[Show abstract][Hide abstract] ABSTRACT: Abstract Mitochondrial toxicity in perinatally human immunodeficiency virus (HIV)-infected pediatric patients has been scarcely investigated. Limited data are available about HIV or antiretroviral (ARV)-mediated mitochondrial damage in this population group, specifically, regarding oxygen consumption and apoptosis approach. We aimed to elucidate whether a given mitochondrial DNA depletion is reflected at downstream levels, to gain insight on the pathology of HIV and highly active antiretroviral therapy (HAART) in perinatally HIV-infected pediatric patients. We studied 10 healthy control participants and 20 perinatally HIV-infected pediatric patients (10 under ARV treatment and 10 off treatment). We determined mitochondrial mass, subunits II and IV of complex IV, global and specific mitochondrial enzymatic and oxidative activities, and apoptosis from peripheral blood mononuclear cells. Global oxygen consumption was significantly compromised in HIV-infected untreated patients, compared to the control group (0.76 ± 0.01 versus 1.59 ± 0.15; P = 0.014). Apoptosis showed a trend to increase in untreated patients as well. The overall complex (C) CI-III-IV activity of the mitochondrial respiratory chain (MRC) was significantly decreased in HIV-infected treated patients with respect to the control group (1.52 ± 0.38 versus 6.38 ± 1.53; P = 0.02). No statistically significant differences were found between untreated and HAART-treated patients. These findings suggest the pathogenic role of both HIV and HAART in mitochondrial dysfunction in vertical infection. The abnormalities in mitochondrial genome may be downstream reflected through a global alteration of the MRC. Mitochondrial impairment associated with HIV and HAART was generalized, rather than localized, in this series of perinatally HIV-infected patients.
Drug and Chemical Toxicology 03/2013; · 1.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Lithium has been used in the treatment of bipolar disorder in pregnant women. However, information on the pharmacokinetics of lithium during perinatal period is scarce.
Objectives: To study pharmacokinetics of lithium during delivery and in the neonatal period.
Methods: A prospective, observational and naturalistic study was conducted at the PERINATAL PSYCHIATRY PROGRAM CLÍNIC-BARCELONA, from 2005 to 2012. We included all consecutive cases of pregnant women with bipolar disorder I or II (n=22), and on maintenance treatment with lithium monotherapy (n=13) or polytherapy (n=9) during pregnancy who elected artificial feeding. Lithium plasma concentrations in maternal blood and umbilical cord were detected. Lithium plasma concentrations in infants (n=16) at delivery and in the neonatal period were obtained to calculate elimination half-life, which was estimated by lineal regression. Technique: AVL 9180 electrolyte analyser using a lithium-selective electrode (detection
limit =0.10 mEq/L).
Results: Women did not fulfil diabetes criteria pre-pregnancy and during pregnancy. Attending to neonatal outcomes, infants exposed to polytherapy had a higher weight at birth (percentils) than those exposed to lithium alone [53.38 (33.40) vs. 70.22 (26.25)]. No statistically significant differences were found in umbilical cord:maternal plasma concentration ratio between those treated with lithium monotherapy and women treated with polytherapy (1.05 vs. 1.08). The lithium mean elimination half-life (SD) in infants was 6.73 (9.12) days.
Conclusions: Lithium crosses placental barrier almost completely. Elimination half-life in neonates exposed to lithium in utero was 6.73 days. Moreover, lithium treatment during pregnancy requires therapeutics monitoring in exposed dyads.
21 st European Congress of Psychiatry (EPA 2013), Nice (France), Nice; 01/2013
[Show abstract][Hide abstract] ABSTRACT: To assess the association between HIV infection and both spontaneous and iatrogenic preterm delivery (PTD), and to explore the impact of HAART on both entities.
A matched retrospective cohort study was carried out on 517 HIV-infected pregnant women who consecutively attended a university referral hospital between 1986 and 2010. Two controls were assigned for each case. They were matched by ethnicity, smoking, maternal age and educational level. Exclusion criteria were multiple pregnancy and active injection drug use (IDU). PTD was defined as delivery less than 37.0 weeks. Spontaneous PTD included preterm premature rupture of membranes. Iatrogenic delivery was considered if medically indicated. Factors associated with PTD among HIV-infected women were analyzed by logistic regression.
A total of 1557 pregnant women were analyzed (519 HIV-infected and 1038 noninfected). The incidence of PTD was 19.7% in HIV-infected women and 8.5% in controls [odds ratio (OR) 2.6; 95% CI 1.9-3.6]. There was a significantly higher incidence of both spontaneous [adjusted OR (AOR) 2.1; 95% confidence interval (CI) 1.5-3.0] and iatrogenic prematurity (AOR 3.2; 95% CI 1.8-5.7). Iatrogenic PTD was significantly associated with the use of HAART during the second half of pregnancy, whereas spontaneous PTD was not related to HAART.
There is a significant association of HIV infection with PTD, both spontaneous and iatrogenic PTD. HAART use was predominantly associated with iatrogenic PTD.
AIDS (London, England) 01/2012; 26(1):37-43. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Highly active antiretroviral therapy (HAART) has decreased the risk of HIV mother-to-child transmission. However, HIV and HAART have been associated with adverse perinatal outcome. HAART has been associated with mitochondrial dysfunction in nonpregnant adults, and HIV, additionally, to apoptosis. We determined whether mitochondrial toxicity and apoptosis are present in HIV-pregnant women and their newborns and could be the basis of adverse pregnancy outcome.
Single-site, cross-sectional, controlled observational study without intervention.
We studied mitochondrial and apoptotic parameters in mononuclear cells from maternal peripheral blood and infant cord blood at delivery in 27 HIV-infected and treated pregnant women, and 35 uninfected controls and their infants, to correlate clinical outcome with experimental findings: mitochondrial number (CS), mtDNA content (ND2/18SrRNA), mitochondrial protein synthesis (COX-II/V-DAC), mitochondrial function (enzymatic activities) and apoptotic rate (caspase-3/β-actin).
Global adverse perinatal outcome, preterm births and small newborn for gestational age were significantly increased in HIV pregnancies [odds ratio (OR) 7.33, 5.77 and 9.71]. Mitochondrial number was unaltered. The remaining mitochondrial parameters were reduced in HIV mothers and their newborn; especially newborn mtDNA levels, maternal and fetal mitochondrial protein synthesis and maternal glycerol-3-phosphate + complex III function (38.6, 25.8, 13.6 and 31.2% reduced, respectively, P < 0.05). All materno-fetal mitochondrial parameters significantly correlated, except mtDNA content. Apoptosis was exclusively increased in infected pregnant women, but not in their newborn. However, adverse perinatal outcome did not correlate mitochondrial or apoptotic findings.
Transplacental HAART toxicity may cause subclinical mitochondrial damage in HIV-pregnant women and their newborn. Trends to increased maternal apoptosis may be due to maternal-restricted HIV infection. However, we could not demonstrate mitochondrial or apoptotic implication in adverse perinatal outcome.
AIDS (London, England) 12/2011; 26(4):419-28. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiretroviral therapy during pregnancy is critical to preventing human immunodeficiency virus vertical transmission. Physiological changes during pregnancy can alter drug kinetics. The aim of this study was to assess the pharmacokinetics (PK) of saquinavir (SQV) boosted with ritonavir during pregnancy and postpartum. Fourteen human immunodeficiency virus-positive pregnant women started SQV 500 mg new tablet formulation plus ritonavir at a dose of 1000/100 mg twice a day + 2 nucleoside retrotranscriptase inhibitors during pregnancy. At weeks 24 and 34 of pregnancy and 6 weeks postpartum, a 12-hour PK study was conducted. PK parameters were calculated using Win Nolin software version 4.1. At week 24, the geometric mean values for SQV area under the plasma concentration-time curve from 0-12 hours (AUC₀₋₁₂), the maximum observed plasma concentration (C(max)), trough plasma concentration (C(min)), and the elimination half-life (t(1/2)) were 24.80 mg·h⁻¹·mL⁻¹, 4.66 mg/mL, 0.93 mg/mL, and 4.31 hours, respectively. At week 34, AUC₀₋₁₂, C(max), C(min), and t(1/2) were 12.71 mg·h⁻¹·mL⁻¹, 3.23 mg/mL, 0.26 mg/mL, and 4.06 hours, respectively. Finally, at 6 weeks postpartum, mean values for SQV AUC₀₋₁₂, C(max), C(min), and t(1/2) were 28.94 mg·h⁻¹·mL⁻¹, 3.92 mg/mL, 0.86 mg/mL, and 3.60 hours, respectively. Although PK parameters in week 24 and postpartum were very similar, those for week 34 showed an important reduction: -71.20%, -30.61%, -48.73%, and -5.81% in C(min), C(max), AUC₀₋₁₂, and t(1/2), respectively, compared with week 24, but no statistically significant differences were shown between patients. No vertical transmissions were reported. Therapeutic drug monitoring of SQV during pregnancy should be considered, mainly during the third trimester, to ensure adequate drug exposure throughout the entire pregnancy.
