Hum. Reprod. Advance Access published online on September 26, 2008
Human Reproduction, doi:10.1093/humrep/den357
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Waiting time to pregnancy according to maternal birthweight and prepregnancy BMI
1 Department of Epidemiology, Institute of Public Health, University of Aarhus, Vennelyst Boulevard 6, Building 260, 8000 Aarhus C, Denmark 2 Department of Biostatistics, Institute of Public Health, University of Aarhus, 8000 Aarhus C, Denmark 3 Department of Health Statistics, National Board of Health, 2300 Copenhagen S, Denmark 4 Department of Occupational Medicine, Aarhus University Hospital, 8000 Aarhus C, Denmark 5 Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA, USA
6 Correspondence address. Tel: +45 8942 6087; Fax: +45 8613 1580; E-mail: ean{at}soci.au.dk
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Abstract |
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BACKGROUND: An association between a woman’s own birthweight and her fecundity has been suggested, but no empirical data have been published on the association between maternal birthweight and waiting time to pregnancy (TTP).
METHODS: In the Danish National Birth Cohort (1996–2002), which is an ongoing study of 92 274 women and their pregnancies, information about TTP and prepregnancy BMI was collected during pregnancy. At the 7-year follow-up of the children, 21 786 mothers reported their own birthweight and whether they were born at term or preterm. The association between maternal birthweight and TTP is presented as adjusted odds ratios with 95% confidence intervals.
RESULTS: Low maternal birthweight (
2500 g for term and 1500 g for preterm birth) was associated with an increased risk of TTP of >1 year [term: 1.2 (1.0–1.5); preterm: 1.8 (1.1–3.1)]. The latter association was strongest in women with a BMI < 25 kg/m2 [2.6 (1.4–4.7)]. High maternal birthweight (>4500 g for term and >3500 g for preterm) was also associated with an increased risk of TTP of >1 year [1.5 (1.0–2.0) and 1.3 (0.7–2.4), respectively], especially in women with a BMI 
25 kg/m2 [1.8 (1.1–3.1) and 2.5 (1.0–6.4), respectively].
CONCLUSIONS: High or low maternal birthweight was associated with TTP > 1 year. Longer waiting times in women with very low birthweight may reflect an effect of being born very preterm. Subfecundity may partly be programmed in foetal life by factors that cause or correlate with foetal growth.
Key words: fecundity/time to pregnancy/maternal birthweight/foetal growth/preterm birth
About 15% of all couples find it difficult to become pregnant and an increasing number of these couples seek infertility treatment (Juul et al., 1999
). Whether or not the infertility problem has been increasing may never be known (Sallmen et al., 2005), but a number of observations indicate that there may be an increase in poor semen quality (Skakkebaek et al., 2006). On the other hand, it is well documented that fertility and semen quality vary between different populations (Jensen et al., 2001; Jorgensen et al., 2001).
Public health research takes an interest in identifying avoidable causes of subfecundity since these causes may be amendable to removal or reduction. The search for such causes was initially focused on exposures during the time period when the couple tried to become pregnant (Olsen et al., 1983; Baird and Wilcox, 1985; Jensen et al., 1998b; Alderete et al., 1995), and later also to the time period of organogenesis in foetal life (Sharpe and Skakkebaek, 1993; Jensen et al., 1998a). The last decade of research results indicate that both of these time periods are important. The function of testes and ovaries in the mature individual have ample programming opportunities during several stages of fetal life (Gluckman and Hanson, 2006).
Since the 1980s, an often used measure for fecundity has been the time it takes to become pregnant for a couple that is planning a pregnancy [time to pregnancy (TTP)] (Bonde et al., 2006). TTP has been shown to be prolonged in individuals who have been exposed to smoking in utero (Weinberg et al., 1989; Jensen et al., 1998a). Recently, obesity in the couple at the time of conceiving has also been associated with longer waiting TTP (Ramlau-Hansen et al., 2007).
