affect intestinal permeability, leading to improved metabolic health of both the mother and fetus. This trial was registered at clinicaltrials.gov as NCT01922791.

The effects of metformin treatment of gestational diabetes on maternal weight and glucose tolerance postpartum--a prospective follow-up study.

INTRODUCTION: Metformin seems to reduce gestational weight gain compared with insulin in women with gestational diabetes (GDM). Women with GDM requiring insulin are more likely to develop abnormal glucose tolerance postpartum than women treated with diet only. In this prospective follow-up study of a randomized clinical trial, we investigated the effect of metformin treatment in women with GDM on weight gain and glucose tolerance postpartum. MATERIALS AND METHODS: Women with GDM with two or more pathologic glucose values at 2-h 75-g oral glucose tolerance test (OGTT) were recruited. Those needing medication to achieve sufficient glycemic control were randomized at 22-34 weeks of gestation to either metformin (n = 110) or insulin (n = 107) treatment until delivery. A third GDM group (n = 128) requiring no medication had only diet treatment. Weight, OGTT and glycosylated hemoglobin (HbA1c) were determined at 6-8 weeks and 1 year postpartum. RESULTS: At least one postpartum visit was attended by 104, 101 and 120 women in the metformin, insulin and diet-only groups, respectively. No significant differences were found in the change of weight, HbA1c or OGTT glucose values between the groups during the study (p ≥ 0.121 in all comparisons). One year postpartum the diet-only group had less impaired glucose tolerance compared with the metformin and insulin groups (7.1%, 19.1% and 15.6%, respectively; overall p = 0.039) and a lower incidence of diabetes (p = 0.027). CONCLUSIONS: Short-term metformin therapy does not affect weight, HbA1c or OGTT glucose values postpartum compared with insulin or diet-only treatments. Women with GDM requiring no medication are least likely to develop impaired glucose tolerance or diabetes postpartum.

Intrahepatic cholestasis of pregnancy: observational study of the treatment with low-dose ursodeoxycholic acid.

BACKGROUND: To exam the biochemical, obstetric management and pregnancy outcome in women with intrahepatic cholestasis of pregnancy (ICP) and treatment with ursodeoxycholic acid (UDCA). METHODS: Pregnancy outcome in patients with ICP (N = 307) was studied and patients treated with UDCA (N = 208) vs. no UDCA were compared. The data of the antenatal visits, deliveries and neonatal outcome of 307 pregnancies with ICP was collected from the hospital computerized delivery room log book. UDCA was used in 208 pregnancies. The diagnosis was made by maternal pruritus and elevation of total fasting bile acid (BA) (>6 µmol/l) and elevation of serum alanine aminotransferases (ALT) (>45 U/l). Maternal and neonatal data was analysed and data of the patients who used UDCA during pregnancy was analysed separately and compared with the data from patients without medication. RESULTS: UDCA was well tolerated. Mothers receiving UDCA had ICP diagnosed five weeks earlier than mothers without medication. At the diagnosis, levels of total BA and ALT were higher in the group using UDCA compared to the group without medication. Most deliveries were induced and perinatal outcome was good. Apgar scores at 5 min were significantly lower in UDCA group (p < 0.05), but fetal umbilical artery pH values were similar in both groups (p > 0.05). There were 30 patients with total BA > 40 µmol/l at diagnosis, 24 with UDCA and 6 without medication and those deliveries were induced soon after diagnosis. The preterm labour was also more common in these patents (p < 0.05). Women with preterm babies had significantly early onset pruritus and ICP was diagnosed earlier. Serum ALT and total BA levels were significantly higher in those pregnancies at diagnosis and also at first control. CONCLUSIONS: Preterm labour was associated in severe ICP (total BA > 40 µmol/l), ALT levels were also significantly higher and ICP was diagnosed earlier (p < 0.05). Apgar scores were lower in preterm babies (p < 0.05), but umbilical artery pHvalues were not significantly lower. UDCA was well tolerated by pregnant women. With low-dose UDCA treatment the obstetric outcome was good. We still recommend careful obstetrical follow-up.

