Caffeine from coffee, but not from other sources, was associated with slightly increased gestational length. Total caffeine and caffeine from all different sources studied was associated with decreased BW. When discussing these results, the caffeine intake pattern in this Norwegian subpopulation must be kept in mind: the dominant caffeine source varied with increasing total caffeine intake, from chocolate in the low consumption group, to black tea in the medium consumption group, and coffee in the high consumption group. Thus, findings attributed to increasing total caffeine intake might be due to a changing distribution of caffeine sources. These results emphasize what Peck et al. and the CARE Study Group pointed out: if the aim of an epidemiologic study is to assess the effect of caffeine, it is not correct to study only coffee caffeine [20, 45].
Many, but not all, women decreased their caffeine consumption considerably during the first trimester but increased it again during the second trimester, a motive for repeated caffeine intake measurements during pregnancy in studies examining exposure in relation to pregnancy outcome [20, 45].
Gestational length and spontaneous PTD
We found that total and coffee caffeine intake was associated with a highly significant increase of gestational length by 5 and 8 hours/100 mg respectively. The corresponding association with total caffeine intake was, conversely, 10 hours decreased gestational length, though only marginally significant, when coffee drinkers were excluded from the model. Additionally, we ruled out a threshold effect, as even the groups with the lowest coffee caffeine intake were significantly associated with gestational length. Our results do not support the hypothesis that caffeine intake influences the risk for spontaneous PTD. The only marginally significant finding was black tea caffeine being associated with higher PTD odds, in the relatively small subgroup of early spontaneous PTD. We therefore conclude that the association of total caffeine intake with gestational length is not related to caffeine but to coffee intake. This study was not designed to disclose the reason for this statistical association; one possible explanation is that there might be some other substance, present in coffee but not in the other caffeine sources, that influences gestational length. Human parturition is depending on a physiological inflammatory reaction leading to cervical ripening and increased uterus tonus . Melanoidins that are generated from coffee bean components during the roasting process are, for example, known to have antimicrobial and anti-inflammatory effects  and thus might influence the timing of parturition. People in Scandinavia who do not drink coffee constitute a definite minority and those with a very low caffeine intake are probably a special group in many other ways. Drinking coffee, but not consuming other caffeine sources, might be associated with gestational length by some lifestyle factor.
The most important confounder on the behavioral level is smoking. Smokers are known to have higher coffee consumption ; furthermore, smoking is an established risk factor for spontaneous PTD. According to our results, however, coffee drinking and smoking have opposing effects on gestational length. The association with coffee intake remained significant after adjusting for smoking and excluding all smokers from the analysis, strongly suggesting an association between coffee consumption and gestational length that is independent of smoking behavior.
There was no major difference regarding the association for coffee consumption during different periods of pregnancy, suggesting either a rather continuous effect of coffee drinking on gestational length or confounding of coffee consumption with some other factor, as opposed to coffee consumption at a specific timepoint affecting some crucial step of pregnancy development.
In summary, we seem to have identified an association for coffee rather than caffeine, which must be kept in mind when discussing our findings in the context of earlier publications. To the best of our knowledge, this study is the first to separately study the associations between gestational length and caffeine from coffee, on the one hand, and caffeine from other sources, on the other. In comparison, most observational studies have not found any associations between caffeine or coffee and gestational length [48–53] and Maslova et al. found no significant association with overall PTD risk in their meta-analysis . There may be several reasons for the fact that we found an association for coffee drinking, but not for caffeine per se. We used self-reported caffeine intake instead of measuring caffeine metabolites [49, 50]. Caffeine from several sources was assessed, rather than caffeine intake from a single source, usually coffee, as in many studies [30, 53–55]. For some populations using only caffeine from coffee would implicate that a major, if not the major, part of total caffeine intake was not considered at all, for example, in a UK study black tea contributed 62% to daily caffeine intake while coffee and cola drinks accounted for about 12% to 14% each . PTD is a heterogeneous group of pregnancy outcomes with heterogeneous etiology . In contrast to the studies mentioned above, we defined a clear spontaneous PTD phenotype by excluding all iatrogenic deliveries as well as all medical or obstetric complications. The etiologies of early and late spontaneous PTD differ, which has not been acknowledged in many other studies . Mikkelsen et al. found an increased risk of early, but not late, overall PTD related to coffee intake of more than 2 cups/day in the Danish Birth Cohort , while Haugen et al. failed to confirm these results in an earlier version of MoBa . In this study, in which only spontaneous PTD in uncomplicated pregnancies was investigated, black tea caffeine intake was significantly associated with increased risk for early spontaneous PTD while significant associations were not found for other caffeine sources, indicating that this association was not caused by caffeine. The association with black tea caffeine was only marginally significant and there was no significant association between black tea caffeine and gestational length so that these results should be interpreted with caution.
