Prospective pregnancy study designs for assessing reproductive and developmental toxicants.

The determinants of successful human reproduction and development may act as early as periconceptionally, underscoring the need to capture exposures during these critical windows when assessing potential toxicants. To identify such toxicants, couples must be studied longitudinally prior to conception without regard to a couple's ability to ascertain a clinically recognized pregnancy. We examined the utility and feasibility of prospective pregnancy study designs by conducting a systematic review of the literature to summarize relevant information regarding the planning, implementation, and success of previously published prospective pregnancy studies. Information concerning design elements and participation was abstracted from 15 eligible studies (from a total of 20 identified studies) using a standardized form. The primary author of each study was contacted to review our summary of their work and obtain missing information. Our findings confirm the ability to recruit women/couples from diverse populations using a variety of recruitment strategies. Among the studies we reviewed, 4-97% of eligible individuals were successfully contacted, with enrollment rates ranging from 42 to 100%. Length of follow-up varied from 3 to 12 months. A high percentage of women provided urine (57-98%) and blood (86-91%) specimens and most male partners (94-100%) provided semen samples. These data support the feasibility of this design. Key words: design, development, fetal, preconception, pregnancy, prospective, reproduction, toxicity.

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A growing body of evidence challenges traditional thinking that only in utero exposures are of concern for the health of the developing fetus. Specifically, reproductive biologists, epidemiologists, and toxicologists recognize the potential importance of parental exposures at critical periconceptional windows, in addition to exposures during organogenesis (Chapin et al. 2004; Selevan et al. 2000). A spectrum of human health end points can be conceptualized for study, as reflected in the evaluative guidelines set forth by various regulatory agencies or organizations (California Environmental Protection Agency 1991; European Commission 2002; International Programme on Chemical Safety 2001; Moore et al. 1995; U.S. Environmental Protection Agency 1991, 1996). Recent biomedical advances offer promise for population-based studies of this type that can potentially address the many critical data gaps that confront this field.

Strategies for weighing scientific evidence regarding reproductive and developmental toxicity highlight study design as a criterion for evaluating the strength of available evidence (Subcommittee on Reproductive and Developmental Toxicology 2001). Although experimental study designs present the strongest data, they are not an ethical option for assessing the effect(s) of potentially toxic exposures on human reproductive and developmental end points. Hence, observational designs are the sole choice for epidemiologic investigation. Among observational studies, data from properly designed and implemented prospective cohort studies usually receive more weight than data obtained via retrospective cohort or case-control studies. This is mainly because of the investigator's ability to ensure a temporal ordering between exposure(s) and outcome(s), measure exposure more accurately, measure relevant covariates at multiple time points, and minimize potential information biases (e.g., recall bias) (Adams 2001; Andersson et al. 2000; Reichman and Hade 2001; Werler et al. 1989). A recent example of recall bias in retrospective design is in a study that found poor reliability and recall bias in women's retrospective reports of exposure to chemicals during pregnancy (Till et al. 2002).

Several cohort studies have followed human development by studying pregnant women (Golding et al. 2001; Niswander and Gordon 1972). These studies, however, could not ascertain exposures (or collect biospecimens) at critical periconceptional windows and could not assess early reproductive outcomes (before clinically recognized pregnancy).

The most comprehensive and informative observational design is a prospective cohort study that measures exposures longitudinally (on both parents) beginning prior to pregnancy and continuing throughout pregnancy (if it occurs) and beyond. This study design, which we call a prospective pregnancy study with preconception enrollment, allows for the assessment of early exposures and a complete range of reproductive and developmental outcomes, key information for avoiding bias in evaluating effect(s) of potential toxicants (Tingen et al. 2004).

Prospective pregnancy studies are often described as difficult, intensive, and expensive to conduct, with limited overall yield, in this article, we examine the empirical evidence on the utility and feasibility of prospective pregnancy study designs for identifying reproductive and developmental toxicants. Although most prospective pregnancy studies focus on the determinants of sensitive end points (e.g., time to pregnancy and early pregnancy loss), a review of these issues is beyond the scope of this article. Our work is based on a systematic literature review to summarize relevant information on the planning, implementation, and relative success of this design.

Methods

Search Strategy

We conducted a MEDLINE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgl) search in May 2002 to locate published prospective pregnancy studies using the following search terms: prospective studies [MeSH term] AND (fertility OR fecundity OR time to pregnancy OR urine OR pregnancy). We sought to identify all large epidemiologic prospective pregnancy studies with preconception enrollment and at least a 3-month follow-up period. We reviewed the references cited by each study investigator to ensure that all relevant published works had been identified. Our initial search yielded 18 studies, of which 13 were selected for review. Five studies were excluded for the following reasons: a) clinical study focusing on postimplantation pregnancy (Miller et al. 1980); b) small sample size (n = 24, 13, and 13, respectively) (Hilgers et al. 1978; Li et al. 2002b; Sanders and Bruce 1997), and c) prospective study comprising only women with clinically recognized pregnancies (Li et al. 2002a). We later added two studies, published while we were finalizing this work (Buck et al. 2002; Wang et al. 2003), which resulted in a total of 15 studies available for review.