The impact of maternal obesity, age, pre-eclampsia and insulin dependent diabetes on severe maternal morbidity by mode of delivery-a register-based cohort study.

PURPOSE: To determine the rate of severe maternal morbidity related to delivery by delivery mode and to assess if the impact of studied risk factors varies by delivery mode. METHODS: A register-based study including all women having singleton delivery in Finland in 2007-2011, n = 292,253, data derived from the Finnish Medical Birth Registry and Hospital Discharge Registry. Diagnoses and interventions indicating a severe maternal complication were searched and the mode of delivery was assessed by data linkage. The impact of obesity, maternal age 35 years or more, pre-eclampsia and insulin dependent diabetes on severe maternal morbidity (all severe complications, severe infections and severe) was studied in each mode of delivery and calculated as Odds ratios. RESULTS: The overall incidence of severe complications was 12.8/1,000 deliveries. The total complication rate was lowest in vaginal deliveries (VD) in all risk groups. Obesity increased the risk for all severe complications and severe infections in the total population, but not significantly in specific delivery modes. Age increased the risk of hemorrhage in VD. Pre-eclampsia increased the risk for hemorrhage in all deliveries except elective CS. In women with pre-eclampsia, overall morbidity was similar in VD, attempted VD and elective CS. The presence of any studied risk factor increased the risk for complications within the risk groups by the high proportion of emergency CS performed. CONCLUSIONS: An attempt of VD is the safest way to deliver even for high-risk women with the exception of women with pre-eclampsia, who had a similar risk in an attempt of VD and elective CS.

Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: a randomized controlled trial.

PURPOSE: To test the efficacy and safety of ursodeoxycholic acid (UDCA) in the treatment of patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In the randomized (double-blind, placebo-controlled) study 20 pregnant women with ICP received (random allocation of) either 450 mg/day UDCA or placebo for 14 days during the third trimester of pregnancy. The severity of pruritus was registered and itching scores were assessed before the treatment and weekly thereafter. The effects of UDCA on liver function and fetoplacental hormone production were measured with covering laboratory testing: serum levels of alanine aminotransferase (ALAT), total bile acids (TBA), estradiol, progesterone, prolactin, cholesterol, HDL-cholesterol, triglycerides, activated partial thromboplastin time, fibrinogen D-dimers (FIDD) and platelet count were assessed before the treatment and weekly thereafter. Data on pregnancy and delivery outcome were recorded and analyzed. RESULTS: UDCA was well tolerated. A significant improvement in itching scores was detected in 2 weeks in the group receiving UDCA. Serum levels of ALAT and TBA fell after 2 weeks treatment. The other laboratory values were not modified by the treatment. CONCLUSIONS: UDCA improves maternal itching scores and liver function tests without interfering with the fetoplacental estrogen production in patients with ICP. UDCA is well tolerated by pregnant women. No fetal or neonatal side-effects could be detected.

Variation in cesarean section rates is not related to maternal and neonatal outcomes.

OBJECTIVE: The aim of this study was to compare the rate of cesarean sections in 12 delivery units in Finland, and to assess possible associations between cesarean section rates and maternal and neonatal complications. DESIGN: Prospective multicenter cohort study. SETTING: The 12 largest delivery units in Finland. POPULATION: Total obstetric population between 1 January 2005 and 30 June 2005 (n = 19 764). METHODS: Prospectively collected data on 2496 cesarean sections and data derived from the Finnish Birth Register on all deliveries in these units were compared. Cesarean section rates and maternal complication rates were adjusted for known risk factors. MAIN OUTCOME MEASURES: Cesarean section rate, maternal complications related to cesarean section, and neonatal asphyxia. RESULTS: The cesarean section rates varied significantly between the hospitals (12.9-25.1%, p < 0.0001), as did the maternal complication rates related to cesarean section (13.0-36.5%, p < 0.0001). There was no relation between maternal complications and the cesarean section rate. The differences remained after adjusting for risk factors. Neonatal asphyxia rates varied between 0.14 and 2.8% (p < 0.0001) and were not related to the cesarean section rates. CONCLUSIONS: The rates of cesarean section, maternal complications and neonatal asphyxia vary markedly between different delivery units. Good maternal and neonatal outcomes can be achieved with cesarean section rates <15%.