It has repeatedly been shown that birthweight, as a marker of foetal growth, correlates with a number of diseases (Barker, 1995; Joseph and Kramer, 1996); not only diabetes and cardiovascular diseases, but also with reduced semen quality (Jensen et al., 2004; Francois et al., 1997), although not all studies have found such an association (Olsen et al., 2000; Ozturk et al., 2001). Also, a woman’s own birthweight or whether she was born preterm or not may be associated with her fecundity, as measured by her age at first birth (Hack et al., 2002; Ekholm et al., 2005; Swamy et al., 2008), or with her ovarian function (Ibanez et al., 2000a,b). It is, however, still unknown if foetal growth may affect the time it takes a woman to conceive.
In this study, we examined whether female birthweight and whether she was born at term or preterm correlated with her TTP. Since a high BMI is associated with being born with a low birthweight, possibly through insulin resistance (Gluckman and Hanson, 2006), we also examined if these associations were modified by a woman’s BMI at the time when she tried to become pregnant. Our hypothesis was that low birthweight, especially in combination with a high BMI in adult life, would lead to a longer waiting time TTP. Also, we hypothesized that being born preterm was associated with longer TTP since being born preterm may interfere with late foetal maturation of reproductive organs.
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Materials and Methods |
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Subjects
The study is based on data from the Danish National Birth Cohort (DNBC), a nationwide study of 100 419 pregnancies recruited in 1996–2002 (92 274 individual women). Detailed descriptions of the study methods, data and the recruitment have been published (Olsen et al., 2001
; Nohr et al., 2006; Homepage for the Danish National Birth Cohort, 2007) and are available on the DNBC website www.dnbc.dk. Briefly, data were collected in two telephone interviews during pregnancy at 
16 and 30 weeks of gestation, and two telephone interviews after birth when the child was 6 and 18-month old. For all children alive at 7 years of age, a follow-up was initiated in July 2005 and planned to be finalized in 2010. As part of the 7-year follow-up, we asked the mothers to report their own birthweight. For this study, we initially considered the first wave of the 7-year follow-up, which was carried out before July 2007 and had a participation rate of 65%. We included 30 355 pregnancies where mothers had also participated in the first pregnancy interview (96%). From this group, we excluded women with missing information about her own birthweight and whether she was born at term or preterm (n = 8311). This resulted in a final study population of 22 044 pregnancies from 21 786 individual women.
Maternal birthweight
The main risk factor was self-reported maternal birthweight at the 7-year follow-up. Half of the mothers chose to fill out a questionnaire electronically, whereas the other half requested a self-administered mailed questionnaire. The mother was asked ‘What was your own birthweight (in grams)?’ and ‘Were you born preterm?’. To maximize the quality and completeness of the self-report, the mother was in advance sent a letter and asked to retrieve important information, including her own birthweight, before she filled out the questionnaire. Prior to data analysis, maternal birthweight was divided into two sets of categories depending on whether the woman was born at term or preterm. Term births were divided into five categories using the cut off points 2500, 3000, 4000 and 4500 g, such that the interval contained the upper limit. Preterm births were categorized similarly using the cut off points 1500, 2000, 3000 and 3500 g.
Validation study
Since little is known about the quality of self-reported birthweight in Denmark, we compared self-reported birthweights and information about preterm birth with birthweights and gestational age available in the National Birth Register, as reported by the midwife who took part in the birth of the child. The Birth Register was established in 1974, and we identified 4164 women in the study population (the youngest women) in the register (18.5%). The mean self-reported birthweight in these women was 3320 g, which was very similar to the corresponding mean birthweight of 3295 g in the register. For 50% of the women, their self-reported birthweights were within 75 g of the birthweight reported by the midwife, and 80% of the women reported within 175 g. The rate of preterm birth was 10%, both based on self-report and on the midwives report of a gestational age <37 weeks at birth. The agreement rate for the categories term and preterm birth was 92%. However, the sensitivity for self-reported preterm birth was only 63% whereas the specificity was 95%. When we used register data on birthweight and term/preterm birth to generate the same 10 combined birthweight categories as used in the study, the agreement rate was 82%.
Pregnancy-related covariates
In this study, estimates of TTP were derived from the following questions: ‘Is this pregnancy planned, partly planned or not planned?’ and ‘How long did it take you to become pregnant?’ Five answer categories (instantly, 1–2, 3–5, 6–12 and more than 12 months) were available for the last question and we combined it with the response to the first question to define a TTP variable with the following categories (not planned, <6, 6–12, >12 months). Partly planners were combined with planners.