In addition to the above-mentioned paper by Mikkelsen et al., Klonoff-Cohen et al. reported decreased gestational length related to caffeine consumption of >50 mg/day, compared to 0 to 2 mg/day, in a sample of 39 pregnancies . To our knowledge, this study of 49,102 pregnancies with spontaneous delivery is the biggest and most detailed observational study so far on the association between caffeine intake and gestational length, particularly spontaneous PTD. Our data do not support the hypothesis that caffeine intake or coffee consumption decrease gestational length or increase the risk for spontaneous PTD. Although we did find a significant association, a change in gestational length of several hours probably lacks clinical implications.
Birth weight and SGA
We found significant associations between caffeine intake and SGA and decreased BW. These associations were strengthened by concordant results for different caffeine sources, comparable overall findings regardless of the growth standard and SGA definition applied, remaining significance after adjustment, biological gradient, stability over period of pregnancy, consistency with other studies and biological plausibility. Caffeine is metabolized more slowly during pregnancy, crosses the placental barrier  and increases maternal levels of 3'5'-cyclic monophosphate and epinephrine , causing uteroplacental vasoconstriction and decreased intervillous placental blood flow, which could restrict fetal growth [48, 54]. Another hypothesis, postulated by Weathersbee et al., is that caffeine inhibits phosphodiesterase, leading to an increase in cellular cyclic adenosine monophosphate, which may interfere with fetal growth .
Smoking is a difficult confounder when studying effects of caffeine consumption . Both smoking and caffeine intake are associated with lower BW. However, the association between caffeine intake and BW remained highly significant after adjustment for smoking and after analysis in the non-smoker subgroup, suggesting an independent association with caffeine consumption.
Caffeine intake reported at gestational week 17 was most strongly associated with BW. This could be explained by reverse causality, according to Lawson's hypothesis, that is, the placenta is comparatively smaller in pregnancies complicated by SGA than in healthy pregnancies, thus producing less hormones and evoking fewer pregnancy symptoms so that these women might maintain a higher caffeine intake [20, 58]. However, remaining significance after controlling for nausea and the finding of a significant association for pre-pregnancy caffeine intake as well contradicts reverse causality as only explanation.
While some earlier studies found no significant association between caffeine consumption and BW [48, 53, 54, 59], most publications are consistent with our findings in MoBa [49, 50, 60–63]. Especially the data from some of the largest observational studies published so far, are consistent with our findings, moreover with comparable effect size of a decrease in BW by 60 to 70 g for >200 mg/day  or 28 g for 100 mg/day caffeine consumption .
In this study population, more than 10% exceeded the NNR recommended maximum intake of 200 mg/day; this subgroup had 20% to 60% higher odds ratios for SGA. Although SGA babies are generally known to be at higher risk for both neonatal morbidity and mortality , this might not be true for babies born SGA due to maternal caffeine consumption. Hernandez-Diaz found that babies born SGA due to maternal smoking might have lower mortality than other SGA babies with more severe causes for being born SGA, such as congenital malformations . However, as our results confirm earlier findings  that the increase in SGA risk can already be found in women following the current recommendations by Norwegian Authorities, further studies are needed to establish the impact of caffeine on neonatal morbidity and mortality. We could not find a threshold for the association of caffeine consumption and SGA risk. Until there is clarity if there is a causal association between caffeine intake and increased risk for SGA, women might be advised to reduce their caffeine consumption as much as possible during pregnancy.
