title: Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis.
abstract: OBJECTIVE
  The objective of this investigation was to assess the potential effect of obesity on the effectiveness of hormonal contraceptives (HCs).
  
  
  METHODS
  A meta-analysis was conducted using individual participant data directly from the Phase 3 clinical trials of combination oral contraceptives (COCs) rather than extracting summary data from literature. Trials selected were reviewed by the US Food and Drug Administration (FDA) between 2000 and 2012, conducted in North America, had more than six 28-day cycle equivalents of exposure, and had readily retrievable participant-level data. Contraceptive effectiveness was measured by the Pearl Index (PI: the number of pregnancies per 100 woman-years) in women aged 18-35 at risk of unintended pregnancy. The incidence rate ratio (IRR), a ratio of PIs for obese women (defined as body mass index [BMI] ≥30 kg/m(2)) compared to non-obese women (BMI <30 kg/m(2)) was calculated. A Cox proportional-hazard regression model with fixed and random-effects were used to estimate hazard ratios (HRs) for unintended pregnancy in obese women compared to non-obese women.
  
  
  RESULTS
  Seven clinical trials with COCs (N=14,024: 2707 obese and 11,317 non-obese women) met the inclusion criteria for the meta-analysis. The PI for each trial varied: 2.05-5.08 for obese and 1.84-3.80 for non-obese women. The pooled PI estimated using direct weighted average method was 3.14 (95% CI: 2.33-4.22) for obese and 2.53 (95% CI: 1.88-3.41) for non-obese women. The pooled IRRs estimated using direct weighted average and Mantel-Haenszel adjustment methods were comparable: 1.37 (95% CI: 1.02-1.84) and 1.43 (95% CI: 1.07-1.92), respectively. The overall HR of 1.44 (95% CI: 1.06-1.95; p=.018) in the meta-analysis suggested a 44% higher pregnancy rate during COC use for obese women after adjusting for age and race.
  
  
  CONCLUSIONS
  Obesity may increase the risk of unintended pregnancy in women using COCs; more data on obese women from ongoing and future Phase 3 clinical trials are necessary to allow further evaluation of this topic.
  
  
  CONCLUSIONS
  Results of this meta-analysis suggest that obese women may have a higher pregnancy rate during COC use compared to non-obese women. Future analysis should assess differences in pharmacodynamics or compliance that could potentially account for the observed difference in unintended pregnancy rates.
authors.affiliation: Division of Clinical Pharmacology 3, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), Center of Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Division of Biostatistics 3, Office of Biostatistics, OTS, CDER, FDA, Silver Spring, MD, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Dwyer
authors.affiliation: Division of Biostatistics 3, Office of Biostatistics, OTS, CDER, FDA, Silver Spring, MD, USA.
authors.forename: Mahboob
authors.initials: M
authors.lastname: Sobhan
authors.affiliation: Division of Bone, Reproductive, and Urologic Products, Office of New Drugs, CDER, FDA, Silver Spring, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Davis
authors.affiliation: Division of Clinical Pharmacology 3, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), Center of Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Myong-Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Division of Bone, Reproductive, and Urologic Products, Office of New Drugs, CDER, FDA, Silver Spring, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Soule
authors.affiliation: Division of Bone, Reproductive, and Urologic Products, Office of New Drugs, CDER, FDA, Silver Spring, MD, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Willett
authors.affiliation: Division of Clinical Pharmacology 3, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), Center of Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD, USA. Electronic address: chongwoo.yu@fda.hhs.gov.
authors.forename: Chongwoo
authors.initials: C
authors.lastname: Yu
mesh_terms: D015992:Body Mass Index; D017326:Clinical Trials, Phase III as Topic; D003267:Contraception / Q000379:methods*; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D019304:Ethinyl Estradiol-Norgestrel Combination / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009656:North America; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D011247:Pregnancy; D018873:Pregnancy Rate; D049168:Pregnancy, Unplanned / Q000187:drug effects*; D016016:Proportional Hazards Models
chemical_list: D003277:Contraceptives, Oral, Combined; D019304:Ethinyl Estradiol-Norgestrel Combination
keywords: Body mass index; Contraceptive effectiveness; Hazard ratio; Meta-analysis; Obesity