Therapeutic drug monitoring 12/2011; 33(6):772-7. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the effects of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on obstetrical and neonatal outcomes.
A case-control study was conducted to compare perinatal outcomes among pregnant women with affective disorder (DSM-IV criteria) and who received SSRIs during pregnancy with those of women without an active psychiatric disorder during pregnancy who were non-exposed to antidepressants during pregnancy. Each case was matched to two controls for maternal age (± 2 years) and parity.
A total of 252 women were enrolled in the study, 84 exposed and 168 non-exposed. Demographic and clinical characteristics did not differ significantly between the groups. The rates of prelabor rupture of membranes, induction of labor and cesarean delivery were slightly higher but not statistically significant in the exposed group. The mean gestational age at birth was 38.8 (± 1.86) weeks for the exposed group and 39.4 (± 1.52) weeks for the non-exposed group (p=.005). Rates for preterm birth were higher in the exposed group (OR=3.44, 95% CI=1.30-9.11). After stratification for dose, it was found that exposure to a high-dose was associated with lower gestational age (p=.009) and higher rates of prematurity (OR=5.07, 95% CI=1.34-19.23). The differences remained significant after controlling for maternal status and the length of exposure.
Women treated with SSRIs during pregnancy, mainly at high-dose, had an increased risk of preterm birth compared to healthy women of similar age and parity who were not exposed to SSRI during pregnancy.
Journal of affective disorders 09/2011; 135(1-3):208-15. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We determined the mitochondrial status of a group of HIV-infected children, some with body fat abnormalities (BFA). We included 24 controls, 16 HIV-infected untreated, 26 HIV-infected treated, 6 BFA-untreated, and 21 BFA-treated patients. Genetic, translational, and functional mitochondrial values were measured. As compared with controls, mitochondrial DNA depletion and a reduction in functionality were found in BFA groups.
[Show abstract][Hide abstract] ABSTRACT: IntroductionThe objective of this study was to evaluate different surgical treatments and radiotherapy on patterns of recurrence and overall IntroductionThe objective of this study was to evaluate different surgical treatments and radiotherapy on patterns of recurrence and overall
survival in patients with endometrioid-type endometrial cancer. survival in patients with endometrioid-type endometrial cancer.
Materials and methodsThe retrospective records of 162 patients with endometrioid endometrial cancer were collected. Patients were surgically treated Materials and methodsThe retrospective records of 162 patients with endometrioid endometrial cancer were collected. Patients were surgically treated
from 1997 to 2002. Recurrence and survival were analyzed according to patient age, surgical procedure, lymphadenectomy, externalbeam from 1997 to 2002. Recurrence and survival were analyzed according to patient age, surgical procedure, lymphadenectomy, externalbeam
irradiation, brachytherapy, surgical stage, myometrial invasion, and tumor grade. Standard statistical calculations were used. irradiation, brachytherapy, surgical stage, myometrial invasion, and tumor grade. Standard statistical calculations were used.
ResultsMedian age was 64 years. Median follow-up was 44 months. Overall, ten patients (5.6%) experienced recurrence and 14 (8.6%) ResultsMedian age was 64 years. Median follow-up was 44 months. Overall, ten patients (5.6%) experienced recurrence and 14 (8.6%)
died. With univariate analysis, statistical significance for survival was found for age older than 70 years, tumor grade, died. With univariate analysis, statistical significance for survival was found for age older than 70 years, tumor grade,
myometrial invasion, and stage. Multivariate analysis, however, found only age, stage, and grade to be significant. With univariate myometrial invasion, and stage. Multivariate analysis, however, found only age, stage, and grade to be significant. With univariate
analysis, statistical significance for recurrence was found for tumor grade, stage, and external-beam radiotherapy as risk analysis, statistical significance for recurrence was found for tumor grade, stage, and external-beam radiotherapy as risk
factors. Multivariate analysis found only radiotherapy and brachytherapy to be significant, but in an inverted sense, with factors. Multivariate analysis found only radiotherapy and brachytherapy to be significant, but in an inverted sense, with
brachytherapy having a protective effect. brachytherapy having a protective effect.
ConclusionOur results suggest that brachytherapy protects against recurrence and that neither a surgical approach nor a lymphadenectomy ConclusionOur results suggest that brachytherapy protects against recurrence and that neither a surgical approach nor a lymphadenectomy
appear to affect recurrence or survival in patients with surgically treated endometrioid endometrial cancer. appear to affect recurrence or survival in patients with surgically treated endometrioid endometrial cancer.
