Long-awaited UK pregnancy guidelines now updated; pregnancy studies in Dublin
Polly Clayden, HIV i-Base
In an oral presentation David Hawkins summarised the updated BHIVA pregnancy guidelines, which have been some while in their gestation. They are due to be published in July 2005 issue of HIV Medicine and are currently on the BHIVA website. [1, 2]
The guidelines were last updated in 2001 and since then there has been an increase in antenatal HIV screening and experience of managing maternal health and mother to child transmission. However, as Dr Hawkins pointed out, there is a paucity of RCT data except with regimens considered suboptimal in pregnant women in the UK.
New sections have been added on pre-conception, fertility, management of CIN and hepatitis coinfection in pregnancy.
This presentation highlighted some of the key areas of recommendation for management of HIV positive women in pregnancy:
- Sexual health routine screening for GU tract infection at presentation and again in the third trimester of pregnancy;
- Psychosocial issues management by a multidisciplinary team and social circumstances should be assessed. HIV disclosure to partner is encouraged. Antenatal classes tailored to HIV positive women particularly concerning breastfeeding and mode of delivery. Testing of other children is also recommended;
- Viral load measure every three months and at week 36 in women on stable therapy, two weeks after initiating and changing therapy, and at delivery. A second test should be performed where there are discrepancies between viral load, CD4 and clinical status;
- Resistance genotype (or phenotype) assay should be performed: pre-treatment, if a woman has detectable viral load on established therapy, at delivery if she is using monotherapy and two to three weeks after stopping therapy;
- Antiretroviral therapy (ART) in pregnancy AZT monotherapy remains an option for women for whom treatment is not indicated for their own health, with very low viral load and wild type virus, who do not wish to use HAART and agree to an elective caesarean section. Alternatively women in this situation should use short term HAART (START). If indicated for maternal health women should receive HAART;
- Mode of delivery elective caesarean section at 38 weeks is recommended for women with detectable viral load, who are using AZT monotherapy or HIV/HCV co-infected. Vaginal delivery is an option for women on stable HAART with viral load <50 copies/mL. Maternal wishes should be considered;
- Other obstetric management invasive monitoring should be avoided; antibiotics given during caesarean section and ROM in early stage of labour; cortisteroids for threatened pre-term delivery; written care plans; ART for invasive diagnostic tests and IV AZT is not usually indicated if viral load <50 copies/ml;
- HIV/HCV coinfection all HIV positive pregnant women should be tested for HCV and HBV; HIV/HCV coinfected women should be treated with combination ART and offered caesarean section. Babies born to HIV positive women who are HBsAg+ or HBeAg+ as well as those with high HBV viral load should receive passive vaccination with HBIg. HIV/HBV coinfected women should receive ART with activity against HBV;
- Neonatal care babies should receive four weeks PEP, usually AZT monotherapy, but triple therapy if the mother has a detectable viral load. HIV DNA PCR at day one, six weeks and 12 weeks. Confirmation of loss of maternal antibodies at 18 months. Clinics should submit reports from mother and baby to surveillance networks and registries. Formula feeding recommended.
Additionally in this presentation Dr Hawkins highlighted the problems with using NNRTIs in pregnancy. Since February 2004 nevirapine is no longer recommended for women with CD4 count over 250 cells/mm3 at baseline, due to increased risk of hepatic adverse events. Although there are no specific recommendations for pregnant women and data in pregnancy are conflicting, pregnant women may be more likely to fulfill this description particularly those electing to use START.
Efavirenz has recently changed from FDA pregnancy category C to category D, due to four retrospective reports of neural tube defects (three meningomyelocele and one Dandy Walker Syndrome). This decision has provoked much discussion and some criticism: first it was unclear out of how many women using efavirenz this figure comes from and secondly, that the Pregnancy Register, which collects prospective data, only reports 5/188 cases of birth defects (none of which were neural tube defects). At 2.6%, this is similar to the expected incidence of birth defects in the background population (see FDA announcement later in this issue).
Both NNRTI drugs have long half-lives, and data with which to make clear recommendations for stopping them safely have not yet been forthcoming. He suggested that PIs may be preferable in pregnancy, but it is still unclear which PI.