Data Collection

We developed a standardized data abstraction form that included author and year of primary (or methodologically oriented) publication; size of the target population; number of individuals contacted; number of eligible individuals; number of study participants; length of follow-up; type(s) of data collection, specifically, use of daily diaries and biospecimen collection (namely, urine and blood); semen collection; number of people dropping out of the study; and type(s) of incentives offered for participation.

Requests for specific information were sent to all primary authors in June 2002, with 100% response. The authors were asked to review and approve our summaries of their work and to provide missing information if possible. Both published and unpublished data obtained from the authors were summarized for our review. Several investigators were unsure or unable to enumerate the exact size of the target population, given the sampling strategy employed. Thus, the eligibility and participation percentages presented here should be regarded as best estimates.

Results

Table 1 summarizes the sampling and recruitment strategies of the 15 selected prospective pregnancy studies. The first prospective pregnancy study with preconception recruitment was published in 1984 (France et al. 1984). By definition and selection, all studies used a prospective design with women/couples recruited prior to becoming pregnant. All but four studies (Brown et al. 1997; Ellish et al. 1996; Hakim et al. 1995; Zinaman et al. 1996) required that women/couples enroll prior to discontinuing contraception to ensure that the first ovarian cycle, measured in terms of the menstrual cycle, was at risk for pregnancy. Six authors estimated the size of their target population (Bonde et al. 1998; Brown et al. 1997; Buck et al. 2002; Ellish et al. 1996; Eskenazi et al. 1995; Hakim et al. 1995). Nine studies did not enumerate a denominator became of their reliance on community volunteers responding to recruitment advertisements or other such attempts to solicit participation (Colombo and Masarotto 2000; de Mouzon et al. 1988; France et al. 1984; Sweeney et al. 1988, 1989; Vartiainen et al. 1994; Wang et al. 2003, Wilcox et al. 1988; Zinaman et al. 1996).

Participants have been recruited from a number of diverse referent populations (general or medical communities, job sites, population-based registries), and on the basis of recreational exposures (e.g., anglers). Most investigators studied women, with only four studies focusing on couples (Bonde et al. 1998; Colombo and Masarotto 2000; de Mouzon et al. 1988; Zinaman et al. 1996). All but three studies (Hakim et al. 1995; Sweeney et al. 1988, 1989) were restricted to presumably fecund women, leaving us with limited understanding of the exposure profiles of couples with impaired fecundity. One author specifically addressed the yield of mixed recruitment strategies, with targeted letters being the most successful (72%), followed by health care providers (12%), health maintenance organization (HMO) newsletters (9%), clinic posters (4%), radio and television announcements (1%), and other methods (2%) (Brown et al. 1997).

When recruitment details were available (Table 2), the percentage of women/couples who were successfully contacted ranged from 2% in a population-based study of first pregnancy planners (Bonde et al. 1998) to 67% in a study of women working in the semiconductor industry (Eskenazi et al. 1995). Of particular note is the high percentage of contacts (46%) achieved by one group of investigators by mailing questionnaires to women of reproductive age who were listed in the New York State registry of licensed drivers (Ellish et al. 1996). The percentage of women/couples successfully contacted or eligible for enrollment could not be determined for every study because of the lack of available denominator information.

The percentage of eligible women/couples among those who were contacted ranged from 4% in a population-based study that targeted women of reproductive age (Ellish et al. 1996) to 95% in a volunteer community-based sample of couples desiring pregnancy (Zinaman et al. 1996) and 97% in a group of newly married textile workers in China (Wang et al. 2003). It should be noted that the number of women contacted and deemed eligible appeared to vary according to the recruitment strategy (i.e., those who publicized their eligibility criteria during the recruitment process contacted fewer women, but more of their contacts were eligible for participation).

Participation rates seemed to be influenced by both the recruitment strategy and the study design features, with rates ranging from 42% of women originally enrolled in a larger cohort study with a less intense protocol to 100% of community volunteers meeting eligibility criteria at one urban medical center. One group of investigators examined the degree to which pregnancy intentions influenced a woman's decision to participate (Sweeney et al. 1989). They found that only 2% of enrolled women reported actively trying to conceive during the 3-month study period, 46% reported using oral contraceptives or intrauterine devices, 24% reported using barrier methods or monitoring their cervical mucus and basal body temperature (BBT) to avoid pregnancy, 18% reported being sexually inactive, 8% reported being sexually active but not using contraception, and 2% reported being infertile.