From the first pregnancy interview, we also used self-reported information on weight and height to calculate prepregnancy BMI, which was categorized as underweight (BMI < 18.5 kg/m2), normal-weight (18.5 BMI < 25 kg/m2), overweight (25 BMI < 30 kg/m2) and obese (BMI 30 kg/m2) (World Health Organization Technical Report Services, 2000). We also extracted data on mother’s age at conception, smoking during pregnancy, social group defined by education and occupation, and infertility treatment. Based on the National Discharge Register, we identified pregnancies complicated with pre-eclampsia or diabetes/gestational diabetes. We suspected some under-reporting of gestational diabetes in the Register and therefore we supplemented with self-reported information about this disease from the pregnancy interviews. The study was approved by the Scientific Ethics Committee for Copenhagen and Frederiksberg on behalf of all the committees in Denmark and by the Danish Data Protection Board.
Statistical methods
First, we described the distribution of birthweight in women born term or preterm across TTP and potential confounders. We then excluded non-planners from the analysis (n = 2085) and used multinomial logistic regression to describe the association between maternal birthweight and TTP in three categories (<6, 6–12 and >12 months). To be able to examine the importance of whether the woman was born at term or preterm, maternal birthweight was entered as a variable with 10 categories (five categories for each term and preterm births) and with term birthweight of 3001–4000 g as reference group. In an adjusted model, we controlled for age, prepregnancy BMI, cigarette smoking in pregnancy and social group. These variables were chosen a priori, because they have been associated with TTP in other studies and may be associated with maternal birthweight.
Because we wanted to examine in more detail if the association between maternal birthweight and TTP was modified by prepregnancy BMI, we divided women into normal-weight (BMI < 25 kg/m2) and overweight (BMI 25 kg/m2). This analysis was done separately for women born at term and preterm, and within each of these groups we generated a maternal birthweight variable with 10 categories (five birthweight categories for each normal-weight and overweight women). We used logistic regression to examine the association between this BMI-specific birthweight variable and TTP > 1 year. In term births, normal-weight women with birthweight of 3001–4000 g were used as reference. In preterm births, we used normal-weight women with birthweight of 2001–3000 g as reference. We adjusted for the same variables as in the model described above. Also, in this model, effect modification was assessed by computing ratios of odds ratios (OR). Effect modification was considered if this ratio differed significantly from 1.
In the above analyses, we did not adjust for parity since parity in itself may be a cause of infertility. However, in additional analyses, we adjusted for parity (parity 1, parity 2+). We also divided the study population into primiparae and multiparae to examine if the results differed according to parity. Since diabetes is a known risk factor for high birthweight and has a heritable component, we repeated all analyses after excluding women with diabetes in the hope of excluding some with a diabetic mother. Using a similar argument for the association between low birthweight and pre-eclampsia, we repeated the analysis after excluding women with pre-eclampsia. We had 1195 women in our study that received infertility treatment of which 84% had a TTP > 12 months. Since the onset of treatment was unknown, which may introduce misclassification, we repeated the analysis after excluding these women. Finally, we also repeated all analyses after excluding 290 pregnancies where the woman had already provided one pregnancy to the study.
A two-tailed significance level of 0.05 was used in all statistical tests, and results are presented with 95% confidence intervals (CI). All analyses were made using STATA 9.0 (Stata-Corp, College Station, TX, USA).
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Results |
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Altogether, we had 22 044 pregnancies ending with liveborn children. Of the mothers, 90% reported that they were born at term and 10% preterm. The self-reported mean birthweight was 3340 g.
Eleven percent of pregnancies were not planned, 64% had a TTP<6 months, 13% had a TTP of 6–12 months and 12% waited more than 12 months to become pregnant. The distribution of TTP according to maternal birthweight categories is presented in Table I. The extreme weight categories had relatively longer waiting TTP. Among mothers born term and preterm, high birthweight was associated with a high BMI later in life, and women who smoked cigarettes in the present pregnancy were born with a lower weight than non-smokers (Table II).
