PMID- 37586112 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20240412 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 95 DP - 2023 Sep TI - Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model. PG - 104762 LID - S2352-3964(23)00328-6 [pii] LID - 10.1016/j.ebiom.2023.104762 [doi] LID - 104762 AB - BACKGROUND: Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. METHODS: C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. FINDINGS: 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. INTERPRETATION: Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. FUNDING: This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network. CI - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Mohan, Haneesha AU - Mohan H AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Nguyen, Jessica AU - Nguyen J AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - MacKenzie, Ben AU - MacKenzie B AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Yee, Audrey AU - Yee A AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Laurette, Evelyn Yukino AU - Laurette EY AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Sanghvi, Tanvi AU - Sanghvi T AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Tejada, Oscar AU - Tejada O AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Dontsova, Valeriya AU - Dontsova V AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. FAU - Leung, Kit-Yi AU - Leung KY AD - Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK. FAU - Goddard, Cameron AU - Goddard C AD - Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - De Young, Taylor AU - De Young T AD - Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Sled, John G AU - Sled JG AD - Mouse Imaging Center, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Greene, Nicholas D E AU - Greene NDE AD - Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK. FAU - Copp, Andrew J AU - Copp AJ AD - Developmental Biology & Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK. FAU - Serghides, Lena AU - Serghides L AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. Electronic address: lena.serghides@utoronto.ca. LA - eng GR - R01 HD104553/HD/NICHD NIH HHS/United States PT - Journal Article DEP - 20230814 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - DKO1W9H7M1 (dolutegravir) RN - 935E97BOY8 (Folic Acid) SB - IM MH - Female MH - Pregnancy MH - Humans MH - Mice MH - Animals MH - Incidence MH - Placenta MH - Mice, Inbred C57BL MH - Folic Acid MH - *Folic Acid Deficiency/complications MH - *Neural Tube Defects/etiology MH - Disease Models, Animal MH - *HIV Infections/drug therapy/complications MH - Maternal-Fetal Exchange MH - Fetus MH - Ontario PMC - PMC10450420 OTO - NOTNLM OT - Axial asymmetry OT - Bleeding OT - Foetal anomalies OT - INSTI OT - Neural tube defects OT - Oedema COIS- Declaration of interests The authors have no conflicts of interest relating to this study. EDAT- 2023/08/16 18:42 MHDA- 2023/09/18 12:42 PMCR- 2023/08/14 CRDT- 2023/08/16 17:59 PHST- 2023/04/26 00:00 [received] PHST- 2023/07/26 00:00 [revised] PHST- 2023/08/03 00:00 [accepted] PHST- 2023/09/18 12:42 [medline] PHST- 2023/08/16 18:42 [pubmed] PHST- 2023/08/16 17:59 [entrez] PHST- 2023/08/14 00:00 [pmc-release] AID - S2352-3964(23)00328-6 [pii] AID - 104762 [pii] AID - 10.1016/j.ebiom.2023.104762 [doi] PST - ppublish SO - EBioMedicine. 2023 Sep;95:104762. doi: 10.1016/j.ebiom.2023.104762. Epub 2023 Aug 14.