Table 3 summarizes the follow-up and specimen collection details for each selected study. The length of follow-up varied by study purpose and intensity of the data collection. Study durations ranged from 3 to 12 months. The least intensive protocols included a minimum of baseline interviews with some prospective recording of relevant study factors with or without the collection of biologic specimens.

Daily diaries were used by 12 (80%) studies for varying periods of time ranging from 1 month to 12 at-risk menstrual cycles. The type of data collected with these diaries varied but typically included exposure(s) of interest, menstruation, fecundity signs (namely, vaginal mucus discharge and/or BBT), sexual intercourse, lifestyle behaviors (e.g., cigarette smoking, alcohol, caffeine, or vitamin/mineral consumption, illnesses, medications), and home pregnancy test results. Among those studies in which compliance rates were available, rates ranged from 80 to 98%, with the exception of one study that reported a 38% completion rate for the entire study protocol (France et al. 1984).

Four types of biospecimens have been collected in prospective pregnancy studies: urine, blood, semen, and breast milk. Biospecimen compliance rates were quite high among the studies for which information was available, ranging from 57 to 98% for urine, 86 to 93% for blood, 94 to 100% for semen, and 97% for a single postpartum breast milk sample. Our review suggests that once enrolled, women (and male partners, if applicable) will provide a variety of specimens for study purposes.

The reported study dropout rates varied widely, in part depending on how withdrawals were handled. (Some authors counted withdrawals as ineligible.) Moreover, some investigators requested that women/couples participate as long as possible, while others asked a priori for participation for a set period of time (e.g., 6 months). The lowest dropout rate (3%) was reported by one group of investigators in their 6-month prospective pregnancy study of community volunteers desiring pregnancy (Wilcox et al. 1988). France and associates reported the highest dropout rate (62%) in their study of couples desiring pregnancy who wished to preselect the sex of their child (France et al. 1984). Of the 148 women who dropped out of that study, 28% cited a change in pregnancy plans, 18% stated that the study was too demanding, 12% felt the study was too stressful, and 7% failed to become pregnant. Among other studies reporting reasons for dropout, the most common reasons were changes in pregnancy plans or health status (Bonde et al. 1998; Brown et al. 1997; Buck et al. 2002; Ellish et al. 1996; Sweeney et al. 1988).

Prospective pregnancy studies have offered varying levels of incentives for study participation. Notably, four (27%) authors reported offering no incentives for participation (Colombo and Masarotto 2000; Sweeney et al. 1988, 1989; Vartiainen et al. 1994). The largest incentive was US$500, which was given to couples upon completion of a protocol that required multiple clinic visits and sensitive procedures such as midcycle postcoital tests (Zinaman et al. 1996). Among U.S. studies reporting the use of incentives, the smallest was US$10, which was given either weekly (Wilcox et al. 1988) or every 2 months (Ellish et al. 1996) to women who participated in a protocol that included daily diaries and urine collection (the former had an attrition rate of 3% and the latter 7%). A recent study conducted in China paid women US$1 per three urine samples provided (Wang et al. 2003). Only two studies reported providing feedback to participants in the form of summarized menstrual cycle information (Buck et al. 2002; Hakim et al. 1995).

Discussion

This review suggests that prospective pregnancy studies are a relatively new, powerful, and feasible design for examining the relation between biological, environmental, and lifestyle exposures and various reproductive and developmental outcomes. The utility of prospective pregnancy studies has greatly furthered our understanding of human reproduction and development, including notable advances such as estimates of the incidence of early [i.e., human chorionic gonadotrophin (hCG) identified] pregnancy loss and the elucidation of daily and cumulative probabilities of conception. Such information is crucial for accurately measuring the reproductive effects of exposures along the continuum of susceptible windows of human development.

Although more contacts may be required to identify a woman eligible for preconception enrollment in a prospective pregnancy study, the participation rates of eligible women are comparable to those seen in prospective studies of pregnant women. For example, 60% of eligible women enrolled in the Pregnancy, Infection, and Nutrition study, a prospective cohort study of the risk factors for preterm birth in North Carolina (Siega-Riz et al. 2001). In a captured HMO population, 39% of the eligible pregnant women were successfully recruited to participate in a population-based prospective cohort study in the Kaiser Permanente Medical Care Program in Northern California (Li et al. 2002a).