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In both women born term and preterm, a tendency towards a U-shaped association between maternal birthweight and prolonged TTP was found (Table III). Thus, the study showed an association between a TTP of more than 12 months and low maternal birthweight in both women born term and preterm (
2500 and 1500 g, respectively). Similar associations were found for high birthweight in both of these groups (>4500 and >3500 g, respectively), but only the association in women born term was significant. The same pattern seemed also to be present for the association between birthweight in women born term and a TTP between 6 and 12 months. The results indicated no effect modification by preterm birth as such, nor did women born preterm have a prolonged TTP > 12 months (adjusted OR: 1.0, CI: 0.9–1.1). However, since we were not able to categorize preterm birth according to severity, the increased risk associated with low birthweight in preterm infants (1500 g) may indicate an increased risk associated with very preterm birth.
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Women with a prepregnancy BMI
25 kg/m2 had an increased risk of TTP of >1 year compared with women with a BMI < 25 kg/m2 [adjusted OR: 1.3 (1.2–1.4)]. In Table IV, we further explored the potential impact of prepregnancy BMI by examining the impact of maternal birthweight within each of these two BMI groups. The predominant association was found for high birthweight in women who were born at term or preterm and had a high prepregnancy BMI. However, in women born preterm, the strongest association with a long waiting TTP was actually found in underweight/normal-weight women born with a low birthweight, which was also the group that included women born very preterm. The results in Table IV also illustrate that the tendency towards a U-shaped association between birthweight and TTP was predominantly in women with a BMI < 25 kg/m2. For both term and preterm birth, the overall test for no interaction between maternal birthweight and BMI group was not significant (P = 0.10 and 0.15, respectively).
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In additional analyses, we examined the importance of parity. As expected, the frequency of TTP >1 year was higher in primiparae than in multiparae (17 versus 8%), but adjusting for parity in two groups did not change the findings displayed in Tables III and IV, and findings related to women born at term did not differ across parity groups. However, in women born preterm with a very low birthweight (
1500 g), an increased risk of TTP > 1 year was only observed in primiparae [adjusted OR 3.1 (1.5–6.4)].
If the association between high birthweight and TTP rests upon confounding by genetic factors related to diabetes, we would expect that excluding all women with diabetes would attenuate the association between high birthweight and TTP, but this was not the case. However, excluding all women with pre-eclampsia in the present pregnancy had some impact on this OR in women with BMI 25 kg/m2 as it decreased from 1.8 (1.1–3.1) to 1.5 (0.9–2.7). When we excluded women who had received infertility treatment, the number of women with a TTP > 1 year substantially decreased to 1350 women born at term and 146 women born preterm, but the main findings remained unchanged. Neither did it alter the results to exclude 290 pregnancies where the women had already provided one pregnancy to the study.
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Discussion |
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The findings from this study indicate that both low and high birthweight correlate with the causes that impact later fecundity as measured by TTP. A high birthweight in a range that indicates exposure to gestational diabetes was associated with a prolonged TTP, especially in women born at term or in women with a BMI of 25 kg/m2 or more. We hypothesized that women with a low birthweight that reached a high BMI in adult life would have an especially high risk of subfecundity, but data showed no support for this. On the contrary, we found a longer waiting time in women with a low birthweight and a BMI of less than 25 kg/m2. This association was especially strong in women who were born preterm, where it may reflect a very preterm effect rather than an effect of low birthweight. Thus, this finding partly supports our second hypothesis that preterm birth is associated with longer TTP.
TTP is measured with some uncertainty even when measured shortly after the end of waiting time, as in this study. The ambiguity in reporting often reflects that a pregnancy may be more or less planned, and to have a good estimate of TTP the pregnancy has to be planned. In this study, 87% of the women indicated that their pregnancy was planned or partly planned. Since the cohort only included women who intended to carry their pregnancy to term, they may have been reluctant to call the pregnancy unplanned. Such misclassification would most likely lead to bias towards the null and this was somewhat supported by the fact that the size of some of the main associations was slightly increased when we excluded the partly planners from the study (results not shown).