[Reproductive health after cancer treatment--contraception, planning and monitoring of pregnancy]. / Lisääntymisterveys hoidetun syövän jälkeen --raskauden ehkäisyä, suunnittelua ja seurantaa.

Infertility is common after cancer treatments, but pregnancies of those treated for cancer usually proceed well. Pretreatment counseling by a fertility doctor improves posttreatment quality of life. The most important issues to be considered in pregnancy planning and monitoring include cytotoxic drug induced organ-specific insufficiencies and radiotherapy targeted at the thoracic region, whole body, or at the uterus during childhood. Hypothyroidism is the most common hormonal complication and is also significant with respect to fertility and gravidity.

Dietary sucrose intake is related to serum leptin concentration in overweight pregnant women.

BACKGROUND: Overweight, characterized by low-degree systemic inflammation, predisposes women to impaired glucose metabolism during pregnancy. Adipokine leptin participates in the regulation of energy balance and immune action. AIMS OF THE STUDY: Objective of the study was to evaluate if aberrations in glucose metabolism during pregnancy are related to leptin concentration and whether serum leptin concentration is affected by diet composition. SUBJECTS AND METHODS: Normal-weight (n = 61) and overweight or obese (BMI > 25, n = 42) pregnant women visited study clinic at third trimester of pregnancy and one month postpartum. Serum fasting leptin and insulin as well as plasma glucose concentrations were measured, insulin resistance (HOMA) and sensitivity (QUICKI) calculated, and dietary intake from food records determined. RESULTS: In overweight women leptin concentration was significantly higher both in pregnancy, 45.27 (95% CI 39.40-51.14) ng/ml, and postpartum, 31.84 (27.38-36.30) ng/ml, than in normal-weight women, 31.09 (95% CI 27.80-34.37) ng/ml and 16.23 (13.93-18.53) ng/ml, respectively. Equally, blood glucose concentration during pregnancy was higher, 4.82 (4.67-4.97)mmol/l, and insulin concentration, 15.34 (12.00-18.68) mU/l, more pronounced in overweight compared to normal-weight women, 4.51 (4.42-4.61) mmol/l and 8.28 (7.21-9.36) mU/l, respectively. Significantly higher HOMA and lower QUICKI were also detected in overweight compared to normal-weight women. At third trimester of pregnancy, leptin concentration correlated positively with insulin concentration in normal-weight (r = 0.561, P = 0.002) and overweight women (r = 0.736, P < 0.001), as well as with HOMA (r = 0.568, P = 0.002 and r = 0.731, P < 0.001, respectively) whereas negative association was found with QUICKI in normal-weight (r = -0.484, P = 0.011) and overweight women (r = -0.711, P < 0.001). Importantly, serum leptin concentration was affected by dietary sucrose intake both as quantitatively (r = 0.424, P = 0.009) and relative to energy intake (r = 0.408, P = 0.012) in overweight but not in normal-weight pregnant women. CONCLUSIONS: Overweight-related elevation in serum leptin is associated with impaired regulation of glucose metabolism during pregnancy. The novel finding that dietary sucrose intake is related to serum leptin concentration is in line with the current dietary recommendations to overweight pregnant women with impaired glucose metabolism advising the lower intake of sucrose during pregnancy.

Cesarean delivery in Finland: maternal complications and obstetric risk factors.

