High levels of P-glycoprotein activity in human lymphocytes in the first 6 months of life.

P-glycoprotein (P-gp) is an efflux transporter that controls the intracellular concentrations of drugs. Human development may modulate P-gp function. We investigated the effect of age on P-gp activity and MDR1 gene expression in lymphocytes. We also assessed the influence of human immunodeficiency virus (HIV) infection. We used 3,3'-diethyloxacarbocyanin iodide (DiOC(6)) efflux, estimated by flow cytometry, to quantify P-gp activity in 94 children (age range, 0-18 years) and 25 adults. MDR1 gene expression was quantified using reverse transcription-PCR (RT-PCR). In T and natural killer (NK) cell populations, P-gp activity peaked at birth, decreased between the ages of 0 and 6 months, and stabilized between the ages of 6 months and 2 years (P < 10(-6)). These maturation profiles were also strongly correlated (r = 0.67, P < 10(-6)). HIV infection did not affect P-gp activity in the lymphocytes of children. MDR1 gene expression was not influenced by age, nor was it correlated with P-gp activity. The high levels of P-gp activity observed in the lymphocytes of children ~6 months of age may affect the efficacy of intracellular drugs.

Factors related to medical appointment attendance after childbirth among HIV-infected women in the Paris region.

This study examined factors related to medical appointment attendance after childbirth among HIV-infected women in the Paris region. We hypothesized that despite regular utilization of prenatal care, many women may not attend medical appointments after delivery for their own HIV infection. This was an observational cohort study of HIV-seropositive women delivering in four Paris hospitals in 2001. Follow-up attendance through 24 months after delivery was defined as 'regular' for women who had > or =4 HIV visits during the period, 'irregular' for <4 visits in the 24-months period and/or a gap between two visits >12 months, and 'no attendance' when < or =1 visit in the 2-year period. Of 169 women enrolled, 125 (75%) had regular attendance, 24 (14%) had irregular attendance, and 18 (11%) had no attendance. Multivariate analysis found the greater number of HIV visits during pregnancy and the prescription of combination therapy (versus zidovudine monotherapy) during pregnancy to be significantly related to regular attendance. Of the 18 women who had no attendance, 8 women (47%) continued to attend regular paediatric appointments with their infants during the 24-month period. Scheduling more frequent HIV visits during pregnancy may establish a pattern that will improve attendance during the post-partum period. In addition, increased communication between the health care providers of the mother and child may increase appointment attendance following delivery.

[Neonatal lenticulostriate vasculopathy. Mid and longterm outcome (70 cases)]. / Devenir des enfants ayant présenté une vasculopathie lenticulostriée néonatale (70 cas).

OBJECTIVES: If the pattern of neonatal lenticulostriate vasculopathies (NLSV) is well-known, the prognosis is unknown except in TORCH syndromes. This study was aimed to describe the short, mid and long-term outcome of NLSV of various origins. POPULATION AND METHODS: Of 9138 neonates (1981-2000) which were submitted to an early brain ultrasound study, 70 presented with a pattern of minor (35), moderate (27) or severe (8) NLSV, a single finding in 42 cases and in association with minor peri-intraventricular haemorrhage and/or leukomalacias in 28. The maternal and neonatal charts were reviewed, and the survivors were followed according to our usual policy. RESULTS: Of nine deaths, eight cases included severe congenital defects (metabolic or malformations or acquired: transfused monochorial twins). Of 61 survivors, eight were lost to follow-up within the first year, 53 were followed for 21 months to 9 years and 7 months (median 4 years 5 months). Of 53 children, 35 (66%) were strictly normal, eight had minor deviations, four had moderate and six had major neurodevelopmental deficits. Of 34 survivors with isolated NLSV and known follow-up, 27 were normal (79%) versus 8/19 (42%) in associated NLSV. CONCLUSIONS: Minor or moderate isolated NLSV generally have a good long-term prognosis. Associated forms of any severity depend mainly upon the severity of periventricular leukomalacias. Major forms of NLSV must be a warning sign of a possible underlying congenital anomaly which will rule the vital and functional prognosis.

Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women.