The cohort included only pregnant women and such a sample does not allow any direct estimates of the underlying fecundability since those who had an unsuccessful pregnancy planning are not included. Thus, if the effect is of the all or none type, it will not be detectable in a pregnancy sample. A study based on pregnant women only allows quantitative indicators of part of the subfecundity spectrum and it rests upon the fact that almost all exposures that affect fecundability will impact the entire TTP distribution. The observed association between birthweight in women born at term and TTP of 6–12 months may indicate that the waiting time is affected before the cut off point for infertility is reached, but this needs to be confirmed by other data.
Maternal birthweight was recalled but part of the cohort gave birth after the National Birth Register was established. The self-reported birthweight was for a majority of the women close to the one measured at birth, and we had an acceptable agreement rate for the combined categorization of term/preterm birth and birthweight given that two self-reported variables were used to define the combined categories. Regrettably, we did not have more precise information about gestational age, but only the woman’s own report of whether she was born preterm or not. However, in mothers who were born term, which was defined with high precision (95%), the chosen cut off points for very low (2500 g) and very high birthweight (>4500 g) were so extreme that these categories should be able to truly reflect being born either very small or very large, regardless of gestational age.
We find it unlikely that differential recall can explain the associations we see and most of the recall was only over short time spans. Selection bias is also an unlikely explanation since participation in the cohort was decided by the women and not related to the hypotheses we addressed.
Confounding may well explain the results. Little is known about prenatal causes of subfecundity, which may be due to the exposures at the time of organogenesis or to epigenetic changes as part of foetal adaptation to the predicted extra-uterine life (Gluckman and Hanson, 2004; Shaw and Elton, 2008). They may also reflect the impact of growth hormones, such as estrogen, on organ development (Sharpe and Skakkebaek, 1993; Woodruff and Walker, 2008) as well as toxic exposures or genetic factors that impact both foetal growth and organ functioning (Gluckman and Hanson, 2006). We find it likely that the observed associations with high birthweight do not reflect direct effects of abnormal fetal growth but rather the underlying determinants of fetal growth. A high birthweight is found in infants of well-fed women with insulin resistance, gestational diabetes or diabetes and these conditions may shape organ growth and thus organ functioning later in life. The increased risk of prolonged TTP in women who were born term with a very high birthweight decreased somewhat after excluding women with pre-eclampsia in the present pregnancy. This may be due to chance, but should be investigated in more detail in a larger data source since pre-eclampsia may be a marker of insulin resistance and cardiovascular dysfunction (Solomon and Seely, 2001; Rodie et al., 2004).
Our best indicator for very preterm birth was a very low birthweight. The strong association between a birthweight 1500 g in women born preterm and a long waiting TTP may indicate that the altered growth conditions for very preterm infants, both in utero but also during the first hard months of extrauterine life, may have an impact on the reproductive organs. It may be that the lack of compensation, which normally happens through fast post partum weight gain, increases the risk of long-term consequences on organ growth and functioning. It is well known that very small or very preterm babies have an increased susceptibility for a number of health problems later in life such as neurodevelopmental handicaps and chronic illness (Hack et al., 2002; Swamy et al., 2008) and it is perhaps not surprising that subfecundity may well be one of them. Also, our findings correspond to those of other studies that also found indicators of subfecundity in women born very preterm (Hack et al., 2002; Ekholm et al., 2005; Swamy et al., 2008).
To add information about parity in statistical models of TTP is not without problems because infertility influences parity. We found similar findings in primiparous and multiparous women except for the association between being born very preterm and a long TTP, which was only present in primiparous women. It may be wise for women born very preterm not to postpone childbearing.
In conclusion, this study confirms that adult BMI correlates with fecundity, at least for females, but it may be important if this BMI is reached during childhood or adult life. Women who were born small and remained thin or normal-weight had a longer waiting TTP, as well as overweight/obese women who were born large. To be born very preterm was also a risk factor for a prolonged TTP. These findings are novel and need to be put to a critical test in a different data source.
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Funding |
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The Danish National Research Foundation established the Danish Epidemiology Science Centre, which initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation and the Augustinus Foundation.
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Submitted on July 13, 2008; resubmitted on September 4, 2008; accepted on September 8, 2008.
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