To address the lack of a sampling frame for women at risk of pregnancy, one investigator employed commercially available telephone directories (Lobdell et al. 2003). These inexpensive (< US$100) computerized directories contain the names, addresses, and telephone numbers of U.S. households, with each entry linked to basic census information. The census information enables investigators to assess sociodemographic differences between respondents and nonrespondents, as well as those that could not be reached because of inaccurate contact information. Targeted sampling is also possible by weighting or stratifying on ZIP or area code, if a specific subpopulation is desired.

An often-cited concern regarding the utility of prospective pregnancy studies is that participants are not representative of pregnant women as a whole because approximately half of all pregnancies in the United States are unintended (Henshaw 1998). Approximately 46% of unintended pregnancies result in live births (many are electively terminated) (Kannitz and Schnare 2001). Little empirical evidence exists to assess whether the prospective pregnancy study design results in a biased estimate of effect because of differing exposure scenarios among women with intended versus unintended pregnancies. However, the possibility of differing exposure profiles should always be given careful consideration, as women who plan their pregnancies are healthier, smoke and drink less, and have better diets than women who do not (Brown and Eisenberg 1995). Similarly, women who change unhealthy or risky behaviors are reported to be more educated, more likely to be employed, and from higher socioeconomic backgrounds than women who do not change behaviors (Beck et al. 2002; Joyce et al. 2000b; Kost et al. 1998).

Though yet unproven, the xenobiotic exposure profiles of women may also vary by pregnancy intention status. For example, hazardous waste sites and industrial sources of environmental pollution are often located in low-income communities (Farber and Krieg 2002; Morello-Frosch et al. 2002; Wilson et al. 2002) whose residents typically do not participate in research studies in the absence of targeted recruiting. Further, lifestyle factors such as cigarette smoking, alcohol use, and medications can influence the effects of environmental chemical exposures in humans (Anwar 1993; McCauley 1998). Given the potential for differing exposure profiles among pregnant women, coupled with the likelihood that some behaviors will be modified during pregnancy, the possible interactive effects of toxic agents and divergent lifestyle profiles during the peri-conceptional period (including those that are paternally mediated) must be evaluated. Prospective pregnancy study designs are the only reliable approach for such inquiry.

Additional concerns have been raised regarding the generalizability of prospective pregnancy studies because of research suggesting that women with intended pregnancies have fewer adverse pregnancy outcomes compared with mothers with unintended pregnancies (Piccinino and Mosher 1998). However, data from the National Longitudinal Survey of Youth suggest that differences in pregnancy outcomes by pregnancy intentions might be explained by the women's socioeconomic status rather than by planning status per se (Joyce et al. 2000a).

The conceptualization and measurement of intended or planned pregnancies has recently come under intense scrutiny, with many researchers in the field suggesting that more accurate measures are needed (Klerman 2000; Luker 1999; Sable 1999; Stanford et al. 2002; Trussell et al. 1999). For example, one study reported that 25% of women gave discordant responses to questions designed to assess pregnancy intentions in two large population-based surveys (Kaufmann et al. 1997). Discrepancies in pregnancy intention responses were associated with age, marital status, income, education, parity, time since pregnancy, and pregnancy outcome.

As with any epidemiologic investigation, researchers must weigh the relative importance of external validity in relation to internal validity (Grimes and Schulz 2002; Rothman and Greenland 1998). Given the difficulty in defining the exact size of the population from which participants in prospective pregnancy studies are recruited, empirical evaluation of external validity is often not possible. Although results from prospective pregnancy studies may not be generalizable to all women of reproductive age, they are likely to yield important observations that prompt additional studies.

As demonstrated in other pregnancy-related studies (Wyatt et al. 2002), prospective pregnancy studies with semen collection were successful in obtaining specimens from most male participants (Bonde et al. 1998; Vartiainen et al. 1994; Zinaman et al. 2000). Couple-based studies permit exploration of developmental toxicants that may be mediated through exposure of the embryo or fetus to the components of seminal fluid via intracanicular exposure or by absorbance of seminal fluid components into the bloodstream of the mother (Benziger and Edelson 1983; Sandberg et al. I968). Semen collection provides the opportunity to measure biological and chemical components of the seminal fluid (Lay et al. 2001; Younglai et al. 2002), perform standard sperm analyses, and even examine spermatozoal gene expression profiles (Ostermeier et al. 2002). The routine collection of semen specimens would further the assessment of human reproductive function, as these data could identify paternally mediated developmental effects. Semen analyses afford an opportunity to identify biomarkers that could delineate causal mechanisms of paternal toxicant exposure and/or fertility.

