Navér, Lars MD, PhD*; Lindgren, Susanne MD, PhD†; Belfrage, Erik MD, PhD‡; Gyllensten, Katarina MD∥; Lidman, Knut MD, PhD∥; Gisslén, Magnus MD, PhD¶; Ehrnst, Anneka MD, PhD§; Arneborn, Malin RN#; Bohlin, Ann-Britt MD, PhD*
From the Department for Clinical Science, Intervention and Technology, *Division of Pediatrics and †Division of Obstetrics and Gynecology, Karolinska University Hospital Huddinge, ‡Department of Women and Child Health, §Department of Microbiology, Tumor and Cell Biology, ∥Department of Medicine, Unit for Infectious Diseases, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm; ¶Department of Infectious Diseases, Sahlgrenska University Hospital/East, Göteborg; and #Swedish Institute for Infectious Disease Control, Stockholm, Sweden.
Received for publication September 22, 2005; accepted March 23, 2006.
Financial support was received from Freemason's in Stockholm Foundation for Children's Welfare.
L.N. and A.B.B. designed the study, collected and interpreted data, and wrote the report. S.L. participated in the design of the study, the collection of data, and the writing of the report. E.B., K.G., K.L., and M.G. participated in the data collection and contributed to the writing of the report. M.A. provided statistical information about HIV-infected pregnant women and children from the Swedish Institute for Infectious Disease Control. A.E. was the clinical virologist, coordinating HIV diagnostic tools and information.
The study was approved by the Ethical Committee of the Karolinska Institutet (Stockholm, Sweden) (Nos. 89:264, 98-184, 03-299).
Reprints: Lars Navér, MD, PhD, Department for Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden (e-mail: firstname.lastname@example.org).
Great advances have been made during the last 10 years in the prevention of mother-to-child transmission (MTCT) of HIV-1, mainly in resource-rich countries. Administration of prophylactic antiretroviral treatment to the women during pregnancy and at delivery and to the infants during the first weeks of life, in combination with elective cesarean delivery, has had a marked impact on transmission rates, which have decreased from 14% to 25%1 to less than 2%, provided the mothers do not breast-feed.2 The consequence is an increasing number of healthy uninfected children born to HIV-infected women.3
In addition to this reduction in vertical transmission, great improvements have been made in the monitoring and treatment of HIV-1 infection. Antiretroviral combination therapy has dramatically improved survival in HIV-1-infected adults and children, resulting in an increasing number of children living in families affected by HIV.
Routine voluntary HIV-antibody testing of pregnant women on an opting-out basis has been recommended by the National Board of Health and Welfare in Sweden since 1987. The acceptance rate is high, ranging from 90% to 99% in different geographic areas.4
The purpose of this study was to describe the HIV-1 epidemic among childbearing women and their children in order to explore changes in vertical transmission rates and demographic characteristics over time.
PATIENTS AND METHODS
All children in Sweden known to have been born to an HIV-1-infected mother and the mothers themselves were included. Children who were born between 1985 and 31 December 2003 were followed prospectively if the parents/guardians agreed, and from 1987, they were also enrolled in the European Collaborative Study.5-7 Information about infected pregnant women and their children was obtained through our contacts as a national resource center for HIV-infected pregnant women and children and from the Swedish Institute for Infectious Disease Control, the main task of which is surveillance of communicable diseases and analysis of the current epidemiological situation in Sweden. All patients in Sweden with an HIV-1 diagnosis are mandatorily reported by code by clinicians and laboratories. To get information on the current status of the mother-child pairs, a questionnaire was sent to physicians known to administer care to HIV-1-infected women and/or children.
Prospectively followed children were not breast-fed; breast-feeding is not allowed by Swedish law when the mother is HIV infected. From 1994, mothers and children were recommended zidovudine prophylaxis to reduce vertical transmission, according to the ACTG-076 protocol.8 Elective cesarean delivery was routinely recommended from late 1998 onward.9,10 Combination antiretroviral regimens were increasingly used in pregnant women during the following years.