The BHIVA guidelines include clinical scenarios for HIV positive pregnant women in different circumstances. Four posters from this meeting discussed some clinical issues highlighted in the new guidelines.
No transmissions with planned vaginal delivery births for women with undetectable viral load
A poster from Rita Browne and colleagues, presented data from a case note review of women having planned vaginal deliveries, in a multi disciplinary setting at Chelsea and Westminster Hospital, London. 
Women with, or who are expected to have, a viral load of <50 copies/ml on HAART at 36 weeks, are offered the option of a vaginal delivery. This is provided there are no complications such as previous uterine surgery or caesarean section, concurrent genital infection or indication of a difficult or prolonged labour.
A high-risk midwife team will have a detailed care plan to further minimise mother to child transmission, which includes avoiding invasive procedures and a low threshold for caesarean section if labour becomes difficult or prolonged.
Between January 1999 and December 2004, 124 women delivered 140 infants. Twenty-four women planned for vaginal delivery and delivered 32 infants. In this group it was the second pregnancy for six women and the third for one. The majority of the women (19) were black African, three white, one black Caribbean and one Middle Eastern. The median age of the women was 32 years (range 19 to 40 years).
During the study period the number of women delivering vaginally significantly increased over time (chi square test for trend: 7.03, p=0.001). None of the 24 women had an AIDS diagnosis and all were on HAART at the time of delivery, all women achieved an undetectable viral load at six weeks before labour. PI containing treatment was as frequent as NNRTI and mostly ritonavir boosted saquinavir or nevirapine containing regimens were used. Women receiving HAART for prevention of mother to child transmission initiated therapy at 22 to 24 weeks. The median CD4 at delivery was 344 cells/mm3 (range 103 to 922 cells/mm3).
The median duration of completed labour was 5 hours and 23 minutes. Five women had an emergency caesarean section after the onset of labour due to failure to progress and one a planned caesarean following viral rebound close to delivery.
The median gestational age of the infants was 39 weeks and weight was 2.9 kg. The authors reported that 13 children had negative antibodies at 18 months and that 17 children had had three negative DNA PCR tests.
The authors concluded: Women with viral loads of <50 copies/mL at 36 weeks should be offered the option of a planned vaginal delivery with optimal intra-partum care and senior review in labour.
Use of protease inhibitors
Two posters presented findings from small retrospective studies evaluating the use of lopinavir/ritonavir or nelfinavir in pregnant women. [4,5]
Ursula Harrison and colleagues from the Royal Free Hospital in London looked at pregnancy outcome, HIV factors, and CD4 and viral load results, of women receiving lopinavir/ritonavir during pregnancy between 2002 and 2004.
In this cohort, 11/35 (31%) women received lopinavir/r-containing therapy in pregnancy, and 6 had initiated therapy before conception. Nine women were black African. The median CD4 counts and viral load of women initiating therapy, during and prior to pregnancy, were 478 cells/mm3 and 6,050 copies/mL, and 499 cells/mm3 and <50 copies/mL respectively.
Nine women were admitted prior to planned caesarean section, 4 women were already in labour, 3 had SROM (Spontaneous Rupture of Membranes), 2 had placental abruptions and 1 had HELLP (Heamolysis Elevated Liver Enzymes and Low Platelets, a severe form of pre-eclampsia). Eight women had emergency caesarean section, 1 had an unplanned vaginal delivery and 2 had elective caesarean section. Median gestation period was 37 weeks (excluding one emergency caesarean at 27 weeks). Nine women had viral load <50 copies/mL at delivery. All babies were HIV negative with no abnormalities.
The authors wrote: Kaletra is a viable choice for HIV positive pregnant women, but additional monitoring during the third trimester is recommended.
Bell and colleagues evaluated the clinical importance of pharmacokinetic changes reduced nelfinavir and M8 concentrations with nelfinavir use during pregnancy. Pregnant women were compared retrospectively to non-pregnant women using nelfinavir-containing HAART, using the initial rate of viral decay in treatment naive patients as a surrogate marker.