OBJECTIVE: The purpose of this study was to investigate placental transfer and amniotic fluid concentrations of lamivudine in human immunodeficiency virus-infected women who received the agent during pregnancy. STUDY DESIGN: Mothers in the study were receiving antiretroviral therapy that included lamivudine in a clinical setting. Maternal blood, cord blood, and amniotic fluid samples were obtained simultaneously at the time of delivery from 57 mother-infant pairs. RESULTS: At a median of 8.5 hours after the last maternal oral 150-mg dose of lamivudine, median maternal and fetal plasma concentrations were 302 and 240 ng/mL, respectively. Individual maternal and fetal concentrations were strongly correlated (r2 = 0.36; P < 10(-4)), and their median ratio was about 1. The median concentration in the amniotic fluid was 5 times higher than that in maternal plasma (upper range of ratio, 133). CONCLUSION: Lamivudine appeared to cross the placenta by simple diffusion and is concentrated in the amniotic fluid. High amniotic fluid levels of lamivudine may carry both benefits and risks for the child.

Frequent detection of HIV-1 in the gastric aspirates of neonates born to HIV-infected mothers.

OBJECTIVE: To evaluate the frequency and correlates of oral route exposure of infants born to HIV-1-infected women. METHODS: A multicenter study was performed within the prospective French Perinatal Cohort Study of mother-to-child HIV transmission. Oropharyngeal and gastric aspirates from 122 neonates were studied by reverse transcriptase (RT) polymerase chain reaction (PCR) for the presence of HIV-1, as well as for standard microbiology (Gram staining and culture). RESULTS: Aspirates from 101 neonates were analyzed by RT-PCR; 28% of these were positive for HIV RNA. Another 21 aspirates could not be tested because of PCR inhibition. The median concentration of HIV RNA in the positive aspirates was 126 copies/ml (range: 8-1270). Detection of HIV-1 in the aspirate was significantly related to high maternal plasma-viral load, presence of blood in the aspirate, positive Gram stain or culture, episiotomy or perineal lesions, and sexually transmitted infections during the pregnancy. Most of the mothers received zidovudine prophylaxis during pregnancy and delivery. Among the six infants who were infected with HIV, three had positive aspirates. Of the three assumed to have acquired the infection intrapartum, only one had an HIV RNA-positive aspirate. CONCLUSION: Exposure of the fetus to HIV via the oral route occurs frequently, even in the presence of zidovudine prophylaxis, and is likely to be one of the mechanisms of intrapartum transmission, but not the only one.

Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.

BACKGROUND: Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS: We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.

Congenital toxoplasmosis due to maternal reinfection during pregnancy.

A case of congenital toxoplasmic chorioretinitis was diagnosed (specific-immunoglobulin G [IgG] and -IgM comparative Western blot analysis) in a baby whose mother was immune during pregnancy. Maternal sera showed an increase in specific IgG and emergence of both IgM and IgA during pregnancy. The mother was probably reinfected through contact with kittens.

Maternal factors associated with perinatal HIV-1 transmission: the French Cohort Study: 7 years of follow-up observation. The French Pediatric HIV Infection Study Group.

A nationwide, longitudinal study of infants born to human immunodeficiency virus-seropositive mothers has been under way in France since 1986. After 7 years of follow-up observations, we will update our assessment of the transmission rate in France and analyze, on a larger number of mother-infant pairs, the influence of maternal factors. Among the 848 pairs included in this analysis, the transmission rate was 20.2 +/- 2.7%. The transmission rate has remained stable with time and was not influenced by the mode of delivery, the mode of maternal infection, or the mother's ethnic origin. It was twice as high among the breast-fed infants as among the bottle-fed infants (40 vs. 19%, p < 0.04). Two factors were identified in a multivariate analysis (that did not include lymphocyte subset counts and the mode of feeding) as being associated with an increased risk of maternofetal transmission: p24 antigenemia (odds ratio = 3.1, confidence interval, = 1.5-6.2; p < 0.003) and elevated maternal age (p < 0.05). In the subgroup of 277 women whose absolute CD4+ lymphocyte counts at the time of delivery were available, the risk of transmission increased gradually from 15% of counts of > 600 CD4+ cells to 43% at counts of < 200. The risk of transmission was also related to the percentage of CD8+ cells, but each of the two factors seemed to play an independent role: the risk was lowest (12%) when the CD4+ cell count was > 500 and the proportion of CD8+ cells was < or = 40%, and was highest (50%) for values < 200 and > 40%.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery.