OBJECTIVE: To assess the rate of maternal complications related to cesarean section (CS) and to compare morbidity between elective, emergency and crash-emergency CS. To establish risk factors associated with maternal CS morbidity. DESIGN: A prospective multicenter cohort study. SETTING: Twelve delivery units in Finland. POPULATION: Women delivering by CS (n = 2,496) during a 6 months period in the study hospitals. METHODS: Data on pregnant women, CS, and maternal recovery during the hospital stay was collected prospectively on report forms. The complication rates by different CSs were calculated, and factors associated with morbidity were analyzed by odds ratios (OR). MAIN OUTCOME MEASURES: Maternal complication rates in different types of CS. The association of risk factors with morbidity. RESULTS: About 27% of women delivering by CS had complications; 10% had severe complications. The complication rate was higher in emergency CS than in elective CS, and highest in crash-emergency CS. Significant independent risk factors for maternal morbidity were emergency CS and crash-emergency CS compared to elective CS (OR 1.8; 95% confidence interval (CI) 1.5-2.2), pre-eclampsia (OR 1.5; CI 1.1-2.0), maternal obesity (OR 1.4; CI 1.1-1.8) and maternal increasing age (OR 1.1; CI 1.03-1.2 per each 5 years). CONCLUSIONS: Maternal complications are frequent in CS, and although performing CS electively reduces the occurrence of complications, the frequency is still high. The complication rate depends on the degree of emergency, and increases with maternal obesity, older age and pre-eclampsia.

Severe maternal morbidity and the mode of delivery.

OBJECTIVE: To define the rate of severe maternal morbidity in different modes of delivery and to find out if the rate of severe morbidity has changed over a 5-year time span. DESIGN: Retrospective register-based study. SETTING: Finnish Medical Birth Registry and Hospital Discharge Registry. POPULATION: All singleton deliveries in Finland in 1997 and 2002 (n=110,717). METHODS: Diagnoses and operative interventions recorded in the Hospital Discharge Registry indicating a severe maternal complication were linked with Birth Register data and compared by mode of delivery: spontaneous vaginal delivery (VD), instrumental VD, elective cesarean section and non-elective cesarean section. Main outcome measures were severe maternal morbidity: deep venous thromboembolism and amniotic fluid embolism, major puerperal infection, severe hemorrhage, events requiring operative intervention after delivery, uterine rupture and inversion, and intestinal obstruction. RESULTS: Severe maternal morbidity was more frequent in cesarean than vaginal deliveries (p<0.001), and more frequent in non-elective than in elective operations (p<0.001). The rate of severe maternal morbidity increased considerably from 1997 to 2002; from 5.9 to 7.6 per 1,000 in all deliveries (p<0.001), from 4.0 per 1,000 to 5.2 per 1,000 in spontaneous vaginal deliveries (p=0.005), from 9.9 per 1,000 to 12.1 per 1,000 in elective cesarean sections (CSs) (p=0.164), and from 19.6 per 1,000 to 27.2 per 1,000 in non-elective CSs (p=0.090), respectively. CONCLUSIONS: Severe maternal morbidity has increased both in cesarean and vaginal deliveries from 1997 to 2002. Cesarean delivery, even an elective one, carries a significantly higher risk of life-threatening maternal complications than VD.

Hepatocellular enzyme glutathione S-transferase alpha and intrahepatic cholestasis of pregnancy.

OBJECTIVE: To evaluate and compare plasma glutathione S-transferase alpha (GSTA) concentrations in the third trimester of pregnancy in patients with intrahepatic cholestasis of pregnancy (ICP) and in healthy pregnant women. DESIGN: Non-randomized clinical study. SETTING: Maternity unit and Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland. POPULATION: Twenty-seven women with ICP and 49 healthy pregnant women. METHODS: GSTA concentrations were assessed in plasma samples in the third trimester of pregnancy using an enzyme-linked immunoassay (HEPKIT Alpha, Biotrin, Sinsheim-Reihen, Germany). MAIN OUTCOME MEASURES: Plasma GSTA, serum alanine and bile acid concentrations were compared between study and control group. Correlation between plasma GSTA levels and serum alanine aminotransferase and bile acid levels in the ICP patients were tested by Spearman correlation coefficients. Main perinatal outcome was compared between the groups. RESULTS: GSTA concentration in the control group was 1.62 microg/l (range: 0.25-6.1). In the ICP patients, the mean plasma GSTA concentration was 51.0 microg/l (range: 2.1-183.5), the mean serum alanine aminotransferase concentration was 145.70 U/l (range: 6-393) and the mean bile acid concentration was 19.2 micromol/l (range: 3-63). There was a statistically significant correlation in ICP patients between plasma GSTA concentration and serum alanine aminotransferase concentration (r=0.694, p=0.0001), but not with serum bile acid concentration. Nor was there any statistically significant correlation between gestational weeks and plasma GSTA concentration in the study group. CONCLUSION: Plasma GSTA measurements may provide a more sensitive and specific diagnostic tool for diagnosis of ICP than the evaluation of transaminases or bile acid concentrations alone. Further studies are needed to evaluate the role of GSTA in the follow-up of patients with ICP and its prognostic value for threatening fetal distress in patients with ICP.

