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Pregnancy outcomes in HAART exposed infants in Johannesburg

HIV Treat Bull - 2009 Sep/Oct;10(9/10): 12

Polly Clayden, HIV i-Base

There are conflicting reports concerning the association between preterm birth or low birth weight and HAART.

Karin van der Merwe and coresearchers investigated the impact of HAART exposure on birth weight and gestational age among infants of South African women with advanced HIV disease attending antenatal antiretroviral clinics in Johannesburg.[1]

This review included 1630 women attending clinics between April 2004 and July 2008. All women had CD4 <250 cells/mm3.

Gestation and birth weight of infants were compared: maternal HAART exposed vs unexposed; early (<28 weeks gestation) vs late (≥28 weeks) and PI-based vs NVP-based vs EFV-based. Multivariate logistic regression was used and included maternal CD4 and infant HIV status (PCR).

The investigators found the median CD4 counts for mothers of infants exposed and unexposed to HAART were 154 (IQR 101-229 and 191(IQR 136-220) cells/mm3 respectively, p<0.001. The two groups were similar for other risks of adverse infant outcomes: smoking, alcohol, hypertension, diabetes, anaemia, syphillis serology and history of previous miscarriage.

Prematurity rates were 6% (8/143) in HAART-unexposed infants vs 14%(129/949) in HAART-exposed infants (p=0.01). The HAART-exposed infants had mothers with a higher rate of previous preterm infants than the unexposed group, 11% vs 6%, p=0.055.

See Tables 1 and 2 for infant outcomes by duration of exposure and HAART regimen.

Table 1: Infant outcomes in women exposed and unexposed to HAART and by duration of exposure
Variables HAART-unexposed A n=233 HAART-exposed B n=1397 p value (A vs B) Early HAART-exposed C n=533 Late HAART-exposed D n=427 p-value (C vs D)
Time received HAART Median weeks (IQR)   9.7(5.0-17.6)
n=921		   18.4 (12.1-42.6)
n=412		 5.8 (3.3-8.5)
n=416		 <0.001
Gestation: n(%) n=147 n=946 0.002 n=389 n=427 <0.001
Extremely preterm 6 (4%) 58 (6%)   40 (10%) 3 (1%)  
Preterm 1 (1%) 80 (8%)   41 (11%) 18 (4%)  
Term/Postdates 140 (95%) 808 (85%)   308 (79%) 406 (95%)  
Birth weight (kg): n n=224 n=1003 0.008 n=388 n=407 0.39
Mean (SD) 2.8 (0.6) 2.9 (0.6)   2.9 (0.6) 2.9 (0.5)  
1.5-2.49
>2.5		 50 (22%)
164 (73%)		 199 (20%)
789 (79%)		 0.015 82 (21%)
298 (77%)		 74 (18%)
331 (81%)		 0.071

Table 2. Infant outcomes in women exposed to HAART by regimen
Variables Early HAART-exposed p Late HAART-exposed p
PI-based
HAART		 NVP-based
HAART		 EFV-based
HAART		 PI-based
HAART		 NVP-based
HAART		 EFV-based
HAART
Time taking HAART n=139 n=192 n=81   n=290 n=107 n=19  
Median weeks (IQR) 17.1 (13.7-23.1) 15.6 (10.7-25.8) 62.7 (33.1-86.4) <0.001 6.1 (3.3-8.7) 5.1 (3.0-7.8) 5.2 (3.9-9.4) 0.38
Gestation: n n=131 n=167 n=91   n=290 n=116 n=21  
Extremely preterm (%) 13 (10%) 15 (9%) 12 (13%) 0.048 0 (0%) 3 (3%) 0 (0%) 0.024
Preterm 6 (5%) 25 (15%) 10 (11%)   9 (3%) 8 (7%) 1 (5%)  
Term/Postdates 112 (86%) 127 (76%) 69 (76%)   281 (97%) 105 (91%) 20 (95%)  
Birth weight (kg): n n=135 n=158 n=95   n=284 n=103 n=20  
Mean (SD) 3.0 (0.6) 2.9 (0.5) 2.7 (0.6) 0.002 2.9 (0.5) 2.9 (0.5) 2.8 (0.5)  
0.75-1.49 5 (4%) 0 (0%) 3 (3%)   2 (1%) 0 (0%) 0 (0%) 0.59
1.5-2.49 18 (13%) 31 (20%) 33 (35%)   46 (16%) 23 (22%) 5 (25%)  
>2.5 112 (83%) 127 (80%) 59 (62%) <0.001 236 (83%) 80 (78%) 15 (75%) 0.50

