Polly Clayden, HIV i-Base
Reports of dolutegravir use in pregnancy from Botswana, Europe and the Antiretroviral Pregnancy Registry to date did not show an increased risk of adverse outcomes compared with other antiretrovirals. [1, 2, 3]
But more data are needed, particularly with dolutegravir exposure before conception, to reach definitive conclusions, according to analyses presented at IAS 2017.
The risk of adverse birth outcomes was similar for dolutegravir-based and efavirenz-based ART among women starting treatment in pregnancy in the Tsepamo study.
Botswana introduced dolutegravir-based first-line ART for all adults, including pregnant women, regardless of CD4 count in May 2016.
Since August 2014 the Tsepamo Study has performed ongoing birth surveillance to evaluate the safety of ART in pregnancy.
Conducted at eight government hospitals, the study captured data on over 47,000 births at study sites (approximately 45% of all deliveries in the country). The majority (99%) had documented maternal HIV status; 25% of mothers with known status were HIV positive; 91% were on ART before delivery; and the regimen was recorded for 94% of treated mothers.
In a previous analysis, at two years, maternal ART of efavirenz, tenofovir and emtricitabine from conception was associated with lower risk of adverse birth outcomes compared with other (older) regimens, among infants exposed to ART from conception in Botswana. [4, 5]
This more recent analysis included women who started either efavirenz, tenofovir and emtricitabine (4593 delivered August 2014 to August 2016) or dolutegravir, tenofovir and emtricitabine (845 delivered November 2016 to April 2017) during singleton pregnancy.
Outcomes included combined endpoints of any adverse outcome (stillbirth, preterm birth <37 weeks, small for gestational age (<10th percentile weight-for-gestational age), or neonatal death (<28 days) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks] and very small for gestational age (<3rd percentile weight-for-gestational age). Results were adjusted for maternal age, educational attainment and gravida.
Women were similar across treatment groups: median age 28, approximately 10% had no primary education, about half delivered at a tertiary facility, for about a quarter it was the first child but 12% already had four or more. They presented at ANC at a median gestational age of 17 weeks, 6% had a history of preterm delivery and 3% of stillbirth. About a third were diagnosed before pregnancy, median ART initiation was at 20-week gestation and median CD4 count above 400 cells/mm3. But women that started on dolutegravir had fewer days between ANC presentation and ART start: median 11 vs 23 days. And they had fewer CD4 results in pregnancy: 17 vs 45%.
The analysis found no significant differences in total and severe adverse birth outcomes, preterm, very preterm birth, small for gestational age, very small for gestational age, stillbirth, and neonatal death. Adjusted risk ratios (aRR) for dolutegravir-based regimens with efavirenz-based regimens as reference were respectively (for the above outcomes): aRR 1.0 (95% CI 0.9 to 1.1), aRR 1.0 (95% CI 0.8 to 1.2), aRR 1.0 (95% CI 0.8 to 1.1, aRR 1.2 (95% CI 0.8 to 1.7), aRR 1.0 (95% CI 0.9 to 1.2), aRR 0.9 (95% CI 0.7 to 1.2), aRR 0.9 (95% CI 0.6 to 1.5), and aRR 1.0 (95% CI 0.5 to 1.9).
Of 512 first-trimester ART exposures (116 dolutegravir and 396 efavirenz), there was one major congenital abnormality: skeletal dysplasia in an efavirenz-exposed infant.
Presenting author Rebecca Zash concluded that these preliminary data are reassuring but not the whole story. Birth outcomes with dolutegravir exposure from conception still need to be evaluated.
European Pregnancy and Paediatric HIV Cohort Collaboration
Data from European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) were presented at the 9th International Workshop on HIV Paediatrics (as an oral presentation) as well as IAS 2017.  Although this is the largest European study to date, small numbers preclude firm conclusions from EPPICC regarding safety of dolutegravir in pregnancy.
EPPICC analyses prospectively collect individual patient data (ie with antiretroviral exposure data collected before pregnancy outcome is known) from observational studies of HIV positive pregnant women and their infants in Europe. This study included women with any prenatal exposure to dolutegravir reported by September 2016.
Of 101 pregnancies, 16 were ongoing at the time of analysis and one was lost to follow up. Of 84 pregnancies with outcomes: 81 live births (83 newborns, two twin pregnancies), one spontaneous abortion, one induced abortion, and one stillbirth, were included in the analysis.
At conception women were a median of 33.1 years, 85% were already diagnosed, and 60% were already on ART. Of the women, 10% were vertically infected, 11% had advanced HIV, 43% had CD4 count 350 cells/mm3 or less in pregnancy, and 9% were HCV coinfected.
Of the total pregnancies, 58 (57.4%) had first trimester earliest dolutegravir exposure, 24 (23.8%) second trimester, 18 (17.8%) third trimester and one unknown.
The spontaneous abortion and induced abortion (personal decision, no foetal abnormality) occurred in pregnancies with first trimester exposure (both conceived on dolutegravir), and the still birth in a pregnancy with second trimester exposure.
Among 80 infants (79 pregnancies singleton live birth and one stillbirth), 16.7% had low birth weight and 18.7% were small for gestational age.