Continuous glucose monitoring versus self-monitoring of blood glucose in the treatment of gestational diabetes mellitus.

OBJECTIVE: To compare Continuous Glucose Monitoring System (CGMS) with self-monitoring of plasma glucose (SM) in detecting patients with gestational diabetes mellitus (GDM) needing antidiabetic drug treatment. RESEARCH DESIGN AND METHODS: Pregnant women at 22-34 gestational weeks had at least two abnormal high values out of three in OGTT. Patients were randomly allocated to have CGMS) (n=36) or SM (n=37). Dietary counselling was similar in both groups. Patients tested their plasma glucose 5 times per day. Need of antidiabetic treatment was determined using the following cut-off values: fasting plasma glucose >5.5mmol/L twice or >5.5mmol/l once and postprandial value>7.8mmol/l, or postprandial value at least twice above 7.8mmol/l. RESULTS: In 11 out of 36 patients (31%) monitored with CGMS) antihyperglycemic drug therapy was introduced (8/36 insulin only, 2/36 metformin only, 1/36 insulin+metformin) whereas only 3/37 (8%) in the self-monitoring group were drug-treated (difference between groups, p=0.0149). There were no statistically significant differences between the groups regarding maternal age, pre-pregnancy BMI, HbA1c, gestational weeks at delivery, rate of pregnancy-induced hypertension, rate of caesarean section, infant birth weight or neonatal hypoglycaemia. CONCLUSIONS: Continuous glucose monitoring system detects a markedly higher proportion of GDM mothers needing antihyperglycemic medication compared with self-monitoring of plasma glucose. Further large-scale studies are needed to evaluate whether CGMS) guided initiation of antihyperglycemic therapy results in less macrosomia and perinatal complications related to GDM.

Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have gained wide acceptance in the treatment of mental disorders in pregnant women, but there seems to be an increased risk for neonatal adaptation problems after exposure to SSRIs in late pregnancy. We aimed to investigate the perinatal sequelae of infants exposed to SSRIs during their fetal life and the relationship of these symptoms to the cord blood monoamine and prolactin concentrations. METHODS: We conducted a prospective, controlled, follow-up study with 20 mothers taking 20 to 40 mg/d of either citalopram or fluoxetine for depression (n = 10) or panic disorder (n = 10) and their infants and 20 matched controls not receiving psychotropic medication for confounding obstetric characteristics. Maternal cord blood and infant citalopram, fluoxetine, and norfluoxetine, cord blood monoamine and metabolite, and prolactin concentrations were measured. The newborns underwent standard clinical examination and specific assessment of serotonergic symptoms during the first 4 days of life and at the ages of 2 weeks and 2 months. RESULTS: There was a statistically significant (P =.008, V = 15, n = 20 for both groups), 4-fold difference in the serotonergic symptom score during the first 4 days of life between the SSRI group and the control group. The SSRI-exposed infants had significantly lower cord blood 5-hydroxyindoleacetic acid (5-HIAA) concentrations (P =.02, t31 = 2.57) compared with the control group. A significant inverse correlation (rs = -0.66, P =.007, n = 15) was seen between the serotonergic symptom score and the umbilical vein 5-HIAA concentrations in the SSRI-exposed but not the control infants. CONCLUSIONS: Infants exposed to SSRIs during late pregnancy are at increased risk for serotonergic central nervous system adverse effects, and the severity of these symptoms is significantly related to cord blood 5-HIAA levels.

Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation.