BACKGROUND: Among infants with maternally transmitted human immunodeficiency virus (HIV) infection, there are two patterns of disease progression. In about a fifth of these infants there is a rapid progression to profound immunodeficiency, whereas in the majority the disease progresses much more slowly. METHODS: We studied the clinical and biologic characteristics of the mothers of infants infected with HIV type 1 (HIV-1) in the French Prospective Multicenter Cohort. Infection in the children was confirmed by serologic tests at the age of 18 months or by death from the acquired immunodeficiency syndrome at an earlier age. Only the 162 infected infants who could be followed for at least 18 months or until death were included in the analysis. RESULTS: The risk of opportunistic infections or encephalopathy in the first 18 months was 50 percent in the infants of mothers with class IV disease, according to the Centers for Disease Control and Prevention classification, and 14 percent in the infants of mothers with class II or III disease (relative risk, 3.6; 95 percent confidence interval, 1.8 to 7.3; P < 0.002). Forty-four percent of the former infants and 9 percent of the latter died before 18 months (relative risk, 4.7; 95 percent confidence interval, 2.1 to 10.4; P < 0.002). The risk of death correlated inversely with the mother's CD4+ cell count and directly with her HIV-1 p24 antigen level at delivery. There was also a direct correlation between the mother's CD4+ cell count and that of the infant at one, three, and nine months of age (correlation coefficient at nine months [n = 44], 0.48; P < 0.002). HIV-1 p24 antigen was detected more often in the infants whose mothers also had the antigen. CONCLUSIONS: In infants whose HIV infection is maternally acquired, the rate of disease progression varies directly with the severity of the disease in the mother at the time of delivery.

[HIV seropositivity and desire for children]. / Séropositivé VIH et désir d'enfant.

Growing numbers of women and men who are HIV infected and aware of their serostatus, want to have children. Gynecologists are involved in the dilemmas of counseling those couples about reproductive decisions. For HIV infected women, pregnancy is contra-indicated, mostly because of the risk of transmission to the fetus/infant. However, no rational argument can abolish the desire of many young women to have children in the face of the life-threatening infection. The clinical and immune status of the would-be mothers, her partner's serostatus and the availability of family members to rear an orphaned child, must be considered. For seronegative women with HIV-infected partners, after confirming that seroconversion is not occurring, the partner's clinical and immune status must be evaluated. The risk of transmission through unprotected intercourse increases with the degree of immune suppression in the partner. The couple's stability and the woman's motivations for becoming pregnant must also be carefully evaluated. About one third of such discordant couples separate after the birth of their child. For selected couples who have clearly decided to attempt pregnancy, the objective of reproductive counseling is to reduce their risk of heterosexual transmission. The partner's sperm should not be used for insemination because techniques have not yet been established to eliminate HIV from sperm preparations. Insemination with HIV-negative donors' sperm can be considered. An alternative is the "natural" method, consisting in having unprotected intercourse only during ovulation. Administration of zidovudine to the man in order to reduce the amount of virus excreted has been discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

[HIV seropositivity and desire for children]. / Seropositive VIH et desir d'enfant.

PIP: The number of women who learn of their HIV seropositivity and still want to have a child is growing. If the woman is HIV seropositive, pregnancy is not advised, but it is difficult if not impossible to prevent a young woman from a having wanted child. No rational argument can suppress this desire that the life-threatening illness exacerbates. The counselor must consider the clinical and immune status of the mother, the serostatus and health status of the partner, and the likelihood of family members raising the child. If the woman is HIV seronegative and her partner is HIV seropositive, the counselor must first make sure that the women does not seroconvert and that her desire for a child is real. Then the counselor must evaluate the partner's clinical and immune status. The risk of HIV transmission to the woman increases with the degree of immune suppression of the partner. It is also important to determine the stability of the discordant couple because about 33% separate after childbirth. It is only after having analyzed all these elements that the counselor and the couple can consider one of the proposed solutions. Since techniques of sperm decontamination having not yet been established, the decision is boiled down to extreme solutions: artificial insemination with sperm from an HIV negative donor or, after a spermogram and hysterography, the natural method involving intercourse only during successive periods of ovulation. The partner needs to take zidovudine to reduce the amount of sperm ejaculated. In case of pregnancy, it is necessary to recognize seroconversion, an indication for AZT. ELISA and studies on p24 antigenemia must be conducted each month of the pregnant woman. Couples must continue to use condoms after the delivery because a seroconversion would nullify all earlier efforts. Breast feeding can transmit HIV to the infant. Professional guidelines forbid tubal infertility surgery and in vitro fertilization in couples where the woman or man is HIV infected. The opinion of the French National Ethics Commission will be sought on less invasive infertility therapy.^ieng

The use of viral culture and p24 antigen testing to diagnose human immunodeficiency virus infection in neonates. The HIV Infection in Newborns French Collaborative Study Group.