The children were regarded as infected if HIV-1 antibodies persisted for longer than 18 months or if 2 HIV-1 virus detection tests, on different sampling occasions, were positive. Children were regarded as uninfected if they lost the HIV-1-specific antibodies or if they were 6 months of age or more and had had at least 2 negative virus detection tests (HIV-1 DNA PCR and/or HIV-1 RNA and/or virus isolation) on 2 different sampling occasions after the neonatal period, the latest after 5 months of age.
The clinical and immunological classifications were done according to the Centers for Disease Control and Prevention (CDC) classifications.11,12 Once classified, a child was not reclassified to a lower category even if improvement occurred after antiretroviral treatment.
Pearson χ2 test and Fisher exact test were used for comparisons of proportions of maternal characteristics and MTCT over time. A multiple exact logistic regression was performed to investigate it antiretroviral prophylaxis/treatment, mode of delivery, sex of the child, maternal age, and CD4 cell count had an effect on MTCT. It was not possible to test for all interaction effects because of the small number of subjects that experienced MTCT; hence, only main effects were controlled for in the model. The analyses were performed using the JMP software package version 3.1.5 from SAS Institute, Inc (Cary, NC) and the LogXact software version 7.0 from Cytel Inc (Cambridge, MA).
Data on All Children
We identified a total of 421 mother-child pairs, and in 357 of these cases, the child was followed prospectively from birth. Sixty-nine sets of siblings were enrolled. The 421 children were followed for 22,189 child-months (median, 36 months), and 407 of them had their infection status determined by the end of 2003. Seventy-two children were HIV-1 infected and 333 were uninfected. Fourteen children had an indeterminate infection status at the last follow-up. Four of these children emigrated and 7 died: 2 in utero, 2 from birth asphyxia, and 3 because of the sudden infant death syndrome. The remaining 3 children with an undetermined infection status were lost to follow-up.
Maternal characteristics are shown in Table 1. The proportion of mothers born in Sweden decreased from 27.5% before 1994 to 13.6% during 1999-2003 (χ2 = 8.379; P = 0.015). Mothers infected through intravenous drug use also decreased in number during the same period, from 13.0% to 3.3% (χ2 = 10.164; P = 0.006). The maternal age at delivery increased during the period (χ2 = 45.332; P < 0.0001). More than half of the mothers originated from sub-Saharan Africa, and the proportion did not change significantly during the study period (Table 1).
Vertical HIV-1 Transmission Among Prospectively Followed Children
Three hundred fifty-seven children (166 boys, 173 girls, and 18 whose sex was not reported) were followed prospectively from birth, and the infection status was determined in 343 of them (Table 2). Twenty-seven children (14 boys and 13 girls) were infected (7.8%, 95% CI 5.5%-11.2%). Between 1985 and 1993, 21 of 85 children (24.7%, 95% CI 16.4%-34.1%) were infected, whereas during 1994-1998 and 1999-2003, 5 of 87 (5.7%, 95% CI 2.3%-12.1%) and 1 of 172 (0.6%, 95% CI 0.1%-3.1%) children were infected, respectively (χ2 = 46.277; P < 0.0001).
Mode of Delivery, Antiretroviral Prophylaxis, and HIV-1 Transmission in Prospectively Followed Children
In 329 of the prospectively followed children, the mode of delivery, the antiretroviral prophylaxis treatment, and the infection status of the child were reported (Table 3). Twenty-two of 121 vaginally delivered children (18.2%, 95% CI 12.3%-26.0%) were infected. In 75 cases with vaginally delivered children, no antiretroviral prophylaxis was given to the mother or child, and 18 (24.0%, 95% CI 15.8%-34.8%) of these children were infected. Four of 35 (11.4%, 95% CI 4.5%-26.0%) of the vaginally delivered children whose mothers received zidovudine monotherapy prophylaxis were infected. In 2 of these cases, the mother had been treated with zidovudine monotherapy also during a previous pregnancy, and in 1 case, the intrapartum intravenous zidovudine infusion was not given.