Abnormalities were reported in 4 of 81 live born/still born infants (no defect in the still born infant): 4.9% (95% CI 1.4 to 12.2). See table 1. Notably, there was no pattern of defects and only infants I and 2 would be classified according to EUROCAT definitions.
|Infant||Abnormality||Earliest exposure||Sex||Maternal details||Other ARVs||Country|
|1||Patent foramen ovale||Conception||Male||Black African, aged 38 at delivery||3TC, ABC||Italy|
|2||Bilateral hexadactyly of hands (father has same defect). Hypospadias||Week 3||Male||White, aged 40 at delivery||3TC/ABC, FTC/TDF in first trimester||Italy|
|3||Ankyloglossia (tongue tie)||Week 12||Male||White, vertically infected, aged 31 at delivery||DRV/r, ATV/r, RAL, TDF in first trimester||Italy|
|4||Hyperpigmentation on back||Week 14||Male||Black African, aged 34 at delivery||3TC, ABC||Switzerland|
Claire Thorne, who presented the data stressed that the European women receiving dolutegravir in this cohort represented a high-risk group including older mothers, those with advanced HIV, treatment experienced and HCV coinfected.
Antiretroviral Pregnancy Registry
The Antiretroviral Pregnancy Registry (APR) analysis of birth defects includes the largest number of prenatal exposures to dolutegravir to date – presented as a poster at IAS and online in the APR interim report through January 2017. 
APR data did not demonstrate an increased risk of congenital anomalies with dolutegravir use above the expected population rate of defects: 2.72 to 4.17 per 100 live births. But this finding was also limited by sample size.
APR is an international (although largely US), registry that monitors prenatal antiretroviral drug exposures to detect potential increases in the risk of birth defects.
Clinicians register pregnant women with prenatal exposure to any antiretroviral before the pregnancy outcome is known, report data on exposure throughout pregnancy and provide birth outcome data. Registration is voluntary and confidential. The APR produces twice-yearly reports.
Antiretroviral exposure is classified by earliest trimester. When at least 200 exposures to a specific drug have been reported, APR can calculate birth defect prevalence and compare it to internal and external comparator groups.
The external comparators are two population-based surveillance systems: Metropolitan Atlanta Congenital Defects Program (MACDP) and Texas Birth Defects Registry (TBDR). Internal comparators include exposure to other drugs and in second and third trimesters. APR has 80% power to detect doubling of risk and type 1 error rate for doubling of risk for overall birth defects with 200 exposures.
As of 31 January 2016, 142 pregnancies with exposure to dolutegravir were prospectively reported to the APR: 88 with earliest exposure first trimester, and 54 second/third trimesters.
At enrolment, 56 (39.4%) women had a CD4 count >500 cells/mm3, 48 (33.8%) 200–499 cells/mm3, 31 (21.8%) < 200 cells/mm3 and results were missing for 7 (4.9%). Mothers were a median of 29 years old. The majority, 126, were from the US.
Of 142 pregnancies, 128 (90.1%) resulted in live births (74 with first and 54 with second/third trimester exposure), 3 (2.1%) resulted in induced abortions (all with first trimester exposure), and 11 (7.7%) resulted in spontaneous abortions (all with first trimester exposure). No stillbirths were reported.
Four birth defects were reported among 133 live births (77 with first and 56 second/third trimester exposure).
Table 2: Congenital abnormalities in APR following dolutegravir exposure starting in first (total 74) or second/third (total 54) trimesters
|Infant||Abnormality||Earliest exposure||Sex||Maternal details||Other ARVs|
|1||Bilateral polydactyly post-axial to both hands||First trimester||Male||Black, aged 26 years at conception||DRV/r in first trimester|
|2||Polydactyly on the ulnar side and syndactyly on the second, third and forth fingers||First trimester||Male||Black, aged 22 years at conception||FTC/TDF in first trimester|
|3||Hypoglossia hypodactylia syndrome||Second/third trimester||Female||Black, aged 31 years at conception||DRV/r, FTC/TDF in second trimester, AZT in third trimester|
|4||Down’s syndrome||Second/third trimester||Female||Hispanic, aged 38 years at conception||ABC/3TC in second trimester|
Among 119 live births without defect other adverse birth outcomes included: 13 preterm <37 weeks of gestation (8 with first and 5 second/third trimester exposure); 14 low birth weight <2500 grams (9 with first and 5 second/third trimester exposure); 5 very low birth weight <1500 grams (3 with first and 2 second/third trimester exposure).
At the time of analysis, the APR had not reached the 200 first trimester exposures needed to estimate overall prevalence of birth defects. APR’s “Rule of 3” (once three or more prospective similar organ system defects have been recorded, these cases will be flagged for immediate review) is being followed for polydactyly.
The APR authors noted hand anomalies are among the most common birth defects identified in infants: approximately 10% of birth defects; 15% of all upper extremity anomalies involve polydactyly.
Risk factors are African origin, male sex, birth order, increased maternal age and maternal smoking.
Global rollout of dolutegravir has been hampered by lack of safety data in pregnancy (as well as with TB co-treatment). So these reports are welcome and reassuring but each one emphasised the need for more preconception dolutegravir exposures.
It should be possible to do a pooled analysis of these data – for the APR/EPPICC the analysis would need to de-duplicate any EPPICC cases reported to APR.
- Zash R et al. Dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Botswana. IAS 2017. 23–26 July 2017. Paris. Oral abstract MOAX0202LB.
- Thorne C et al. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. IAS 2017. 23–26 July 2017. Paris. Poster abstract MOPEC0609.
- Vannappagari V et al. Dolutegravir use during pregnancy and birth outcomes: data from the Antiretroviral Pregnancy Registry (APR). IAS 2017. 23–26 July 2017. Paris. Poster abstract MOPEBO283.
- Clayden P. Efavirenz, tenofovir and emtricitabine associated with fewest adverse birth outcomes in Botswana. HTB 27 February 2017.
- Zash R et al. Adverse birth outcomes differ by ART regimen from conception in Botswana. CROI 2017. 13–17 February 2017. Seattle, Washington. Oral abstract 25.
- Thorne C et al. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. 9th International Workshop on HIV Pediatrics 2017. 21–22 July 2017. Paris. Oral abstract 10.
- Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2017.