Clinical and Translational Oncology 08/2008; 10(8):505-511. · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is becoming increasingly important to address the issue of reproductive counselling and management of HIV-infected individuals during their reproductive years. Sexual and reproductive health-related needs and aspirations are similar to those of uninfected individuals but some differences require specific attention, which are discussed in this review.
Hormonal contraception should be used with caution in women on antiretroviral treatment. Its impact on both HIV infectivity and disease progression is still controversial. An intrauterine device can be considered for pregnancy prevention and pregnancy termination should be offered in safe conditions. HIV-infected women have a lower spontaneous fertility rate, which may persist after assisted reproduction. Data on safety of antiretroviral treatment during conception are reassuring. No clear association can be found between exposure to antiretrovirals and fetal abnormalities. Secondary prevention remains crucial and condom use remains a key method.
Different topics related to fertility choices among HIV-infected patients should be addressed. Family planning methods and termination of pregnancy have specific aspects among infected individuals. When needed, medically assisted reproduction may be required and antiretroviral treatment should be adapted before conception. Secondary prevention has a key role in reducing newly acquired infections.
Current opinion in HIV and AIDS 04/2008; 3(2):186-92. · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate acceptance, feasibility and difficulties in the application of a policy of vaginal delivery in selected cases in HIV-infected women.
HIV-infected women delivering March 2002 to December 2004 and enrolled in a prospective observational study in a University hospital tertiary care center were included. A vaginal delivery was not considered if labor before 36 weeks of pregnancy, preterm premature rupture of membranes, on non-highly active antiretroviral therapy (HAART) or viral load >1000copies/mL. Main outcome measures were mode of delivery, prematurity, acceptance of vaginal delivery and mother-to-child transmission of HIV infection.
The study included 91 pregnancies, with a total of 95 fetuses. Eighty percent (n=73) of women knew their HIV infection status before becoming pregnant and 57 (63%) were on HAART at conception. Median gestational age at delivery was 37 weeks (range 22-41). Twelve women delivered a live-born before 36 weeks, all with a caesarean section. Among 74 women who reached 36 weeks gestation, 47 (64%) met the pre-established criteria for vaginal delivery, of whom 21 (45%) delivered vaginally. The most common reason for not having a vaginal delivery was the woman's request for a caesarean section. No cases of HIV vertical transmission occurred (0/90, 95% CI 0-4.02%).
Recommending vaginal delivery among HIV-infected women in selected cases was well accepted, particularly once the policy became established. Nevertheless, a high proportion of HIV-infected women will continue to require caesarean section delivery.
European Journal of Obstetrics & Gynecology and Reproductive Biology 02/2008; 139(2):127-32. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HIV-infected women under highly active antiretroviral therapy (HAART) undergoing in vitro fertilization (IVF) have a lower pregnancy rate than noninfected controls, which depends on oocyte-related factors. We hypothesized that mitochondrial toxicity caused by antiretrovirals could be the underlying mechanism of such disturbance.
We have studied 16 and 19 frozen-thawed oocytes obtained after oocyte retrieval IVF cycles from 8 and 14 infertile HIV-infected and uninfected women, respectively, matched by age. At inclusion, HIV-positive women had been infected for >13 years and had received HAART for >9 years, including at least one nucleoside reverse transcriptase inhibitor. All of them had undetectable HIV viral load and a good immunological status. Mitochondrial DNA (mtDNA) content was determined by quantitative real-time PCR in each individual oocyte.
HIV-infected infertile women on HAART showed significant oocyte mtDNA depletion when compared with uninfected controls (32% mtDNA decrease, P<0.05). This oocyte mtDNA depletion was even greater on those HIV-infected women who failed to become pregnant when compared with controls (39% mtDNA decrease, P=0.03). No significant correlation was found between mtDNA oocyte content and cumulative doses of antiretrovirals or the immunological status of HIV patients.
Oocytes from infertile HIV-infected HAART-treated women show decreased mtDNA content, and this could explain their poor reproductive outcome.
[Show abstract][Hide abstract] ABSTRACT: To assess the amniopatch procedure when premature rupture of membranes occurs after first-trimester chorionic villus sampling (CVS).
From May 2001 to June 2004, the amniopatch procedure was offered in cases of premature rupture of membranes after CVS when severe oligohydramnios was present (largest vertical pocket < 2 cm) and persistent (more than 1 week).