Limitation and strengths
To the best of our knowledge, with its sample size of 59,123 pregnancies, this is the largest study performed so far on the association between caffeine intake and pregnancy outcome. The MoBa participation rate is 38.5%, and demographic comparison with the MBRN in 2002 showed that single women and women aged <25 are underrepresented in MoBa. Regarding SGA (4.6% in MoBa and 5.1% in the MBRN) and PTD (7.2% in MoBa and 7.7% in the MBRN), the differences are minor and the subgroup composition is similar to that in the total population, with spontaneous PTD accounting for 42% of all PTD . Additionally, a recent study found no bias in eight selected exposure-outcome associations .
Due to the large study sample, there were 1,411 cases defined as spontaneous PTD and 852 (Marsal), 4,503 (Skjaerven) or 4,733 (Gardosi) cases of SGA in the study population. Estimation of gestational length by second-trimester ultrasound and clear definition of a spontaneous PTD phenotype are additional strengths of this study [20, 24, 32]. Different standard growth curves were applied and this study is one of the first caffeine effect studies using customized growth curves at all [20, 45]. The overall results for all three models indicate an adverse effect of caffeine consumption on SGA risk, strengthening the association found.
All dietary assessment methods have limitations, and so does the self-reported caffeine intake in this study. The mean caffeine concentrations in seven main categories of food and drinks were used for the exposure calculations, while large variations may actually exist within each category . The caffeine contributed by soft drinks is likely to be underestimated as Coca Cola and Pepsi (including their diet versions) were the only soft drinks distinguished from other soft drinks in the FFQ. However, some other soft drinks also contain caffeine, for example, Urge, a citrus flavored soft drink produced by Coca Cola Norway. However, this soft drink comprised a rather small share of the market.
Relying exclusively on self-reported data without a biological marker to confirm the accuracy of estimated caffeine exposure is a weakness. For the present study we evaluated the agreement between caffeine intake estimated by the FFQ and a food diary. The estimated caffeine intake did not differ between the methods, and a high correlation was observed (r = 0.70, 95% CI 0.59 to 0.78). Furthermore, the MoBa FFQ has been extensively validated in a MoBa subpopulation using the four-day weighed food diary and several biomarkers as reference measures [42, 43]. The agreement between the FFQ and the food diary was particularly high for coffee and tea, which are the main sources of caffeine in this study. Coffee intake according to both the FFQ and the food diary correlated with serum β-carotene (0.31 and 0.36, respectively), which can be explained by interplay between antioxidants in coffee with β-carotene, as also reported by Svilaas et al.. Likewise, tea intake according to both the FFQ and the food diary correlated with kaempferol, a flavonoid found in tea (r = 0.41 and 0.50 for the FFQ and food diary, respectively ). Similar, but slightly weaker correlations were observed for estimated caffeine contributed by coffee and tea. A Bland-Altman plot for the differences in caffeine intake between the FFQ and the food diary is available as Additional file 1.
There are further strengths related to the caffeine intake assessment: the prospective design ensured that women's responses were not influenced by their knowledge of pregnancy outcome. Caffeine intake assessment from different sources, as well as different coffee preparations being taken into account, are also clear strengths of this study . As the FFQ covers the first four to five months of pregnancy, when many women change their dietary habits due to nausea, some women may have had difficulties reporting the frequency and amount of caffeine consumption for the whole period correctly. Coffee and black tea intake varies less and is easier to recall than intake of most other food groups. The associations with caffeine intake based on the FFQ were corroborated by caffeine intake estimates based on reported consumption of caffeine-containing drinks in the other two questionnaires (Q1 and Q3). As the relevant window of susceptibility for caffeine effects is not yet known , caffeine consumption assessment at different timepoints is a further strength of this study.
There is always a possibility of residual confounding in observational studies, but we reduced this possibility by controlling for a number of relevant factors, including history of PTD, nausea and smoking. Our smoking variable has been shown to be a valid marker for tobacco use when tested against plasma cotinine concentration .