No neural tube defects among pregnancies with periconception dolutegravir exposure in the Dolomite-EPPICC cohort study
Polly Clayden, HIV i-Base
Data from the European Dolomite-EPPICC cohort study, presented at the 10th International Workshop on HIV and Women, did not show any neural tube defects (NTD) among pregnancies with periconception dolutegravir (DTG) exposure. But the dataset is not yet large enough to rule out an increase in these rare events. 
In May 2018 the Tsepamo Study reported a significantly increased NTD risk in women conceiving on DTG (0.94%), leading to a safety alert and a lot of uncertainty and misinformation. 
Additional data, presented July 2019, showed NTD prevalence with periconception DTG to be lower than in the 2018 analysis, but still higher for other antiretroviral exposures (0.3% vs 0.1%). 
The Antiretroviral Pregnancy Registry reported 1 NTD with 312 periconception DTG exposures (0.3%) July 2019 – but the number of exposures is small. 
Dolomite-EPPICC is a multi-cohort European observational study: it includes pooled data from the Dolomite Study which was set up in 2017 to look at the use and safety of DTG in pregnant women and exposed infants in Europe and Canada within the NEAT-ID network, and EPPICC (the European Pregnancy and Paediatric Infections Cohort Collaboration).
The investigators conducted an analysis of prospectively collected data on all pregnancies with any prenatal DTG exposure and with birth outcomes reported by February 2019.
Periconception exposure was defined as within the first 6 weeks of gestation.
The aim of the study is to assess pregnancy and neonatal outcomes following DTG use during pregnancy in real-world European settings.
The analysis included 453 pregnancies among 428 women from 6 countries: UK and Ireland (76%), Spain (9.9%), Switzerland (6.4%), Italy (6.4%) and Romania (0.7%). Women were mostly of black African (54%) and white (30%) ethnicity. Just over 10% were vertically infected.
Of 453 pregnancies (including outcomes from 10 twin pregnancies): 18 were terminated and 22 ended in spontaneous abortion.
There were 417 live-born infants; 280 with periconception exposure. There were 5 stillbirths, all exposed to periconception DTG, none with birth defects: 11.8 per 1000 (95% CI 3.9 to 27.4). One neonate died at 2 days (born at 23 gestational weeks) with periconception DTG exposure.
Among the 417 live-born infants there were 17 with reported birth defects: 4.1% (95% CI 2.4 to 6.5); one infant had 2 defects. Among infants with periconception exposure, 12/266 had reported birth defects: 4.5% (95% CI 3.9 to 5.1).
There were no defects among the stillborn infants. Of 18 induced abortions, 1 was carried out due to birth defects (at gestation week 29 for neuronal migration disorder and severe microcephaly). This terminated pregnancy had periconception DTG exposure.
The 18 defects were in the following systems: genitourinary (7), heart (3), limb addition (polydactyly, 3), gastrointestinal (2), other (3). No CNS defects were reported.
This dataset is the largest to date of European DTG use in pregnancy. The majority (70%) of pregnancies had periconception DTG exposure.
The overall prevalence of defects was 4.1% (3.1% if only EUROCAT defects).
There were no NTDs reported but this is unsurprising as the sample size is too small to come to any conclusion about these rare events (2000 exposures required to rule out a three-fold increase).
But these data add to the current evidence base and the study is ongoing.
At the same meeting Lynne Mofenson provided a typically comprehensive overview of ART in pregnant women. This included an updated list of all published/presented data on NTD with periconception exposure to DTG to date. See Table 1.
Using the available prevalence data, Dr Mofensen calculated, preconception DTG NTD prevalence without food folate fortification: 0.27% (6/2233). This compares with the general population prevalence without food folate fortification: 0.09–0.1%.
With folate food fortification, preconception DTG NTD prevalence: 0.12% (1/847). Compared with general population prevalence with food folate fortification: 0.06%.
Table 1: Published or presented data on neural tube defects with preconception DTG
|Study||Food folate fortification||NTD / preconception exposure|
|Tsepamo 2019 (NEJM 2019)||No||5/1683 (0.30%)|
|CDC-MoH Botswana||No||1/152 (0.66%)|
|Sibiude, France (CROI 2019)||No||0/41|
|Chouchana, France (JAIDS 2019)||No||0/49|
|Thorne, Dolomite-EPPICC 2020||No||0/266*|
|Weissmann, Germany (Glasgow 2018)||No||0/3|
|Kowalska, eastern Europe (Glasgow 2018)||No||0/24|
|Bornhede, Sweden (Eur J ID 2018)||No||0/14|
|Orrell, ARIA (Lancet HIV 2017)||No||0/1|
|APR July 2019||Most||1/312 (0.32%)|
|Brazil case-control (IAS 2019)||Yes||0/384|
|ADVANCE, S Africa (IAS 2019)||Yes||0/54|
|Money, Canada (BJOG)||Yes||0/69|
|Grayhack, US (AIDS 2018)||Yes||0/28|
Source: Mofensen L. 10th International Workshop on HIV and Women 2020. *Dolomite-EPPICC updated to include presentation above.
- Thorne C et al. Outcomes following prenatal exposure to dolutegravir: the Dolomite-EPPICC Study. 10th International Workshop on HIV & Women. Boston, MA. 6–7 March 2020. Oral abstract 2.
- Mofensen L. Prevention of Mother-to-Child Transmission. 10th International Workshop on HIV & Women. Boston, MA. 6–7 March 2020.