Data from an unplanned interim analysis of an observational study conducted in Botswana that was released on May 18, 2018, reported a possible increased risk of neural tube defect (NTD) in women taking dolutegravir preconception (0.9% vs 0.1% among non-DTG ART from conception).
New data from the same study, published and also presented at the International AIDS Society meeting in July 2019, reporting the prevalence of NTDs in women taking DTG at conception was 0.3% compared with 0.1% among women taking non-DTG ART at conception.
The neural tube closes very early in embryonic development at day 28 post conception (6 week post last menstrual period in women with regular, 28-day cycles). This emphasizes the importance of pre-conception counselling and the importance of highly reliable contraception in WLWH as the best opportunity for risk reduction occurs prior to pregnancy.
Based on this data, revised, updated recommendations follow:
- Women who are taking any antiretrovirals including dolutegravir and become pregnant and are past 6-7 weeks of gestation should continue the same antiretroviral therapy if effective and well tolerated but have that regimen reviewed in light of pregnancy overall. Women who had dolutegravir exposure at conception should be advised to perform prenatal screening for NTD. Recommendation for termination of pregnancy on the basis of peri-conceptional dolutegravir exposure alone is not appropriate.
- If women who are taking dolutegravir present earlier than 6-7 weeks gestation, and wish to change from a dolutegravir regimen they should be counselled of the low absolute risk of dolutegravir exposure. This should be taken on balance with the potential risks of changing regimens given unknown tolerance and ability to adhere to a new regimen. A woman centered decision for a regimen switch or continuation of Dolutegravir based on her values should be made.
- Non-pregnant, reproductive aged women should have their pregnancy intentions and contraceptive use reviewed in each HIV visit. * Encourage the use of highly reliable methods of contraception (e.g. intrauterine device) and perform a pregnancy test prior to or at the time of initiating Dolutegravir based regimens.
- Reproductive aged women who are not on highly reliable methods of contraception should be counseled on the risks associated with being on a dolutegravir containing regimen if they become pregnant and the safety of alternative regimens which do not carry the same NTD risk. Decisions to switch should be based on informed choice. If pregnancy is a possibility, switching to non-dolutegravir containing regimen should be considered.
- Given the lack of safety information on any new antiretroviral formulations, including but not limited to elvitegravir, bictegravir, TAF and cobisistat containing regimens, caution should be used in prescribing these in non-pregnant, reproductive aged women and they should be avoided in the first trimester of pregnancy when possible.
Information on dolutegravir in pregnancy to date:
Data was released on May 18, 2018 based on an interim analysis of an NIH funded birth surveillance study, the Tsepamo study, based in Botswana. At that time, they found that in 11,558 women living with HIV in Botswana who became pregnant, 0.9% of babies (4 of 426) whose mothers became pregnant while taking dolutegravir had a NTD, compared with 0.1% of babies (14 of 11,173) whose mothers took other antiretroviral combinations (1,2).
Since that time, further study data from the Tsepamo has been released and was presented at the International AIDS Society (IAS) conference on July 22, 2019. The new data reported that the prevalence of NTD associated with dolutegravir use in the first trimester was 0.30% (5 of 1683) compared to 0.1% (15 of 14, 792) in non-dolutegravir exposed pregnancies (10).
This reported decline in the risk of neural tube defects has downgraded the ‘safety signal’ of concern for use of dolutegravir however the risk remains higher than other antiretroviral drug exposure groups. Moreover, data recently reported, from 22 sites in Botswana not included in the Tsepama study, between 2014-2019, showed a rate of NTD of dolutegravir exposed pregnancies of 0.65% compared to 0.08% in non-dolutegravir exposed pregnancies (11). Canadian surveillance data on congenital anomalies in pregnancies exposed to dolutegravir pre-conception and in the first trimester did not show a significant difference in overall rate of congenital anomalies between women on antiretroviral therapy compared with those not exposed; 3.9% vs 3.0%. Of the 4 of the 80 neonates born to women on dolutegravir during the first trimester who had congenital anomalies, none had NTD (12). (In Canada, folic acid is recommended prior and during pregnancy, which has been shown to reduce the rates of NTD).
A systematic review of safety of dolutegravir in pregnancy (4) reported information on congenital anomalies in 442 women exposed to dolutegravir. This review, included data from six main studies including, an ongoing observational study in Botswana with 845 women on dolutegravir compared to 4,593 women on efavirenz; 142 women reported to be taking dolutegravir during pregnancy (88 exposed in first trimester) from the antiretroviral pregnancy registry; 81 pregnancies from EPPICC, PANNA, NEAT-ID; dolutegravir phase 3 trials; dolutegravir post marketing surveillance; and 15 women enrolled in IMPAACT P1026s. Of the total of 442 women exposed to dolutegravir in pregnancy 16 had congenital anomalies (3.6%), which is in keeping with the global rate of congenital anomalies of 3-5%. Of the congenital anomalies, most were polydactyly, which is a common anomaly in children of African descent (1%), and there were two renal cysts. None were documented to be NTD. In a single center retrospective cohort analysis from Sweden (5), 36 pregnant women seen at the Karolinska University Hospital were treated with dolutegravir; 14 before pregnancy and 22 started during pregnancy. There were 4 early spontaneous abortions, one late termination and no congenital malformations.