The amniopatch was placed in five pregnancies at 12-18 weeks of gestation, resulting in amniotic fluid restoration in all but one pregnancy. In three pregnancies, fetal demise was observed at 1, 2 and 36 days after the procedure. The last procedure resulted in a healthy newborn.
Although the amniopatch restored normal amniotic fluid levels in all cases, 4 of the 5 cases resulted in fetal demise.
[Show abstract][Hide abstract] ABSTRACT: The objective of the study was to assess the fertility of non-infertile couples seeking pregnancy in whom the woman was HIV infected. Therefore, a cross-sectional study was conducted between January 1998 and March 2005. A standardized fertility assessment was performed in all the included couples. A total of 130 women and 121 men were evaluated. Their median age was 34 years (range 22-43). Only 7.2% of the women were severely immunocompromised. The majority of women had regular cycles. Only one woman had an active sexually transmitted disease at the time of evaluation. A tubal occlusion on hysterosalpingogram was present in 27.8% of the women with no proven fertility. In 50.5% of the women, hepatitis C virus co-infection was present. One-third of the male partners (38/121) was infected with HIV. Abnormal semen parameters were observed in 83.4% of HIV-infected and 41.7% of HIV-uninfected partners (OR = 7; 95% CI = 2.1-23). It is concluded that the great majority of the HIV-infected women seeking pregnancy had a good infection status. Because in many of the couples, the women presented unexplained tubal occlusions and the men presented semen alterations, a hysterosalpingography and semen analysis should be part of the preconceptional investigations.
[Show abstract][Hide abstract] ABSTRACT: This study was undertaken to describe a new prenatal diagnosis program among human immunodeficiency virus (HIV)-infected women, and the perinatal outcome of this program's application over a more than 2-year period.
From June 2000 to December 2003, all HIV-infected women who were booked into the antenatal clinic before 20 weeks were offered a screening for chromosomal anomalies, with midtrimester amniocentesis in the tests that were positive.
A total of 116 pregnancies (including 3 sets of twins) were seen: 96 women were offered and accepted screening for chromosomal anomalies. Thirteen pregnancies had a positive screening test and amniocentesis was performed in 10 at median 16.5 gestational weeks: a trisomy 21 and a monosomy X were diagnosed. No vertical transmissions were documented by age 6 months in the 6 liveborn infants who underwent amniocentesis.
A program of prenatal diagnosis for chromosomal anomalies appears to be effective when applied to HIV-infected women, although safety remains to be proven.
American journal of obstetrics and gynecology 02/2006; 194(1):192-8. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART.
The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003).
In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985-2000 (n = 390) to 2001-2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3-5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4-10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58-0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46-0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7-18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054-0.627; P = 0.007) were risk factors in HIV-infected women.
HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to determine the value of myometrial invasion by magnetic resonance imaging (MRI), histologic typing and grading by endometrial biopsy, and the intraoperative evaluation of both parameters by frozen section in the evaluation of endometrial cancer. The preoperative and intraoperative records of 180 patients with endometrial cancer were used to compare the preoperative endometrial biopsy, the myometrial invasion by MRI, and the intraoperative frozen sections, with the final histopathologic findings. The preoperative endometrial biopsy gave us the tumor histologic type and grade. MRI gave us the depth of myometrial invasion. The evaluation of intraoperative frozen sections gave us the tumor histologic type, the tumor grade, and also the myometrial invasion. Patients were classified as low risk (grade 1 and 2, and myometrial invasion <50%) and high risk (grade 3 or myometrial invasion >50%). Standard statistical calculations were used. Evaluation of the tumor grade by preoperative biopsy has a sensitivity and a specificity of 75% and 95%, respectively. Evaluation of the tumor grade by intraoperative biopsy has a sensitivity and a specificity of 40% and 98%, respectively. Evaluation of the depth of myometrial invasion with MRI has a sensitivity and a specificity of 79% and 82%, respectively. Evaluation of the depth of myometrial invasion with intraoperative frozen sections has a sensitivity and a specificity of 74% and 95%, respectively. Evaluation of all four of the parameters together has a sensitivity and a specificity of 80% and 82%, respectively with a kappa of 0.621. In our opinion, the combination of preoperative biopsy and intraoperative frozen section is the best way to decide whether a lymphadenectomy is necessary with a low rate of understaging patients. MRI would have a fringe benefit in these patients.
International Journal of Gynecological Cancer 01/2006; 16(1):385-90. · 1.94 Impact Factor