Table 1.

Main Sources of Bias in Studies of Environmental Impacts on Time to Pregnancy

Source of Bias	Description of Potential Bias	Possible Approaches to Limit Bias
Study design	Exclusion of infertile couples (e.g., in a pregnancy-based design) (30–34)	Consider alternative designs (incident or prevalent cohort, current duration approach). In a population-based retrospective setting, try to collect information on unsuccessful attempts at pregnancy.
	Truncation (of short/long TTPs at the beginning/end of the study period, respectively) (40, 106)	Define the study period with respect to the date of the beginning (and not the end) of the period of unprotected intercourse; include current attempts.
	Pregnancy planning bias 1: exclusion of unplanned/mistimed pregnancies	Ascertain exposures for nonplanners as well and conduct sensitivity analyses (21, 107).
Outcome assessment	Pregnancy planning bias 2: unplanned pregnancies can retrospectively be described as planned (also termed “wantedness bias”)	Reanalyze excluding declared cycle 1 conceptions. Define inclusion criteria on contraceptive use rather than pregnancy wish.
	Pregnancy planning bias 3: exclusion of couples who have unprotected intercourse without planning to become pregnant	Try to include periods of unprotected intercourse corresponding to couples not planning to become pregnant and reanalyze.
	Pregnancy recognition bias: couples in whom pregnancy is diagnosed very early may identify pregnancies ending with an early loss that would not have been identified by other couples (21)	Record when and how pregnancy was recognized. Restrict analyses to pregnancies leading to a livebirth.
	Use of oral contraception may vary with exposure and might be associated with decreased fecundability in the first cycles	Assess the last contraceptive method used; ask if couples used abstinence after discontinuation of pill; treat pill use as time-varying covariate.
	In a retrospective setting, couples may recall TTP with some error (e.g., digit preference) (22)	Focus on pregnancies leading to a livebirth, for which recall may be better; group consecutive TTP values (e.g., 5–7, 11–13 months).
Medical intervention	Medical intervention bias: 1) medical treatments may modify the probability of pregnancy; 2) if couples remaining childless are not recruited and if exposure is associated with the delay before couples resort to medical help, bias may occur	Treat infertility treatment as a censoring mechanism; try to assess if infertility treatments depend on exposure (conditionally on waiting time).
Exposure assessment	Bias due to time trends in exposure and TTP: if, for example, TTP tended to be longer at the start of the pregnancy period, and if exposure tended to decrease over time, then a spurious association (corresponding here to an apparently longer TTP in association with exposure) might be induced (28)	Simulate by using external data on the time trends in exposure (28).
	Exposure is assessed during or after pregnancy instead of at the start of the period of unprotected intercourse. Bias can occur if exposure varies quickly over time (e.g., from month to month) or increases with time (creating a spurious association with TTP)	Assess exposure at the start of the period of unprotected intercourse (38).
	Behavior modification bias (if exposure is influenced by behaviors; for example, couples may stop smoking after a delay of unsuccessful attempt at pregnancy)	Use date of discontinuation of contraception as a reference date to define exposure and confounders. Assess modifications of behavior and use a model with time-dependent covariates. Censor TTP (e.g., at 12 months).
	Toxicokinetic bias (in studies relying on exposure biomarkers): bias due to toxicokinetic changes in the body burden of the environmental factor following a previous pregnancy (108)	Stratify analyses on parity (37).
Statistical analysis	Proportional hazard hypothesis not verified	Test for different effects of exposure during months 1–3 and 4–12 (or other cutoff) of the pregnancy attempt.

Abbreviation: TTP, time to pregnancy.