Our review suggests that study participants were generally willing to participate in studies even when they included time-consuming and/or invasive protocols for extended periods of time. Future studies may yield even higher rates of participation as technologic advances are incorporated into study protocols. Examples of relatively inexpensive technologies that could be implemented include specially programmed handheld devices to record menstrual cycle symptoms (Wyatt et al. 2002), home fertility monitors based on daily urine dipsticks (Behre et al. 2000) or salivary or vaginal probes (Fehring and Schlaff 1998), one-step luteinizing hormone tests (Nielsen et al. 2001), fingerprick blood spots (Worthman and Stallings 1997), home semen collection (Royster et al. 2000), and mouthwash methods for collecting genomic DNA (Lum and Le Marchand 1998). These technologies will be a useful addition to the biomarkers of fecundity and ovulation currently in use (e.g., vaginal mucus and BBT) (Stanford et al. 2002). For example, one recent study suggests early pregnancies can be detected with home pregnancy test kits (Buck et al. 2002). These kits have high sensitivity and specificity for detecting hCG concentrations of 25 mIU/mL, the level anticipated on the day following expected menstruation when conception has occurred (Ehrenkranz 2002). Because the timing of ovulation can vary in healthy women, this approach would be most accurate if used with a marker for ovulation (Wilcox et al. 2001).

Our assessment of the utility and feasibility of prospective pregnancy studies has several limitations. Only published prospective pregnancy studies were summarized for review. Though we made every effort to learn of all large-scale prospective pregnancy studies undertaken to dare, both published and unpublished, the possibility remains that we may have missed some studies. Further, although it would have been valuable to be able to include estimates of study costs and personnel, most investigators were unable to provide us with that information.

In summary, recruiting women/couples for prospective pregnancy studies prior to conception is feasible for both those planning pregnancy and those at risk of pregnancy. Among the population-based studies of women of reproductive age examined in this review (Bonde et al. 1998; Brown et al. 1997; Ellish et al. 1996), the number of participants divided by the size of the target population ranged from 0.8 to 4%. Using a conservative estimate, it therefore appears that about 120 women of reproductive age would need to be approached to identify one eligible woman/ couple planning pregnancy who might be willing to participate in a study of this type. Our review suggests that once recruited, women/ couples are often willing to complete very intensive protocols, even if only a modest incentive is provided. In one study, when an urban sample of women was presented with the choice of four protocols that ranged in intensity, 74% opted to participate in the most intense protocol (Sweeney et al. 1989).

As previously noted, individuals from underrepresented minority or economically disadvantaged groups should be targeted for recruitment, given their potentially higher risk of exposure to toxicants and possibly greater susceptibility (Sexton 1997). In so doing, investigators should consider factors reported to enhance participation, such as building trust with community participants (Shavers et al. 2002). Finally, couples experiencing fecundity-related impairments, including those undergoing assisted reproductive technologies, might represent another group suitable for study, in that exposure(s) to toxicants may be impairing their ability to conceive or carry a pregnancy to term.

Table 1. Target population, sampling unit, and recruitment strategy
among the selected prospective pregnancy studies.

Primary author                       Sampling
(year)           Target population     unit        Recruitment strategy

Bonde (1998)     Trade union         Couples       Letters
                  members
Brown (1997)     HMO women of        Women         Letters to female
                  reproductive                      HMO members (also
                  age                               media and health
                                                    providers)
Buck (2002)      Anglers and         Women         Letters
                  partners
Colombo (2000)   Women seeking       Couples       Fertility awareness
                  medical care                      teaching centers
de Mouzon        Community           Couples       Media and letters
 (1988)
Ellish (1996)    Motor vehicle       Women         Letters
                  registry
Eskenazi         Semiconductor       Women         Letters (also
 (1995)           workers                           informational
                                                    meetings)
France (1984)    Women seeking       Women         Media and fertility
                  medical care                      awareness teachers
Hakim (1995)     Semiconductor       Women (a)     Outreach talks and
                  workers                           posters
Sweeney (1988)   Community           Women (a)     Media and letters
Sweeney (1989)   Motor vehicle       Women (a)     Letters
                  registry and
                  telephone
                  directory
Vartiainen       Community           Women         Media
 (1994)
Wang (2003)      Newly wed           Women         Letters
                  textile workers
Wilcox (1988)    Community           Women (b)     Media
Zinaman (1996)   Community           Couples (c)   Media, physician,
                                                    and acquaintance
                                                    referral

(a) The sampling units were not required to be free of known fecundity
or fertility impairments. Media include television, radio, and
newspaper/poster announcements. (b) Men were enrolled after study was
implemented; baseline questionnaire data available from approximately
two-thirds of husbands. (Personal communication with authors.)
(c) Female partner of couple had to be free of fecundity impairments.