Four of 182 children (2.2%, 95% CI 0.9%-5.5%) who were born by elective cesarean delivery became HIV-1 infected (2 boys and 2 girls). Two of the 12 children (16.7%, 95% CI 4.7%-44.8%) who were born by elective cesarean delivery and had a mother who did not receive antiretroviral prophylaxis were infected. In the other 2 cases, the zidovudine prophylaxis was incomplete, as it was introduced after gestational week 37.
Twenty-one of the 94 children (22.3%, 95% CI 15.1%-31.7%) who were born without antiretroviral prophylaxis were infected, and 6 of 76 (7.9%, 95% CI 3.7%-16.2%) with zidovudine monotherapy were infected [odds ratio (OR) 3.26, 95% CI 0.96 to 13.88, P = 0.059]. None of the 137 children born after prophylaxis with 2 or more antiretrovirals was infected, which was significantly lower than in the group without prophylaxis (OR 32.43, 95% CI 3.049 to >200, P < 0.0001) and in the group receiving zidovudine monotherapy (OR 12.33, 95% CI 1.051 to >200, P = 0.013) (Table 4).
Statistics about prevention of mother-to-child transmission from the most recent part of the period, the year 2003, are separately presented (Table 5).
Infected Children Born in Sweden but Not Prospectively Followed From Birth
Four of the 31 infected children who were born in Sweden were not followed prospectively from birth because their mothers were not identified in the antenatal screening program. One child was born in 1985 before the screening program started. Three children were born during 1996-1997. The mother of one of them tested HIV-antibody negative in the screening program, but was presumably infected later on during pregnancy. Two women were not tested because of known or presumed previous negative HIV-antibody test results.
Seventy-two vertically HIV-1-infected children (29 boys, 40 girls, and 3 whose sex was not reported) were identified. Thirty-one (42.5%) of them were born in Sweden, and abroad. One child who died in 1982 after a clinical course compatible with AIDS was diagnosed retrospectively as HIV infected by stored serum.13
Origin of the Mothers and the Route of HIV-1 Transmission
The mothers of 52 infected children originated from Africa, 10 were Europeans (nine Swedish), 6 Asians, 4 Latin Americans. Four women, all Swedish, were most probably infected by intravenous drug use. In 65 cases, heterosexual intercourse was the most probable route of infection of the mother, and in 3 cases, the infection route was unknown.
The subtype of HIV-1 was determined in 34 children. Six different subtypes were identified; 11 children had subtype A, 7 had B, 8 C, 3 D, 4 Crf_01_AE, and 1 child had subtype G.
Children Who Died or Emigrated
One infected child died in 198213 and 10 infected children died between 1987 and 1996. Ten children died of AIDS and one of an HIV-1-unrelated condition. Their median age at death was 4.6 (0.2-8.5) years. No HIV-1-related child death has been reported in Sweden after 1996. Ten children left Sweden between 1994 and 1998 at a median age of 4.6 (1.2-8.0) years and were lost to follow-up. Nine of these 10 children were born outside Sweden to mothers of African origin. Two children lived in refugee families who were denied permission to stay in Sweden, 1 returned to relatives in Africa after the death of the mother in Sweden, 3 moved to other European countries, 2 children with AIDS and probably returned to their home country to die, and in 2 cases, information about the reason for emigration is missing.
Fifty-One Vertically HIV-1-Infected Children Living in Sweden in 2003
The children were followed for 5924 child-months, and the median age at the latest follow-up was 10.8 (2.7-17.6) years. Their CDC classification and antiretroviral therapy at the end of 2003 are shown in Table 6. The CD4+ cell counts ranged from 10 to 1600 × 106 (median, 670 × 106), and the HIV-1 RNA numbers ranged from undetectable (<50 copies/mL) in 67% of the treated children to 445,000 copies/mL (median, < 50 copies/mL).