BACKGROUND: The aim of this prospective clinical trial was to investigate the pharmacokinetics of fluoxetine and its active metabolite, norfluoxetine, during pregnancy, delivery, and lactation in mothers and their infants. METHODS: Eleven mothers taking fluoxetine and their infants were enrolled in the study. A control group of 10 women who were not taking psychotropic medication were prospectively matched for confounding obstetric characteristics at the time of delivery. Trough plasma samples and breast milk samples were collected from mother-infant pairs during pregnancy, at delivery, and up to 2 months after delivery in the fluoxetine group. The pregnancy outcome was recorded, and the growth and neurologic development of the children were followed up to the age of 1 year in both study groups. RESULTS: The fluoxetine dose from 20 mg to 40 mg once daily resulted in relatively low trough fluoxetine-norfluoxetine concentrations during pregnancy (range, 317-850 nmol/L). The mean norfluoxetine/fluoxetine metabolic ratio was 2.4-fold higher during late pregnancy than at 2 months after delivery (P = .0072). At delivery, the infant plasma fluoxetine and norfluoxetine concentrations were 65% and 72%, respectively, of those found in mothers. The mean estimated infant exposures from breast milk to fluoxetine-norfluoxetine were 2.4% and 3.8% of the maternal weight-adjusted daily dose at age 2 weeks and age 2 months, respectively. The pregnancy outcome, as well as the growth and neurologic development of all infants up to 1 year of age, was normal. CONCLUSION: Common clinical doses of fluoxetine resulted in relatively low concentrations of fluoxetine during pregnancy, which can be explained at least partly by increased demethylation of fluoxetine by cytochrome P450 (CYP) 2D6. This might indicate that these low blood levels could lead to therapeutic failure, and clinicians should be alert to this possibility so that depression in pregnancy is not undertreated.

Citalopram in pregnancy and lactation.

BACKGROUND: Although citalopram has gained wide acceptance in the treatment of depression and anxiety disorders, its use during pregnancy and lactation has been poorly characterized. The aim of this study was to examine the efficacy and safety of citalopram in relation to concentrations of citalopram and its metabolites during pregnancy and lactation. METHODS: Eleven mothers taking citalopram and their infants were enrolled in the study, and a control group of 10 women who were not taking medication were prospectively matched for confounding obstetric characteristics at the time of delivery. Plasma and breast milk samples were collected from mother/infant pairs during pregnancy, at delivery, and for up to 2 months after delivery. Trough plasma and breast milk concentrations of citalopram, desmethylcitalopram, and didesmethylcitalopram were measured by HPLC. The pregnancy outcome was recorded, and the neurodevelopment of children was monitored for up to 1 year. RESULTS: Although the citalopram dose of 20 mg to 40 mg once daily resulted in low maternal trough plasma concentrations (range, 46-214 nmol/L) and metabolites during pregnancy, only one subject required an increase of daily dose. The mean didesmethylcitalopram-desmethylcitalopram metabolic ratio was significantly higher during pregnancy (54%, P <.001) than at 2 months after delivery, indicating induction of cytochrome P450 (CYP) 2D6 during pregnancy. At delivery, the trough plasma citalopram, desmethylcitalopram, and didesmethylcitalopram concentrations in the infants were 64%, 66%, and 68% of the maternal concentrations, respectively. The citalopram and metabolite concentrations in the milk were 2- to 3-fold higher compared with maternal plasma concentrations, but the infant citalopram and metabolite plasma concentrations were very low or undetectable. The delivery outcome and the neurodevelopment of all infants up to the age of 1 year were normal. CONCLUSION: Even though the sample size was limited, results from this prospective clinical trial suggest uncomplicated pregnancy outcome in mothers using citalopram during pregnancy and minimal exposure of the infants to citalopram during lactation. However, maternal therapeutic drug monitoring of citalopram should be recommended to minimize fetal exposure.

Low cerebral blood flow resistance in nonventilated preterm infants predicts poor neurologic outcome.