Table 2. Recruitment details for the selected prospective pregnancy
studies. (a)

Primary
author
(country)    Year   Context                    Eligibility criteria

Bonde        1998   Couples recruited from     No children
(Denmark)            Danish trade unions,      Cohabiting
                     office workers, nurses,   Age 20-35 (nurses 23-39)
                     and daycare workers        years
                                               Planning to discontinue
                                                contraception
                                               Access to a telephone
                                               Working home freezer
                                               Partner within [+ or -]
                                                10 years
                                               Excluded if either
                                                partner had previous
                                                reproductive experience

Brown        1997   Participants recruited     Female HMO member
(United              from Group Health,        Age 18-35 years
States)              Inc., a large HMO in      Planning to attempt
                     Minneapolis and St.        pregnancy in < 3 months
                     Paul, Minnesota           Nulliparas were
                                                recruited first,
                                                multiparas included
                                                later
                                               Multiparas excluded if
                                                planned attempt was
                                                within 12 months of
                                                most recent delivery
                                               Excluded if history of
                                                > 1 loss at less than
                                                20 weeks, history of
                                                > 2 abortions, history
                                                of infertility,
                                                hypertension, diabetes,
                                                heart or kidney
                                                disease, or if
                                                pregnancy plans changed
                                                or pregnancy occurred
                                                before planned

Buck         2002   Female members of the      Indicated that they had
(United              New York State Angler      not yet started or
States)              Cohort Study who           completed childbearing
                     indicated at enrollment   Age 18-35 years
                     in 1991 that they had     Absence of infertility
                     not yet completed          or fecundity problems
                     childbearing               (self-reported)

Colombo      2000   782 women recruited at     Women experienced in the
(Europe)             seven European centers     use of natural family
                     (Milan, Verona, Lugano,    planning
                     Duesseldorf, Paris,       Married or in a stable
                     London, Brussels); most    relationship
                     were trying to avoid      Age 18-40 years
                     pregnancy                 In multiparas, must have
                                                had at least one menses
                                                after delivery/
                                                breastfeeding
                                               Excluded if women were
                                                taking hormonal meds
                                                that could affect
                                                fertility or if either
                                                partner was sterile or
                                                had an endocrine
                                                disorder

de Mouzon    1988   Couples in France          Absence of contraception
(France)             without a history of       during the study
                     infertility who desired   Existence of at least
                     pregnancy                  one eligible menstrual
                                                cycle
                                               Interpretable cycles
                                               Knowledge of smoking
                                                status

Ellish       1996   Women randomly selected    Off contraception for
(United              from the 1987-1988 New     [less than or equal to]
States)              York State Department      12 months
                     of Motor Vehicles         Planning to discontinue
                     database of licensed       contraception within 6
                     drivers who were living    months
                     in Albany County when     Residence within the
                     they applied for or        prescribed area
                     renewed their license     Regular menstrual cycle
                                                length ([+ or -] 5
                                                days)

Eskenazi     1995   Women were recruited       Not currently pregnant
(United              from seven silicon        Menstruated within the
States)              wafer fabrication sites    past 2 months
                     in five U.S. companies    Intercourse within the
                                                past 2 months
                                               Working home freezer
                                               No plan to leave the
                                                company within the next
                                                3 months
                                               Ability to speak in
                                                English, Spanish,
                                                Vietnamese, or Tagalog
                                               Excluded if sterilized,
                                                using oral
                                                contraceptives, IUDs,
                                                had a sterilized
                                                partner, or using
                                                hormonal steroids that
                                                might affect fertility

France       1984   Couples contemplating      Proven fertility
(New                 pregnancy in Auckland,
Zealand)             New Zealand, from 1979
                     to 1985 who had the
                     desire to preselect the
                     sex of their child

Hakim        1995   Female employees at two    Proven fertility
(United              semiconductor             Women desiring pregnancy
States)              facilities in Vermont     42 years of age or
                     and New York from May      younger
                     1989 to August 1991       Excluded if using oral
                                                contraceptives, using
                                                an IUD, or surgically
                                                sterilized

Sweeney      1988   University of Pittsburgh   Women trying to become
United               employees and other        pregnant
States)              area volunteers who
                     were trying to become
                     pregnant from October
                     1985 to October 1986

Sweeney      1989   Women were recruited       Age 16-44 years
(United              from a particular         Not currently pregnant
States)              section of Pittsburgh,    Not menopausal
                     Pennsylvania, in which    Excluded if woman had a
                     89% of people were         history of hysterectomy
                     employed in
                     service-oriented and
                     blue-collar jobs

Vartiainen   1994   First-time pregnancy       Healthy couples without
(Finland)            planners were recruited    a history of
                     from the Kuopio area in    infertility
                     Eastern Finland           Planning to have a baby

Wang         2003   Newly married female       Full-time employment
(China)              textile workers in        Newly married
                     China who intended to     Age 20-34 years
                     conceive                  Had permission to
                                                conceive