BACKGROUND: Early diagnosis of human immunodeficiency virus (HIV) infection in infants born to infected mothers is important for the infants' medical care, but the presence of maternal antibodies makes serologic tests uninformative. METHODS: In a cohort study of 181 infants born to HIV-infected mothers, we assessed the diagnostic value of HIV viral culture and testing for the presence of p24 antigen. The infants were tested at birth, again during the first 3 months, then followed and tested at the age of at least 18 months. RESULTS: Of the 181 infants, 3 died of HIV infection and 37 were seropositive after the age of 18 months. Viral cultures at birth were positive in 19 of the 40 infected infants and in none of the uninfected infants, yielding a sensitivity of 48 percent (95 percent confidence interval, 32 to 63 percent) and a specificity of 100 percent (95 percent confidence interval, 97 to 100 percent). By the age of three months, 30 of the 40 infants (75 percent) had positive cultures; again, there were no false positive results among the infants who were tested a second time, of the 141 who remained uninfected. The sensitivity of testing for p24 antigen at birth was only 18 percent, with a specificity of 100 percent. The presence of p24 antigen at birth was associated with the development of early and severe HIV-related disease (P less than 0.04). CONCLUSIONS: Viral culture at birth can correctly identify about half of newborns with HIV infection. The fact that this usually sensitive technique fails to identify about half the ultimately infected neonates suggests that vertical transmission of HIV may occur late in pregnancy or during delivery.

HIV replication during the first weeks of life.

Diagnosis of HIV infection among children born to HIV-positive mothers can be made in the first 12 months, but few studies have examined HIV status during the first weeks of life. In a prospective longitudinal study of 50 infants born to HIV-1 seropositive women, blood samples were obtained at birth and at 4-9 weeks and 5-9 months of age, and were tested for HIV-1 by the polymerase chain reaction (PCR), viral culture, and p24 antigen measurements. 16 were diagnosed as HIV-infected by the age of 4-9 weeks according to both PCR and culture; by contrast, infection could be detected in only 5 children at birth. No changes in HIV status were observed between 4-9 weeks and 5-9 months in the 44 children who could be retested. Perinatal HIV-1 infection can therefore be diagnosed in the first 2 months of life, either by PCR or viral culture. Our inability to detect HIV-1 infection at birth in almost 70% of babies subsequently found infected suggests an active replication of HIV during the first weeks of life. Our results might favour the hypothesis that transmission of HIV-1 takes place either at the end of pregnancy or at delivery.

A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. HIV Infection in Newborns French Collaborative Study Group.

Assessment of the risks of transmission of infection with human immunodeficiency virus type 1 (HIV-1) from mother to newborn is difficult, partly because of the persistence for up to a year of maternal antibodies transmitted passively to the infant. To determine the frequency of perinatal transmission of HIV infection, we studied from birth 308 infants born to seropositive women, 62 percent of whom were intravenous drug abusers. Of 117 infants evaluated 18 months after birth, 32 (27 percent) were seropositive for HIV or had died of the acquired immunodeficiency syndrome (AIDS) (n = 6); of the 32, only 2 remained asymptomatic. Another 76 infants (65 percent) were seronegative and free of symptoms, whereas 9 (8 percent) were seronegative but had symptoms suggestive of HIV-1 infection. The infants infected with HIV-1 did not differ from the others at birth with respect to weight, height, head circumference, or rate of malformations, but as compared with newborns who were seronegative at 18 months, their serum IgM levels were higher (78 +/- 81 mg per deciliter vs. 38 +/- 39 mg per deciliter; P less than 0.03) and their CD4 lymphocyte counts were lower (2054 +/- 1221 per cubic millimeter vs. 2901 +/- 1195 per cubic millimeter; P less than 0.006). Neither maternal risk factors nor the route of delivery was a predictor of seropositivity at 18 months; however, 5 of the 6 infants who were breast-fed became seropositive, as compared with 25 of 99 who were not (P less than 0.01). We conclude that approximately one third of the infants born to seropositive mothers will have evidence of HIV-1 infection or of AIDS by the age of 18 months, and that about one fifth of this group will have died.