Overall, the data reported to date appears to reaffirm that there is a small increased risk of NTDs, in the Botswana setting, in dolutegravir exposed pregnancies, however, that the absolute risk is very low. As a result, the WHO has recommended dolutegravir based regimens for first line therapy in all adults due to their risk/benefit analysis for population-based treatment recommendations in sub-Saharan Africa. (WHO press release regarding dolutegravir in pregnancy (10)
General background on congenital anomalies and neural tube defects:
It is important to note that at a population level approximately 4-5% of infants have major congenital anomalies. Therefore, any increased risk associated with prescribing Dolutegravir should be considered in this context. With the advent of modern prenatal screening capabilities, prenatal genetic testing and detailed ultrasound examinations for fetal anomalies, the majority of these anomalies can be recognized. NTD occur at variable rates in different populations and in different countries. The incidence of NTD in Canada is approximately 0.04%. This has decreased from 0.076%, (6) following folate supplementation in grain products, which started in 1998.
In Canada, although there is folate supplementation in food, additional folate supplementation is recommended 12 weeks prior to conception and through at least the first 12 weeks of the pregnancy. In low risk women (without a prior or family history), the supplementation in multivitamins of 0.4-0.6mg of folic acid is sufficient or prenatal vitamins which contain 1mg (7).
Studies globally have shown variability in rates of NTDs from 5.2/10,000 live births to 75.4/10,000 live births in African countries (8). Of note, the highest rate is less than 0.1% which is the rate noted in women living with HIV on non-dolutegravir containing regimens in the above-referenced report from the Botswana surveillance study. NTDs appear very early in the embryo development, as the neural tube closure is at day 28 post conception (6 weeks post LMP in women with very regular 28 day cycles). (14,15)
In summary, this information on dolutegravir is less concerning than the initial data from May 2018, but it highlights the importance of careful consideration when prescribing ART for women of reproductive potential or during pre-conception. In countries where individualized, patient specific prescribing can be conducted, choosing regimens that have long track records of safety in pregnancy is the wisest option. It takes many years of post-marketing surveillance to reveal if there are concerns regarding low event rate complications including teratogenicity. Few pre-licensure studies include women and very few include pregnant women so new drugs on the market need to be assumed to have unknown risks in pregnancy and caution should be exerted in prescribing to women in reproductive age (13).
- WHO Statement on DTG – Geneva 18 May 2018.
- European Medicines Agency statement. New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir. May 18, 2018.
- Tivicay® Product Monograph, ViiV Healthcare ULC, February 3, 2017.
- Hill A, Clayden P, Thorne C, Christie R, Zash R. Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review. Journal of Virus Eradication. 2018;4:66-71
- Bornhede R, Soeria-Atmadja S, Westling K, Pettersson K, Naver L. Dolutegravir in pregnancy-effects on HIV-positive women. European Journal of Clinical Microbiology & Infectious Diseases. 2018;37:495-500.
- Public Health Agency of Canada. Congenital Anomalies in Canada 2013 : A Perinatal Health Surveillance Report. Ottawa, 2013.
- Wilson D et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can 2015;37(6):534-549.
- Zaganjor I, Sekkarie A, Tsang, BL, Williams J, Razzaghi H, Mulinare J, Sniezek JE, Cannon MJ, Rosenthal J. Describing the prevalence of neural tube defects worldwide: A systematic literature review. Plos One 2016;137:1-31.
- Health Canada letter June 7, 2018. RA-66998
- Zash R., Holmes L, Diseko M, Jacobson, DL, Brummel S, Mayondi G, Isaacson A et al. "Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana." N Engl J Med, July 22, 2019.
- Money D, Lee T, O’Brien C, Brophy J, Bitnun A, Kakkar F , Boucoiran I, Alimenti A, Vaudry W, Singer J, Sauve LJ., for the Canadian Perinatal HIV Surveillance Program. Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study. BJOG 2019; https://doi.org/10.1111/1471-0528.15838.
- Mofenson, L. M., Pozniak AL, Wambui J, Raizes E, Ciaranello A, Clayden P, et al. "Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects." J Int AIDS Soc;2019 22(7): e25352.
- Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, Speer MC. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol. 2005;27(3):515–524. doi:10.1016/j.ntt.2004.12.007
- Sadler, T. (2005), Embryology of neural tube development. Am. J. Med. Genet., 135C: 2-8. doi:10.1002/ajmg.c.30049