Table 2.
Stratified meta-analysis of caffeine intake (per 100 mg/d increment) and risk of pregnancy loss
| Characteristic | No. of studies | Summary RR | 95 % CI | P for difference | P for heterogeneity | I 2 (%) | 95 % CI |
|---|---|---|---|---|---|---|---|
| All studies | 13 | 1·07 | 1·03, 1·12 | <0·01 | 80·9 | 68·4, 88·5 | |
| Region | |||||||
| USA | 9 | 1·09 | 1·02, 1·17 | Ref. | <0·01 | 79·0 | 60·6, 88·8 |
| Europe | 4 | 1·06 | 1·02, 1·10 | 0·85 | 0·07 | 57·3 | 0·0, 85·8 |
| Year of publication | |||||||
| In or after 2000 | 8 | 1·07 | 1·02, 1·13 | 0·30* | <0·01 | 86·2 | 74·9, 92·4 |
| Before 2000 | 5 | 1·07 | 1·03, 1·11 | 0·61 | 0·0 | 0·0, 79·2 | |
| Study population | |||||||
| <2500 | 7 | 1·08 | 1·00, 1·16 | Ref. | <0·01 | 78·3 | 55·0, 89·5 |
| ≥2500 | 6 | 1·06 | 1·03, 1·10 | 0·90 | 0·21 | 29·4 | 0·0, 71·2 |
| Study design | |||||||
| Cohort | 11 | 1·09 | 1·03, 1·15 | Ref. | <0·01 | 81·8 | 68·5, 89·4 |
| Nested case–control | 2 | 1·05 | 1·02, 1·08 | 0·52 | 0·39 | 0·0 | NA |
| Exposure | |||||||
| Caffeine intake | 10 | 1·10 | 1·03, 1·17 | Ref. | <0·01 | 76·8 | 57·2, 87·4 |
| Coffee intake | 2 | 1·05 | 1·03, 1·08 | 0·62 | 0·33 | 0·0 | NA |
| Paraxanthine level | 1 | 1·06 | 1·02, 1·10 | 0·69 | – | – | – |
| Outcome | |||||||
| Spontaneous abortion | 9 | 1·08 | 1·04, 1·13 | Ref. | 0·13 | 35·8 | 0·0, 70·5 |
| All pregnancy loss | 3 | 1·03 | 0·96, 1·11 | 0·31 | <0·01 | 93·1 | 83·1, 97·2 |
| Stillbirth | 1 | 1·09 | 1·02, 1·16 | 0·91 | – | – | – |
| Measure of association | |||||||
| Odds ratio | 8 | 1·06 | 1·03, 1·09 | Ref. | 0·35 | 10·7 | 0·0, 71·1 |
| Hazard ratio | 2 | 1·14 | 0·94, 1·39 | 0·73 | 0·01 | 84·4 | NA |
| Risk ratio | 3 | 1·15 | 0·89, 1·48 | 0·62 | 0·02 | 75·9 | 20·5, 92·7 |
| Age† | |||||||
| <30 years | 8 | 1·05 | 1·04, 1·07 | Ref. | 0·45 | 0·0 | 0·0, 67·6 |
| ≥30 years | 4 | 1·23 | 1·09, 1·38 | 0·02 | 0·25 | 26·7 | 0·0, 72·3 |
| NA | 1 | 0·98 | 0·97, 1·00 | <0·01 | – | – | – |
| Method of exposure assessment | |||||||
| Interviewer-based | 7 | 1·10 | 1·03, 1·17 | Ref. | 0·15 | 37·1 | 0·0, 73·5 |
| Biomarker | 1 | 1·06 | 1·02, 1·10 | 0·67 | – | – | – |
| Self-administered | 5 | 1·06 | 0·99, 1·14 | 0·58 | <0·01 | 85·2 | 67·3, 93·3 |
| Exposure period assessed‡ | |||||||
| First trimester | 9 | 1·11 | 1·05, 1·17 | Ref. | 0·04 | 49·7 | 0·0, 76·5 |
| Pre-pregnancy | 6 | 1·02 | 0·97, 1·07 | 0·05 | 0·03 | 60·6 | 0·0, 81·9 |
| NA | 1 | 1·06 | 1·02, 1·10 | 0·52 | – | – | – |
| Adjustment for nausea | |||||||
| No | 11 | 1·06 | 1·02, 1·11 | Ref. | <0·01 | 81·5 | 68·0, 89·3 |
| Yes | 2 | 1·17 | 0·96, 1·43 | 0·21 | 0·12 | 58·6 | NA |
| Adjustment for smoking§ | |||||||
| Fine | 7 | 1·05 | 1·00, 1·10 | Ref. | <0·01 | 84·8 | 70·4, 92·2 |
| Crude | 3 | 1·11 | 1·01, 1·21 | 0·40 | 0·07 | 62·9 | 0·0, 89·4 |
| Not applicable | 3 | 1·18 | 0·98, 1·43 | 0·29 | 0·23 | 31·9 | 0·0, 92·9 |
| Median population caffeine intake | |||||||
| <200 mg/d | 7 | 1·18 | 1·07, 1·30 | 0·11* | 0·11 | 41·5 | 0·0, 75·4 |
| ≥200 mg/d | 4 | 1·05 | 1·03, 1·07 | 0·63 | 0·0 | 0·0, 84·7 | |
| NA | 2 | 1·01 | 0·90, 1·13 | 0·22 | 32·2 | NA | |
RR, relative risk; NA, not available; Ref., reference.
P value was obtained by modelling year of publication and median of assigned doses as continuous variables.
Mean age <30 years or ≥30 years. If mean age is not available, classification was based on whether majority of the population (>50 %) is <30 years or ≥30 years.
Total number of studies is more than thirteen because some studies reported additional (usable) results for a different exposure period.
Fine adjustment for smoking refers to studies that adjusted for amount of smoking or studies that adjusted for smoking using a biomarker; crude adjustment refers to studies that did not adjust for amount of smoking; ‘Not applicable’ refers to studies that presented estimates without adjustment for smoking as adjustment for smoking did not change the results substantially.