Introduction

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Randomised controlled trials have established that zidovudine can significantly reduce the risk of vertical transmission of HIV.¹ The protective effect of elective caesarean section has been confirmed by a recent meta-analysis of cohort studies² and a randomised controlled trial.³ The combined effect of these interventions is reported to reduce transmission to 2% or less in some cohort studies.^{2 4}

However, the general population of infected women may differ from those recruited into trials or cohort studies in terms of adherence to antiretroviral treatment, previous exposure to antiretroviral treatment, and uptake of elective caesarean section. It is therefore essential to monitor uptake of interventions and vertical transmission rates in the wider population. Here we present estimates of HIV vertical transmission rates in the British Isles.⁵

	Methods

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Population studied
Since 1989 pregnant women in the British Isles known to be infected with HIV have been notified to the Royal College of Obstetricians and Gynaecologists. Obstetricians are asked to report on outcome of pregnancy and, since 1995, on mode of delivery and uptake of antiretroviral treatment. After initial notification of children born to infected mothers to the British paediatric surveillance unit, paediatricians are asked for diagnostic and clinical data. Subsequently, children of indeterminate infection status are followed until infection status is known.⁵ All reporting is voluntary and confidential. This analysis is confined to prospectively ascertained children whose mothers' HIV infection was reported to have been diagnosed before delivery.

Statistical methods
Statistical methods to avoid biased estimation of vertical transmission rates due to incomplete follow up of indeterminates⁶ were adapted and extended. These involve estimating the probability of infection for each indeterminate child based on when they were last known to be seropositive and the fact that they have not yet been reported to have AIDS. The method takes account of AIDS incubation time, delay in AIDS reporting, and time to antibody loss in uninfected children. It was assumed that progression to AIDS in the first six months would have been reduced since 1994 because prophylaxis against Pneumocystis carinii pneumonia became routine at that time following UK and US guidelines.^7-8

	Results

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By the end of January 1999, a total of 800 prospectively ascertained non-breast fed children born to HIV infected women between 1984 and 1998 had been reported (table 1).

The overall estimation-maximisation algorithm estimate for vertical transmission, which removes the bias caused by indeterminate children, is 12.1% (9.7% to 14.7%). The transmission rate rose to 19.6% (8.0% to 32.5%) in 1993 and from 1995 decreased steeply to 2.2% (0% to 7.8%) in 1998 (figure). The decline in transmission rate from 1995 onwards was significant (odds ratio of 0.51 a year; 95% confidence interval 0.27 to 0.77, ²₂=8.8, P=0.003).

View larger version (22K): [in this window] [in a new window]   Year on year estimates of vertical transmission rates and 95% confidence intervals for HIV among children born to mothers known to be infected with HIV and who did not breast feed

Infected children progressed to AIDS within the first 6 months of life at an estimated baseline rate of 17.7% (6.8% to 30.8%) before 1994 and 7.2% (0% to 15.7%) from 1994 onwards. The difference did not reach significance (² =2.51, P=0.11). After 6 months of age, an estimated 5.0% (2.4% to 8.5%) of children who had not yet developed AIDS would do so each year.

Uptake of antiretroviral treatment increased significantly between 1995 and 1998, as did the proportion taking more than one antiretroviral drug (table 2). The proportion of mother-baby pairs receiving all three components of treatment¹ (antenatal, during delivery, and post partum to the baby) also increased significantly.

Table 3 shows that the risk of HIV transmission was significantly lower in infants with exposure to antiretroviral treatment than in those without. The effect of caesarean section was not significant after antiretroviral treatment was adjusted for. The baseline transmission rate among infants delivered vaginally or by emergency caesarean section in the absence of antiretroviral treatment was estimated to be 31.6%. Elective caesarean section or antiretroviral treatment alone reduced the transmission rate to 15.3% and 10.1%, respectively, and when combined reduced transmission to 4.2%.

	Discussion

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HIV vertical transmission rates rose gradually from 1984 to 1994 and then fell rapidly between 1995 and 1998. The earlier rise could be accounted for by changes in the epidemiology of HIV in infected women.⁵

In the four years ending 1998, during which uptake of elective caesarean section and antiretroviral treatment was increasing, the estimated vertical transmission rate fell steeply to 2.2% (0% to 7.8%) in 1998. This is comparable with a 2.0% estimate based on a meta-analysis,² and 0.8% (1/133) in the French cohort⁴ among women taking antiretroviral treatment (mainly zidovudine only) and having an elective caesarean section. These findings are consistent with previously published data.¹⁰

Progression to AIDS (70% of which was P carinii pneumonia) within the first 6 months of life was reduced by nearly 60% in infants born after the beginning of 1994 compared with those born before. The effect was not significant, but a similar reduction of 66% in AIDS in infancy since 1993 was recently reported in the United States.¹¹ This change is likely to be due to prophylactic co-trimoxazole given to most children born to infected women from 6 weeks of age. ^{7 8}

Prospective cohort studies tend to be set in specialist centres, whereas randomised trials may use exclusion criteria. National surveillance data have the advantage of being population based but are more likely to suffer from missing data and less frequent follow up. However, as long as bias caused by children of indeterminate status is removed, surveillance data should accurately reflect vertical transmission rates in clinical practice. Trials may, in any case, become increasingly difficult to carry out. Antiretroviral treatment is becoming increasingly diverse, more women will have received antiretroviral treatment before pregnancy, and the transmission rates now being reported are very low.^12-15 If the possibility of teratogenic effects becomes a major concern,¹⁶ compliance with treatment regimens may fluctuate. Surveillance data may eventually become the most reliable way to monitor uptake of interventions and HIV vertical transmission rates.

	Acknowledgments

We thank obstetric and paediatric respondents to the surveillance schemes of the Royal College of Obstetricians and Gynaecologists and the British paediatric surveillance unit of the Royal College of Paediatrics and Child Health, as well as colleagues at the Communicable Disease Surveillance Centre, Colindale, and the Scottish Centre for Infection Environment and Health, Glasgow. We also thank David Dunn for help in developing the statistical methods.

Contributors: TD elaborated the statistical methods, programmed them, carried out the analyses, and drafted the methods and results section. AEA obtained funding for the surveillance (with Professor C S Peckham), conceptualised the analysis, and supported TD. TD and AEA are the guarantors. Introduction and discussion sections were drafted by DMG. PAT and JM assembled the surveillance data and assisted in its interpretation. All authors commented on all drafts of the paper.

	Footnotes

Funding: TD, PAT, and JM were supported by grants from AVERT (Aids Education and Research Trust) and the Department of Health.

Competing interests: None declared.

website extra: A longer version of this paper is available on the BMJ's website www.bmj.com

	References

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(Accepted 19 July 1999)