Association between timing of maternal ART and risk of infants born small for gestational age in Dutch ATHENA cohort

Polly Clayden, HIV i-Base

HIV positive women receiving ART before conception had an increased risk of infants being born small for gestational age in the Netherlands, according to data published in 19 January 2018 in PLOS ONE. However, the link is only related to protease inhibitors and the study makes no adjustment for changes in standards of care.

The study included singleton uninfected infants born to mothers registered in the ATHENA cohort 1997–2015. The investigators used multivariate logistic regression analysis for single and multiple pregnancies to evaluate predictors of small for gestational age (SGA), preterm delivery and low birth weight.

In total, 1392 singleton births – born to 1022 mothers – were included in the analysis. Of the mothers, 550 received ART before or at the time of conception for a median of 3.48 years (IQR 2.08–5.35).

Women who started ART before conception were older (32.7 vs 28.8), on an NNRTI-based regimen (47.8% vs 20.8%) and with a lower nadir CD4 count (55.6% vs 22.0% were of <200 cells/mm3) compared to women who started ART after conception, all p<0.001. They were also more often multiparous (70.2% vs 62.8%), p<0.01. Median baseline CD4 count at the start of pregnancy were similar between the two groups.

Of the total births, 331/1392 (23.8%) children were SGA (birth weight less than 10th percentile for gestational age): 27.3% vs 21.5% in women who started ART before and after conception respectively, p=0.01.

In multivariate analysis, adjusting for ART regimen, region of origin and parity (variables with p≤0.1 in the univariate analysis) the risk for SGA was significantly higher among women who started ART before vs after conception: OR 1.35 (95% CI 1.03 to 1.77), p=0.028.

Multivariate analysis also suggested a significantly increased risk of SGA for mothers who received a PI-based regimen before conception vs those who received this regimen after conception: OR 1.49 (95% CI 1.08 to 2.10), p=0.016.

The investigators noted that they did not see this increased risk of SGA for infants of mothers who started a NNRTI-based regimen before vs after conception: OR 0.97 (95% CI 0.62 to 1.52), p=0.91.

Preterm delivery (<37 weeks) occurred in 14.7% of infants. When the investigators looked at the association between preterm delivery and preconception ART, this was significant in univariate analysis, but it did not remain so in multivariate analysis: OR 1.39 (95% CI 0.94 to 1.92), p=0.06. Nor did the risk for very preterm delivery (<32 weeks): OR 1.25 (95% CI 0.86 to1.86), p = 0.22.

Low birth weight (<2.5 kg) was seen in 12.4% of infants. In multivariate analysis, the risk of low birth weight was not statistically different between women who started ART before vs after conception: OR 1.34, (95% CI 0.94 to1.92), p=0.11. And there was no difference between the two groups in very low birth weight: OR 1.36 (95% CI 0.64 to 2.90), p = 0.42.


Perhaps more striking than the elevated risk of SGA among women who received ART before conception was the comparison that investigators made to the Dutch HIV negative Generation R population. In this group the overall risk of SGA was far lower (1.8%). And in this was similar the subset of HIV negative women of sub Saharan African origin (1.4%).

This suggests differences directly or indirectly associated with being HIV positive had a larger impact than the differences between timing of starting ART.

In the discussion, the investigators note that few data exist describing a potential link between SGA and HIV, ART and PI-based regimens. And the data are not consistent among the existing studies. One study found an increased risk of SGA in HIV positive women who were not receiving ART.

More information is needed about the mechanisms underlying foetal growth restriction in HIV positive pregnant women receiving ART. The investigators stressed that only when the potential impact of ART is fully understood can the optimal regimen for HIV positive women of childbearing age be determined.

This dataset compiled results from nearly 20 years during a period of very different approaches to HIV treatment. Despite mentioning this as a limitation – “This study covered several years of observation. Over time the guidelines for cART initiation changed and were based on different CD4-cell count levels.” – the authors did not stratify results by calendar year.

It is important that no association between timing of ART and SGA (or with low birth weight) was seen with NNRTI-based ART, which most women now use. PI use is already avoided in pregnancy and in the future access to integrase inhibitors will increasingly become standard of care.


Snijdewind IJM et al. Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age. PLOS ONE (2018), 13(1):e0191389. DOI: 10.1371/journal.pone.0191389. (19 January 2018).

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