Wilcox       1988   Women in the Research      Age 18 years or older
(United              Triangle Park, North      Not currently pregnant
States)              Carolina, area who were   Excluded if they had a
                     planning to discontinue    history of fertility
                     contraception              problems or chronic
                                                illness

Zinaman      1996   Couples discontinuing      Women age 21-37 years
(United              contraception to become   Men age 21-60 years
States)              pregnant                  Regular menstrual cycles
                                                (25-33 days)
                                               Men willing to provide
                                                semen samples
                                               Excluded if couples had
                                                been without
                                                contraception for > 3
                                                months or if either
                                                partner had a history
                                                of infertility early
                                                pregnancy loss

Primary
author
(country)    Target (n)       Contacts      Eligible      Participants

Bonde        52,255           1,113 (2%)    851 (76%)     430 (51%)
(Denmark)

Brown        28,000           2,840 (10%)   1,649 (58%)   1,152 (70%)
(United
States)

Buck         2,637            1,031 (39%)   244 (24%)     102 (42%)
(United
States)

Colombo      (b)              (b)           (b)           782
(Europe)

de Mouzon    (b)              4,200         (b)           1,887
(France)

Ellish       16,800           7,649 (46%)   293 (4%)      227 (77%)
(United
States)

Eskenazi     3,915            2,639 (67%)   739 (28%)     481 (65%)
(United
States)

France       (b)              (b)           (b)           239
(New
Zealand)

Hakim        Over 5,000 (c)   (b)           (b)           148
(United
States)

Sweeney      (b)              88            (b)           82
United
States)

Sweeney      (b)              (b)           (b)           104
(United
States)

Vartiainen   (b)              443 (c)       (b)           191
(Finland)

Wang         (b)              1,006 (c)     971 (97%)     961 (99%)
(China)

Wilcox       (b)              (b)           (b)           221 (c)
(United
States)

Zinaman      (b)              210           200 (95%)     200 (100%)
(United
States)

Abbreviations: HMO, health maintenance organization; IUD, intrauterine
device.

(a) Cycles refer to menstrual cycles, whereas months refer to calendar
time. (b) Information not available. (c) Personal communication with
author(s).

Table 3. Follow-up and specimen collection details for the selected
prospective pregnancy studies. (a)

Primary
author
(country)    Year   Participants   Length of follow-up   Daily diaries

Bonde        1998   430 (51%)      6 cycles or until     1,329/1,657
(Denmark)                          pregnancy occurred    completed
                                                         (80%)

Brown        1997   1,152 (70%)    12 cycles, second     N/A
(United                            miscarriage, or
States)                            delivery if
                                   pregnancy
                                   occurred (b)

Buck         2002   102 (42%)      12 cycles, or until   7 women
(United                            first postpartum      missing 1+
States)                            visit or cessation    weekly
                                   of breastfeeding      cards (b)
                                   (if nursing)

Colombo      2000   782            Average of 8.6        80.6% included
(Europe)                           cycles per woman      BBT, 85.2%
                                                         included
                                                         cervical mucus
                                                         score (b)

de Mouzon    1988   1,887          12 cycles or until    (c)
(France)                           delivery if
                                   pregnancy occurred

Ellish       1996   227 (77%)      12 cycles or until    1,304/1,516
(United                            pregnancy occurred    (86%)
States)                                                  completed (b)

Eskenazi     1995   481 (65%)      6 cycles or           403 (84%)
(United                            clinical pregnancy    completed at
States)                                                  least one
                                                         cycle (b)

France       1984   239            6 months oruntil      91 (38%)
(New                               pregnancy occurred    completed the
Zealand)                                                 entire
                                                         protocol (b)

Hakim        1995   148            At least 6 months     Near 100% (b)
(United                            or until pregnancy
States)                            occurred (mean = 7
                                   cycles)

Sweeney      1988   82             12 months or until    (c)
(United                            pregnancy occurred
States)

Sweeney      1989   104            3 cycles or until     81%
(United                            the end of the
States)                            first trimester if
                                   pregnancy occurred

Vartiainen   1994   191            6 months or until     88% first f/u;
(Finland)                          pregnancy occurred    59% second
                                                         f/u; 39% third
                                                         f/u (b)

Wang         2003   961 (99%)      12 months or          545 (57%)
(China)                            clinically            completed at
                                   confirmed pregnancy   least one
                                   after stopping        cycle (b)
                                   contraception

Wilcox       1988   221 (b)        6 months or until     98% (b)
(United                            pregnancy occurred
States)

Zinaman      1996   200 (100%)     12 months or until    Over 90% (b)
(United                            pregnancy occurred
States)