OBJECTIVES: To examine whether cerebral blood flow variables during the first critical day of life can predict the 1-yr neurologic outcome in ventilated and nonventilated preterm infants. DESIGN: Prospective follow-up study. SETTING: Neonatal intensive care unit of university central hospital. PATIENTS: Forty-nine preterm infants <33 wks of gestation. INTERVENTIONS: Doppler ultrasound investigations of the brain circulation, heart rate, and systemic blood pressure were performed in ventilated (n = 35) and nonventilated (n = 14) preterm infants during the first day of life. The neurologic development was evaluated using Griffith's subscales at 12 months of corrected age. MEASUREMENTS AND MAIN RESULTS: Cerebral blood flow velocity measurements were obtained from the anterior cerebral artery and internal carotid artery. Cerebral blood flow, cerebral blood flow resistance, and cerebral perfusion pressure subsequently were derived. These derived cerebral perfusion variables were associated with the sum of Griffith's developmental scales (p <.02). However, the slopes of regression lines between cerebral blood flow or cerebral blood flow resistance and the sum of Griffith's psychomotor developmental scales tended to be different in the ventilated and nonventilated infants (p =.06, p =.003, respectively). The correlations between these variables and the sum of Griffith's psychomotor developmental scales were significant only in nonventilated preterm infants (r =.69, p =.007, and r = -.85, p =.001, respectively). CONCLUSIONS: Our data suggest that lowered cerebral blood flow resistance reflecting lowered cerebral blood flow during early circulatory transition is associated with adverse outcome in nonventilated preterm infants, but no connection in ventilated infants was found.

The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus.

The purpose of the study was to examine in vivo placental transfer of metformin, its association with neonatal outcome in metformin-treated gestational diabetes (GDM) patients, and influence of metformin exposure on maternal glycemic control and weight gain. Two hundred and seventeen GDM patients were randomized to metformin or insulin in Turku University Hospital, Finland. Metformin concentrations were determined by mass spectrometry in maternal serum at 36 gestational weeks (gw) and at birth, and in umbilical cord blood. Main outcome measures were birth weight, gw at birth, umbilical artery pH and neonatal hypoglycemia, maternal weight gain, HbA1c and fructosamine concentration. Median umbilical cord/maternal serum metformin concentration ratio was 0.73. There were no differences in birth weight measured in grams or SD units (p = 0.49), or gw at birth (p always ≥0.49) between insulin- and metformin-treated patients stratified by trough metformin concentration tertiles measured at 36 gw. Rate of neonatal hypoglycemia (p = 0.92) and umbilical artery pH value (p = 0.78) was similar in insulin- and metformin-treated patients stratified by cord metformin concentration tertiles. Maternal glycemic control was similar in metformin concentration tertiles at 36 gw. Maternal weight gain was 223 g greater per week (p = 0.038) in the lowest metformin tertile compared to other tertiles combined. Maternal and fetal exposure to metformin is similar. Maternal or fetal metformin concentrations do not predict maternal glycemic control or neonatal outcome, but low maternal exposure may lead to greater maternal weight gain.

Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs).

OBJECTIVES: Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. STUDY DESIGN: Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. RESULTS: Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P<0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. CONCLUSIONS: The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide.

The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta.

OBJECTIVES: Our aim was to investigate the mode of placental transfer of metformin in term human placenta with special reference to involvement of the organic cation transporters (OCTs). STUDY DESIGN: Twenty-nine placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of metformin, which is a substrate for OCTs by using antipyrine as a reference of passive diffusion transfer compound. Cimetidine was used as an inhibitor for OCT-dependent active transfer. RESULTS: Maternal-to-fetal transfer of metformin and antipyrine were 3.7% and 10.0%, respectively, and fetal-to-maternal transfers were 15.5% and 42.3%, respectively. Cimetidine did not have any effect on the transfer of metformin. Fetal-to-maternal transfer of metformin was significantly higher than maternal-to-fetal transfer (P<0.05) in perfusions performed with or without cimetidine. CONCLUSIONS: A higher transfer rate of metformin was detected in fetal-to-maternal than maternal-to-fetal direction, but a similar difference was observed with antipyrine. Inhibition of OCTs did not have a significant effect on the placental transfer of metformin. Although the existence of other active transporting systems cannot be ruled out, the influence of OCT-dependent active transport system on the placental pharmacokinetics of metformin is unlikely significant.