Ten children acquired AIDS (Table 6). In 8 of these children aged 3.7 to 13.7 (median, 7.4) years, the current treatment, CD4+ cell count, and viral load were reported. They were all being treated with combination therapy consisting of 3 to 6 antiretrovirals, all combinations including at least 1 protease inhibitor. The median CD4+ cell count was 560 (10-1600) × 106/mL. The HIV-1 RNA copy numbers in blood varied from <50 (3 of 8) to 445,000 copies/mL. The child with the lowest CD4+ cell count and the highest viral load suffered therapeutic failure and at the latest follow-up had clinical symptoms related to the HIV-1 infection. The remaining 7 children with previous AIDS-defining diagnoses were asymptomatic at latest follow-up.
This study reports of all children in Sweden known to be born to HIV-1-infected women. It is extremely rare that pregnant women in Sweden do not attend antenatal care. The national screening program offers HIV testing to all women regardless of risk factors or ethnic origin, which may be one explanation to the high acceptance rate. This makes it probable that most pregnant HIV-1-infected women in Sweden have been identified.4 Inasmuch as all HIV-1-infected individuals in Sweden are reported by code to the Swedish Institute for Infectious Disease Control, all identified HIV-1-infected children in Sweden were included.
The decrease in the mother-to-child transmission rate from 24.7% in 1985-1993 to 5.7% in 1994-1998 reflects the introduction of the ACTG 076 protocol in 1994, and the reduction rate is similar to what was seen in the ACTG 076 study.8 After 1998, only 1 infected child has been born in Sweden (in 1999), which most probably reflects the effect of the increasing use of antiretroviral combination therapy in pregnant women and the routine use of elective cesarean delivery.
Although these are results obtained in routine care, the transmission rates are as low as in intervention and/or prospective studies.2 National guidelines for the management of HIV-1-infected pregnant women elaborated by the Swedish Reference Group for Antiviral Therapy14 together with the Swedish Medical Products Agency and the high acceptance rate in the pregnancy screening program are factors that probably contributed to the low transmission rate.
Six infected children were born after prophylactic intervention according to the ACTG 076 protocol. In 3 of these cases, the prophylaxis was suboptimal, and in 2 cases resistance against ZDV could be expected, which emphasizes the importance of adequately performed prophylactic interventions. The fact that 4 children were vertically infected by women who were not diagnosed with HIV before delivery emphasizes the importance of continued high antenatal testing rates even in countries with low HIV-1 prevalence such as Sweden.
No child was infected when the mother received prophylaxis with 2 or more antiretroviral agents. In other studies, low vertical transmission rates have been observed in women on one or two antiretroviral agents with undetectable virus (<500 copies/mL) in late pregnancy15,16 and in women receiving combination antiretroviral therapy during pregnancy.17,18 In the United States, elective cesarean delivery is recommended for women with HIV-1 RNA greater than 1000 copies/mL near the time of delivery. According to the American College of Obstetricians and Gynecologists, elective cesarean delivery would probably not provide additional benefit in the reduction in transmission if the woman is treated with antiretroviral drugs and the plasma HIV-1 RNA is fewer than 1000 copies/mL.19 Our study confirms the low transmission rate when combination antiretroviral combination therapy is used, and we could not detect any difference between groups according to the mode of delivery. Recent data from the European Collaborative Study do indeed support that elective cesarean delivery further reduces the mother-to-child transmission rate even in women with an undetectable viral load.20 Elective cesarean delivery is recommended in the Swedish national guidelines for pregnant HIV-infected women.14
Although MTCT of HIV is almost eradicated in Sweden at present, the number of children living with HIV and AIDS is increasing. The survival has improved dramatically and there is an increasing immigration of HIV-infected children. To keep the number of infected children as low as possible, it is important to continue to provide good access to antenatal care, and offer universal antenatal HIV screening, and prophylactic measures against MTCT of HIV to all women independent of risk factors, ethnic origin, and economical status.
We thank the pediatricians, obstetricians, specialists in infectious diseases, nurses, and midwives who helped us in the collection of the data and Jakob Bergstrom for help with statistical analysis.
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