Thirty-nine pregnant women (17 using nevirapine and 22 using nelfinavir) and 27 non-pregnant (22 and 5 respectively) were identified. Pre-treatment rate of viral decay was compared to first on-treatment viral load and compared for significance using t-test.
The authors reported a prolonged viral half-life in pregnant women taking nelfinavir compared to non-pregnant women (4.15 vs 2.94 days p=0.03). No significant difference was seen between pregnant and non-pregnant women in women taking nevirapine (2.1 vs 1.75 p=0.18). Viral decay at two weeks was significantly prolonged in the pregnant nelfinavir group compared with nevirapine (3.02 vs 1.94 days, p=0.004).
They wrote sampling the reduced rate of viral decay in pregnant women taking a nelfinavir-containing regimen suggest that PK data are of clinical importance.
Genital infections are associated with adverse pregnancy outcomes. A poster from Claire Brookings and colleagues investigated the prevalence of genital infections in a cohort of HIV positive pregnant women .
A retrospective analysis was performed using data from the SPLASH (Safe Positive Living and Sexual Health) clinic at Chelsea and Westminster Hospital. This service is based in the HIV clinic, run by a specialist GUM nurse and offers all HIV positive pregnant women a vaginal examination and screen for infections at 16-18 and at 32 weeks.
Between May 2003 and December 2004, 42/55 women offered screening accessed the service. The womens median age was 33 years (range 19 to 41 years) and median CD4 was 314 cells/mm3 (range 86-713 cells/mm3). Eight women were newly diagnosed with HIV and 69% were asymptomatic at diagnosis.19 women had two screens and 23 women had one screen.
The authors reported detectable infections in 22 women: 8 candida, 7 bacterial vaginosis, 1 chlamydia, 1 B-haemolytic streptococcus, 1 genital warts, 1 bacterial vaginosis, 1 HSV and candida and 1 genital warts and HSV. One woman had bacterial vaginosis and candida initially and candida alone on second screen. This is an overall prevalence of 52%.
They recommended that all HIV positive women should be routinely screened for genital infections and added that research is needed to clarify the effect of genital infection on genital viral load especially with women <50 copies/mL opting for vaginal delivery.
These reports reflect some of the existing concerns and confusions in the management of HIV in pregnancy.
Since the nevirapine hepatoxicity warning, UK clinical practice (and the new BHIVA guidelines) is shifting towards use of PIs but with some safety concerns.
The median gestation in the Royal Free study was 37 weeks for women using Kaletra; and 8 women had emergency rather than elective C-sections. Perhaps they could have been allowed to have a spontaneous vaginal delivery given the data from the Chelsea & Westminster. Additionally, there are still insufficient data to inform mothers of the benefits of pre-labour C-section when HIV plasma contains less than 50 HIV RNA copies/mL.
The European Collaborative Study reported an advantage with C-section but only 44% of the women evaluated had vial load below 50 copies/mL. A meta analysis of European and North American cohort data is planned which should address this.
Meanwhile, the risks and benefits of each component of management need to be carefully weighed. It is as important to know what we dont know as to know what we do, to keep an open-mind, and to ensure that the mother is given sufficient information to be able to make informed choices.
- Hawkins DA. Pregnancy Guidelines Update. 11th BHIVA Conference, Dublin 2005.
- BHIVA Guidelines for the Management of HIV infection in Pregnant Women and the Prevention of Mother-to-Child Transmission of HIV. 31 March 2005. Available online
- Browne R, Lyall EG, Penn Z et al. Outcomes of planned vaginal delivery of HIV-positive women managed in a multi-disiplinary setting. 11th BHIVA Conference, Dublin 2005. Abstract P45.
- Harrison U, Shah S, Montgomery H et al. Kaletra in pregnancy experience of a north London teaching hospital. 11th BHIVA Conference, Dublin 2005. Abstract P44.
- Bell C, Slater C, DeRuiter A et al. Potential clinical importance of altered nelfinavir pharmacokinetics in pregnancy. 11th BHIVA Conference, Dublin 2005. Abstract P43.
- Brookings C, Browne R, Ratcliffe P et al. Prevalence of genital infections in a cohort of HIV-positive pregnant women. 11th BHIVA Conference, Dublin 2005. Abstract P42.