Pregnancy outcomes in breech presentation analyzed according to intended mode of delivery.

INTRODUCTION: Optimal mode of delivery in breech presentation has been widely examined and debated. The aim of this study was to compare perinatal and maternal outcomes with either a policy of planned vaginal delivery or planned cesarean section in breech presentation. MATERIAL AND METHODS: This was a registry-based retrospective cohort study from Turku University Hospital, Finland with 1418 singleton breech deliveries at term over a period of 11 years (January 2002 to December 2012). Data were collected from the mothers' medical records. RESULTS: Apgar scores at 5 min as well as umbilical artery pH values were significantly lower in the planned vaginal breech delivery group compared with the planned cesarean section group, suggesting a short-lasting delayed recovery after birth. There were more puerperal infections in planned cesarean section group compared with the planned vaginal delivery group. CONCLUSIONS: The results confirm that planned vaginal breech delivery results in short-lasting delayed recovery after birth compared with planned cesarean section.

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.

The effect of probenecid and MK-571 on the feto-maternal transfer of saquinavir in dually perfused human term placenta.

Human placenta, particularly the blood-placenta barrier, with various transporters has crucial role to protect the fetus and, on the other hand, to facilitate movement of compounds towards the fetal circulation. This study aimed to characterize the role of basal transporters of the syncytiotrophoblast, which appear to be yet less studied, in the fetal-to-maternal transfer of saquinavir by use of dually perfused human placentas. A dual perfusion of human placenta was performed to study effect of MK-571 and probenecid, inhibitors of the MRP1 and OATP transporters, expressed in the basal trophoblast membrane, on the transfer of saquinavir. The fetal-to-maternal placental transfer of saquinavir in the control group as measured by TPT(AUC)% (absolute fraction of the dose crossing placenta) was 14.0%, which is 73% less than the transfer of the freely diffusible antipyrine. The two inhibitors, MK-571 and probenecid caused a non-significant (P = 0.34 for ANOVA) reduction of 43% and 24%, respectively, in the mean amount of saquinavir transferred from the fetal to the maternal side. MK-571 also somewhat (by 31%) reduced the TPT(AUC)% of antipyrine, but this finding did not reach statistical significance (P = 0.25). Neither of the employed inhibitors had an effect on the placental transfer index of saquinavir transfer (P = 0.77). The present results indicated lack of significant effect by MK-571 and probenecid on the fetal-to-maternal transfer of saquinavir and suggest that MRP1 and, possibly, OATP2B1 do not play a significant role in the fetal-to-maternal transfer of saquinavir.

MAO-A and COMT genotypes as possible regulators of perinatal serotonergic symptoms after in utero exposure to SSRIs.

Intrauterine exposure to SSRIs in late pregnancy can cause various serotonergic symptoms in the newborns. We associated the severity of these symptoms to neurotransmitter concentrations and genetic polymorphisms in the cytochrome P450, MAO-A and COMT enzymes. Altogether 20 children with prenatal exposure to citalopram or fluoxetine were genotyped. Infants with two high-activity alleles of the MAO-A gene had significantly higher serotonergic symptom scores than infants with at least one low-activity allele (mean 8.8 vs. 2.4, p=0.024). These infants had also higher cord blood DHPG concentrations (p=0.0054). Carriers of the high-activity COMT alleles had higher cord blood prolactin concentrations (p=0.044). According to our results, the higher serotonergic symptom score and cord blood DHPG concentration in rapid MAO-A metabolizers suggest that norepinephrine may modify the severity of perinatal serotonergic symptoms. The COMT 1947G>A polymorphism may affect the occurrence of respiratory distress symptoms in infants with prenatal SSRI-exposure via a mechanism involving prolactin.

Placental transfer of quetiapine in relation to P-glycoprotein activity.

Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPT(AUC) % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPT(AUC) % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPT(AUC) %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood-placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.

Transfer of proinflammatory cytokines across term placenta.

OBJECTIVE: Increased concentrations of proinflammatory cytokines in amniotic fluid indicate the presence of intra-amniotic inflammation and increase the risk of preterm birth, cerebral palsy, and bronchopulmonary dysplasia. The purpose of this study was to find out if the proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, transfer across the placenta, and thereby determine whether intra-amniotic inflammatory response, measured from the amniotic fluid, is of maternal or fetal origin. METHODS: Nineteen placentas from healthy women undergoing elective cesarean delivery at term with intact membranes and without labor, were dually perfused ex vivo in an open circulation system for either 30 minutes or 2 hours. Tumor necrosis factor-alpha, IL-1beta, and IL-6 were added to maternal or fetal circulation in a concentration usually found in chorioamnionitis. As a reference, placentas without added cytokine were also perfused. The concentrations of cytokines were determined by enzyme immunoassays (enzyme-linked immunosorbent assay [ELISA]). RESULTS: After the addition of the cytokine to the arterial perfusate, the venous concentration on the same side of the placenta increased rapidly and reached a plateau at 10 minutes. No transfer of any cytokine in either direction was detected. Some endogenous release of IL-6 was observed in response to the perfusion. CONCLUSION: Proinflammatory cytokines do not cross normal term placenta.

Functional role of P-glycoprotein in the human blood-placental barrier.

OBJECTIVE: In vitro and animal experiments suggest that P-glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P-glycoprotein in the blood-placental barrier by use of dually perfused human placenta. METHODS: Twenty-eight human placentas were obtained after delivery, and both the maternal side and the fetal side were perfused for 2 hours. Saquinavir was used as a probe drug for P-glycoprotein-dependent active transfer, and PSC833 (valspodar) or GG918 was used as an inhibitor of P-glycoprotein function in a maternal-to-fetal and fetal-to-maternal perfusion setting. Genotyping for ABCB1 (C3435T and G2677A/T) polymorphism and quantification of P-glycoprotein expression were done for each placenta. RESULTS: The fetal-to-maternal transfer of saquinavir was 108-fold higher (P = .003) compared with transfer from the maternal to the fetal direction. Preperfusion with PSC833 increased the placental transfer of saquinavir by 7.9-fold (P < .001), and preperfusion with GG918 increased it by 6.2-fold (P < .001). The end-perfusion transfer (percentage) of saquinavir at 120 minutes was 11-fold (P < .001) and 6-fold (P < .001) higher in placentas preperfused with PSC833 and GG918, respectively, compared with control. However, PSC833 had no effect on the transfer of saquinavir from the fetal to the maternal direction (P = .79). P-glycoprotein expression was correlated with the PSC833-induced change in the saquinavir transfer (r = 0.75, P = .086). ABCB1 polymorphism did not affect the PSC833- or GG918-induced change in the saquinavir transfer. CONCLUSIONS: P-glycoprotein has a major functional role in the human blood-placental barrier but a negligible role in the removal of substances from the fetal circulation to maternal blood. Pharmacologic blockade of P-glycoprotein function can lead to disruption of the blood-placental barrier and increase the transfer of P-glycoprotein substrates to the fetal side by several-fold, which may be a noteworthy mechanism for teratogenicity.

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.