Primary
author        Urine            Blood           Semen
(country)    samples         sample(s)       sample(s)

Bonde        Women:          Women:          418/430
(Denmark)    9,671 (83%)     288/317 (91%)   (97%)
             Men:            Men:
             820 (59%)       350/376 (93%)

Brown        N/A             N/A             N/A
(United
States)

Buck         N/A             88/102 (86%)    N/A
(United
States)

Colombo      N/A             N/A             N/A
(Europe)

de Mouzon    N/A             N/A             N/A
(France)

Ellish       95%             N/A             N/A
(United
States)

Eskenazi     84%             N/A             N/A
(United      completed
States)      at least
             one cycle (b)

France       (c)             N/A             N/A
(New
Zealand)

Hakim        90%             N/A             N/A
(United
States)

Sweeney      Among those     N/A             N/A
(United      conceiving,
States)      84% provided
             daily urines
             (88% weekly
             urines)

Sweeney      80%             N/A             N/A
(United
States)

Vartiainen   N/A             N/A             180 (94%) (b)
(Finland)

Wang         545 (57%)       N/A             N/A
(China)      completed at
             least one
             cycle (b)

Wilcox       98%             N/A             N/A
(United
States)

Zinaman      Over 90% (b)    (c)             100%
(United                                      (participation
States)                                      requirement)

Primary
author       Dropped out
(country)    of the study     Incentive(s) to participate

Bonde        35 (8%)          $200 for specimens;
(Denmark)                     participants entered in
                              a lottery for $3,000 (b)

Brown        510 (44%)        $100 for completion and
(United                       small gifts (e.g., pencils)
States)                       with newsletters

Buck         20 (20%)         $50 for completion
(United                       through postpartum
States)                       blood and breast milk
                              (97% of women provided
                              a postpartum breast milk;
                              74% provided a second
                              sample upon weaning) (b)

Colombo      300 (25%)        None (b)
(Europe)     84 of these
             women
             re-entered (b)

de Mouzon    687 (36%)        (c)
(France)

Ellish       7%               $10 for every 2 months of
(United                       participation; lab results
States)                       were forwarded to
                              physicians (b)

Eskenazi     78 (16%)         $35 for each month of
(United                       participation; eligible for
States)                       a prize drawing for a trip
                              to Hawaii or other local
                              resort

France       148 (62%)        Personal instruction
(New                          regarding fertility
Zealand)                      awareness and the
                              Shettles theory of sex
                              selection (b)

Hakim        24 (16%) (b)     $100 for completion of
(United                       the study, feedback on
States)                       menstrual cycles

Sweeney      45 (55%)         None (b)
(United
States)

Sweeney      (c)              None (b)
(United
States)

Vartiainen   11 (6%)          None (b)
(Finland)

Wang         35 (4%)          $1 per three urine
(China)                       samples (b)

Wilcox       6 (3%)           $10/week for urine
(United                       collection
States)

Zinaman      8 (4%)           $500 for completion of
(United                       the study
States)

Abbreviations: f/u, follow-up; N/A, information not applicable.

(a) Cycles refer to menstrual cycles, whereas months refer to calendar
time. (b) Personal communication with author(s). (c) Information not
available.

We thank the principal investigators of the prospective pregnancy studies included in this review for their pioneering work and generous time devoted to answering our many inquiries. In addition, we acknowledge members of the Fertility and Early Pregnancy Working Group, National Children's Study, for their critical review of this work.

This article is part of the mini-monograph "Understanding the Determinants of Children's Health."

The views in this article reflect those of the authors and not necessarily those of their affiliated institutions. The information in this document has been subjected to review by the National Health and Environmental Effects Research Laboratory (U.S. EPA) and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

The authors declare they have no competing financial interests.

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Germaine M. Buck, (1) Courtney D. Lynch, (1) Joseph B. Stanford, (2) Anne M. Sweeney, (3) Laura A. Schieve, (4) John C. Rockett, (5) Sherry G. Selevan, (6) and Steven M. Schrader (7)

(1) Epidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA; (2) Department of Family Preventive Medicine, Health Research Center, University of Utah, Salt Lake City, Utah, USA; (3) Department of Epidemiology, Texas A&M University Health Science Center, School of Rural Public Health, Bryan, Texas, USA; (4) Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; (5) Gamete and Early Embryo Research Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; (6) National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA; (7) Reproductive Health Assessment Section, Division of Applied Research and Technology, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio, USA

Address correspondence to G. Buck, Epidemiology Branch, NICHD, NIH, DHHS, 6100 Executive Blvd., Rm. 7B03, Rockville, MD 20852 USA. Telephone: [phone]. Fax: [phone]. E-mail: [e-mail]

Received 6 February 2003; accepted 2 September 2003.