The investigators concluded that, in this analysis, any HAART exposure was associated with preterm birth between 34-37 weeks gestation. This was strongest when HAART was initiated before 28 weeks gestation. However, they did not find an increased risk of extremely preterm birth (<34 weeks gestation).

Overall, they found neither low birth weight nor very low birth weight to be associated with HAART exposure. In this cohort, infants unexposed to HAARTwere more likely to have low birth weight.

PI exposure was not a risk factor for preterm or low birth weight. But, of the three regimens, early EFV exposure was associated with low birth weight. The investigators suggested that higher levels of TB among this group of women could be confounding, as EFV is frequently used in South Africa in pregnancy in the presence of HIV/TB coinfection. TB is a risk factor for preterm birth and low birth weight.

They added that these findings could help guide PMTCT policies in South Africa.

Comment:

As the investigators suggest, the observation that there was an association between early efavirenz exposure and low birth weight may be subject to confounding due to TB.

They included two useful tables (see Tables 3 and 4) showing published studies that looked at HAART exposure and preterm delivery or low birth weight. Data from Africa is slowly emerging.

Table 3: Major studies showing a link between preterm birth or low birth weight and HAART exposure
Study Year of publication Population Findings
European Collaborative and Swiss Mother and child HIV cohort study[2] 1998 3920 mother-child pairs in Europe Protease inhibitor exposure linked with preterm birth
European Collaborative study [3] 2004 4372 live births in Europe HAART-initiation pre-pregnancy associated with preterm birth especially extreme preterm birth
Miami study, Cotter et al [4] 2006 1337 women in Miami Protease inhibitor exposure associated with preterm birth
National Population-based surveillance study, Townsend et al [5] 2007 4445 pregnancies in UK and Ireland HAART exposure associated with preterm birth especially extreme preterm birth

Table 4: Major studies showing no link between preterm birth or low birth weight and HAART exposure
Study Year of publication Population Findings
US combined cohort [6] 2002 3266 women in the US No association between LBW or preterm birth and HAART exposure
WITS[7] 2005 2543 women in the US Preterm birth decreased in association with HAART exposure
Szyld et al [8] 2006 681 women in Latin America and the Caribbean PI-exposure not significantly associated with LBW or preterm birth compared to NNRTI exposure
Paediatric Spectrum of Diseases[9] 2007 11 321 infants in the US HAART not significantly associated with preterm birth

References:

  1. van der Merwe K et al. The impact of in-utero antiretroviral therapy (HAART) exposure on infant outcomes in Johannesburg, South Africa. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Poster abstract WEPEB262.

  2. Lorenzi P et al. Antiretroviral therapies in pregnancy: maternal, foetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS. 1998 Dec 24;12(18):F241-7.

  3. Thorne C et al. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS. 2004 Nov 19;18(17):2337-9.

  4. Cotter A et al. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. 2006 May 1;193(9):1195-201.

  5. Townsend CL et al. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS. 2007 May 11;21(8):1019-26.

  6. Tuomala RE et al. Antiretroviral therapy in pregnancy and the risk of adverse outcome. N Engl J Med. 2002 Jun 13;346(24):1863-70.

  7. Tuomala RE et al. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr. 2005 Apr 1;38(4):449-73.

  8. Szyid EG et al. Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. AIDS. 2006 Nov 28;20(18):2345-53.

  9. Schulte J et al. Declines in low birth weight and preterm birth among infants who were born to HIV-infected women during an era of increased use of maternal antiretroviral drugs. Pediatric spectrum of HIV disease, 1989-2004. Pediatrics. 2007 Apr;119(4):e900-6.

2009-09-10
IB2009-09-12

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