Respiratory pauses in very low risk prematurely born infants reaching normal term. A comparison to full-term newborns.

We studied the occurrence of greater than or equal to 2 sec. respiratory pauses (RP) in very low risk, normal prematurely born infants (less than or equal to 36 wks. of gestation), recorded when they reached 37-40 wks. conceptional age and compared the results with those of full-term (37-41 wks. of gestation) newborns. The influence of gestational age at birth (GA), postnatal age, sleep states, twin birth and gross body movements was tested. We recorded 2434 central RP and only one 4 sec. duration obstructive RP. We never observed RP greater than 15 sec. 10-15 sec. RP were rare, noted only in 37-38 wks. GA newborns. We found some differences between prematures reaching normal term on one hand and full-term newborns on the other: a) RP frequency and periodic breathing were higher in prematurely born infants; b) Between-sleep state differences leveled out in prematures reaching normal term (they had more numerous RP in all sleep states), while the prevalence of RP in active sleep compared to quiet sleep was constant in full-term newborns. There were no significant differences between prematurely born twins and singletons. When they reached normal term, infants born before 35 wks. of gestation had more RP, compared to infants born at 35-36 wks. of gestation. About 12% of RP occurred after gross body movements.

[Placental smears in a maternity ward. Importance of early diagnosis of neonatal bacterial infections caused by materno-fetal contamination]. / Frottis placentaires en maternité. Intérêt pour le diagnostic précoce des infections bactériennes néonatales par contamination materno-foetale.

Direct cytobacteriological investigation of the amniochorionic plate of the placenta has been used systematically in the Maternity Hospital as a test to detect amniotic infection. This test was practised on fresh placentae in the laboratory of Histology, preceding the examination of the placenta. The test gave, within 30 minutes of delivery, information about the presence of bacteria of fungi on the amniotic surface, their abundance and their morphology. The results of the placental smears were compared to the results of bacteriological cultures obtained from the placenta, the infant and occasionally the mother. The diagnosis of neonatal infection was established from clinical, biological and bacteriological criteria which were defined in advance. Two series are presented: the first concerns 2,514 cases selected in the delivery room over a period of 4 years for high risks infection, i.e. 1 in 6 of the 15,377 deliveries registered during this period. The rate of positive smears was 9%: 63% Gram positive, 17% Gram negative, and 20% mixed. The most common bacteriologically proven neonatal infections were streptococcus B (40%) and Escherichia coli (33%). The second is a prospective survey of 400 unselected consecutive cases observed during a period of 7 weeks: 1% of the smears were positive - and the test would have been justified in 1 in 5 cases. From these two surveys, it appears that placental smear is a good test to detect maternofetal contamination. The positive predictive value of the test is 80%. The negative predictive value is 98% and approaches 100% if cases where the mother received antibiotics before delivery are excluded.

[Cerebral symptoms in the term newborn infant. Results of a prospective survey]. / La souffrance cérébrale du nouveau-né à terme. Résultats d'une enquête prospective.

1785 newborns of 37 weeks GA or more, were studied during a 15 months period at the Port-Royal Maternity Hospital. This study suggests that cerebral abnormalities during the neonatal period in fullterm neonates are related to deleterious intra partum factors. In 57 newborns, clear cut signs of cerebral birth injury were observed, in 31 newborns only mild and transitory signs were observed. These 88 newborns were compared with 1655 having had a normal neurological examination within the first week of life. We focused particulary on dysfunctional labor patterns, specifically false labor, protracted active phase dilatation, protracted descent or a marked caput succedaneum. When these abnormal patterns are followed by oxytocin infusion and forceps extraction, primiparity appears linked with a high risk of cerebral birth injury. Within cephalic presentations, the occipito-posterior position is carrying the same high risk. The most severe degree of cerebral birth injury has nearly disappeared. However, the main problem of modern obstetrics is one of eradicating brain damage of moderate degree without reaching an excessive incidence of C. section.