title: Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.
abstract: OBJECTIVE
  The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy.
  
  
  METHODS
  Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies).
  
  
  RESULTS
  More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group.
  
  
  CONCLUSIONS
  The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy.
  
  
  BACKGROUND
  ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694.
  
  
  BACKGROUND
  The study was funded jointly by AstraZeneca and Takeda.
authors.affiliation: Department of Internal Medicine, University of Turin, Corso AM Dogliotti 14, 10126 Torino, Italy. massimo.porta@unito.it
authors.forename: M
authors.initials: M
authors.lastname: Porta
authors.forename: J W
authors.initials: JW
authors.lastname: Hainer
authors.forename: S-O
authors.initials: SO
authors.lastname: Jansson
authors.forename: A
authors.initials: A
authors.lastname: Malm
authors.forename: R
authors.initials: R
authors.lastname: Bilous
authors.forename: N
authors.initials: N
authors.lastname: Chaturvedi
authors.forename: J H
authors.initials: JH
authors.lastname: Fuller
authors.forename: R
authors.initials: R
authors.lastname: Klein
authors.forename: T
authors.initials: T
authors.lastname: Orchard
authors.forename: H-H
authors.initials: HH
authors.lastname: Parving
authors.forename: A-K
authors.initials: AK
authors.lastname: Sjølie
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology; D000293:Adolescent; D000328:Adult; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000209:etiology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000188:drug therapy* / Q000503:physiopathology; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D012307:Risk Factors; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan