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1.  No excess risk of adverse pregnancy outcomes among women with serological markers of previous infection with Coxiella burnetii: evidence from the Danish National Birth Cohort 
Q fever caused by Coxiella burnetii is transmitted to humans by inhalation of aerosols from animal birth products. Q fever in pregnancy is suspected to be a potential cause of fetal and maternal morbidity and fetal mortality but the pathogenesis is poorly understood, and even in Q fever endemic areas, the magnitude of a potential association is not established.
We aimed to examine if presence of antibodies to C. burnetii during pregnancy or seroconversion were associated with adverse pregnancy outcomes.
The Danish National Birth Cohort collected blood samples and interview data from 100,418 pregnant women (1996–2002). We sampled 397 pregnant women with occupational or domestic exposure to cattle or sheep and a random sample of 459 women with no animal exposure. Outcome measures were spontaneous abortion, preterm birth, birth weight and Small for Gestational Age (SGA).
Blood samples collected in pregnancy were screened for antibodies against C. burnetii by enzyme-linked immunosorbent assay (ELISA). Samples positive for IgG or IgM antibodies in the ELISA were confirmed by immunofluorescence antibody test (IFA).
Among the 856 women, 169 (19.7%) women were IFA positive; 147 (87%) of these had occupational or domestic contact with livestock (IFA cutoff > =1:128).
Two abortions were IFA positive vs. 6 IFA negative (OR: 1.5; 95%CI: 0.3-7.6). Three preterm births were IFA positive vs. 38 IFA negative (OR: 0.4; 95% CI: 0.1-1.1). There was a significant difference in birth weight of 168 g (95% CI: 70-267 g) with IFA positive being heavier, and the risk of being SGA was not increased in the newborns of IFA positive women (OR: 0.4; 95%CI: 0.8-1.0).
Most seropositive women were IgG positive indicating previous exposure. Seroconversion during pregnancy was found in 10 women; they all delivered live babies at term, but two were SGA.
We found no increased risk of adverse pregnancy outcome in women with verified exposure to C. burnetii.
To our knowledge, this is the first population-based seroepidemiologic study evaluating pregnancy outcome in women with serologically verified exposure to C. burnetii against a comparable reference group of seronegative women.
PMCID: PMC3585700  PMID: 23413787
Q fever; Coxiella burnetii; Infection; Human; Pregnancy; Spontaneous abortion; Preterm birth
5.  Fetal Growth and Schizophrenia: A Nested Case-Control and Case-Sibling Study 
Schizophrenia Bulletin  2012;39(6):1337-1342.
The association between low birth weight and schizophrenia has been suggested by many studies. Small for gestational age (SGA) is a measure used as a proxy for intrauterine growth restriction. We aim to examine if children who are born SGA are at increased risk of developing schizophrenia and whether an association may be explained by factors shared among siblings. We linked 3 population-based registers: the Danish National Medical Birth Register, the Danish Psychiatric Central Register, and the Danish Civil Registration register to identify all persons born between 1978 and 2000. A nested case-control study and a case-sibling study design were used. There were 4650 cases of schizophrenia. Incidence rate ratios (IRRs) were estimated using conditional logistic regression. SGA was defined as the lowest 10th birth weight percentile for a given sex and gestational age. SGA was associated with an IRR of 1.23 (95% CI: 1.11–1.37) for schizophrenia in the case-control study. An IRR of 1.28 (95% CI: 0.97–1.68) was found in the case-sibling study. There is a modest association between SGA and schizophrenia. Our results indicate that this association is due to an independent effect of factors associated with low birth weight for gestational age per se, rather than other factors shared by siblings.
PMCID: PMC3796081  PMID: 23236080
register; Denmark; cohort study; epidemiology
6.  Predictors for an unsuccessful INtubation-SURfactant-Extubation procedure: a cohort study 
BMC Pediatrics  2014;14:155.
The INtubation-SURfactant-Extubation (INSURE) is a procedure that is increasingly being used to treat the respiratory distress syndrome in preterm infants. The objective of this study was to identify predictors for an unsuccessful INSURE procedure.
The neonates included were less than 32 weeks’ gestation, treated with surfactant in the neonatal intensive care unit, and born 1998–2010. INSURE was defined as surfactant administration during intubation for less than 2 hours without the need for mechanical ventilation. INSURE success was defined as no re-intubation within 72 hours after INSURE, and INSURE failure was defined as re-intubation within 72 hours after INSURE. An unsuccessful INSURE procedure was either INSURE failure or mechanical ventilation for more than 24 hours immediately after surfactant administration. All predictors were defined a priori and were present before surfactant administration. Multivariate logistic regression was performed.
In total, 322 neonates were included: 31% (n = 100) had INSURE success, 10% (n = 33) had INSURE failure, 49% (n = 158) needed mechanical ventilation for more than 24 hours, and the remaining 10% (n = 31) needed mechanical ventilation for less than 24 hours. Predictors for INSURE failure were low gestational age and hemoglobin below 8.5 mmol/l. Predictors for mechanical ventilation for more than 24 hours were low gestational age, Apgar at 5 minutes below 7, oxygen need above 50%, CO2 pressure above 7 kPa (~53 mmHg), pH below 7.3, lactate above 2.5 mmol/l, need for inotropes, and surfactant administration shortly after birth, whereas preeclampsia reduced the risk.
We identified specific predictors associated with an unsuccessful INSURE procedure. Keeping high-risk neonates with one or several predictors intubated and treated with mechanical ventilation after surfactant may prevent a re-intubation procedure.
PMCID: PMC4072617  PMID: 24947477
Respiratory distress syndrome; Pulmonary surfactants; Premature neonates; Mechanical ventilation; Continuous positive airway pressure
7.  Adverse Pregnancy Outcomes and Coxiella burnetii Antibodies in Pregnant Women, Denmark 
Emerging Infectious Diseases  2014;20(6):925-931.
Q fever may be associated with complications, but overall risk is low.
A high risk for obstetric complications has been reported among women infected with Coxiella burnetii, the causative agent of Q fever, but recent studies have failed to confirm these findings. We reviewed national data collected in Denmark during 2007–2011 and found 19 pregnancies in 12 women during which the mother had a positive or equivocal test for antibodies to C. burnetii (IgM phase I and II titers >64, IgG phase I and II titers >128). Of these 12 women, 4 experienced obstetric complications (miscarriage, preterm delivery, infant small for gestational age, oligohydramnion, fetal growth restriction, or perinatal death); these complications occurred in 9 pregnancies (47% of the 19 total pregnancies identified). Our findings suggest an association between Q fever and adverse pregnancy outcomes, but complications were identified in only 9 pregnancies during the study’s 5-year period, indicating that the overall risk is low.
PMCID: PMC4036770  PMID: 24856281
Q fever; Coxiella burnetii; Denmark; pregnancy; fetus; infant; mother; bacteria; zoonoses; infertility; seropositivity; antibodies; miscarriage
8.  Seasonal Variation of Dystocia in a Large Danish Cohort 
PLoS ONE  2014;9(4):e94432.
Dystocia is one of the most frequent causes of cesarean delivery in nulliparous women. Despite this, its causes are largely unknown. Vitamin D receptor (VDR) has been found in the myometrium. Thus, it is possible that vitamin D affects the contractility of the myometrium and may be involved in the pathogenesis of dystocia. Seasonal variation of dystocia in areas with distinct seasonal variation in sunlight exposure, like Denmark, could imply that vitamin D may play a role. This study examined whether there was seasonal variation in the incidence of dystocia in a Danish population.
We used information from a cohort of 34,261 nulliparous women with singleton pregnancies, spontaneous onset of labor between 37 and 42 completed gestational weeks, and vertex fetal presentation. All women gave birth between 1992 and 2010 at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Skejby. Logistic regression combined with cubic spline was used to estimate the seasonal variation for each outcome after adjusting for calendar time.
No evidence for seasonal variation was found for any of the outcomes: acute cesarean delivery due to dystocia (p = 0.44); instrumental vaginal delivery due to dystocia (p = 0.69); oxytocin augmentation due to dystocia (p = 0.46); and overall dystocia (p = 0.91).
No seasonal variation in the incidence of dystocia was observed in a large cohort of Danish women. This may reflect no association between vitamin D and dystocia, or alternatively that other factors with seasonal variation and influence on the occurrence of dystocia attenuate such an association.
PMCID: PMC3988070  PMID: 24736600
9.  The Danish neonatal clinical database is valuable for epidemiologic research in respiratory disease in preterm infants 
BMC Pediatrics  2014;14:47.
We examined the quality of the information on the use of surfactant and the use of and duration of nasal continuous positive airway pressure (nCPAP), oxygen supplementation, and mechanical ventilation in the Danish Neonatal Clinical Database (NeoBase).
We included all neonates born with a gestational age < 32 weeks admitted to a Neonatal Intensive Care Unit (NICU) at two university hospitals in 2005. On discharge, the clinicians complete a structured form with information related to the delivery and course of stay in the NICU. These forms were entered into the NeoBase. The nurses’ daily bedside documentation was used as reference standard. Concordance was used as a measure of agreement between the NeoBase and the reference standard. For the dichotomous variables the concordance was defined as the sensitivity of the information registered in the NeoBase. For the continuous variables, it was based on the discrepancy in days between the NeoBase and the reference standard. The percentage of concordance was described as high (> 90), moderate (70–90) or low (< 70).
Overall, 153 infants participated in the study. Concordance was high for all dichotomous variables. The NeoBase slightly underestimated the duration of nCPAP and mechanical ventilation. The duration of oxygen therapy was neither over- nor underestimated in the NeoBase. Concordance was low for all continuous variables if we assumed that the registered information was identical. It was 100% for duration of mechanical ventilation and moderate for nCPAP and oxygen supplementation if we allowed for a discrepancy of 1 day.
The NeoBase is a valuable tool for clinical and epidemiologic research and quality assurance regarding neonatal respiratory disease.
PMCID: PMC3930301  PMID: 24528529
Respiratory variables; Very preterm infants; Validation; Epidemiology; Quality assurance
10.  Randomised Trial of Planned Caesarean Section Prior to Versus after 39 Weeks: Unscheduled Deliveries and Facility Logistics - A Secondary Analysis 
PLoS ONE  2013;8(12):e84744.
To compare the impact of scheduling caesarean section prior to versus after 39 completed weeks of gestation on the occurrence of unscheduled caesarean section and rescheduling of the procedure.
Secondary analysis from a multicentre randomised open-label trial including singleton pregnant women with a healthy foetus and a reliable due date. Women were allocated by computerized telephone randomisation to planned caesarean section at 38 weeks and three days or 39 weeks and three days. The outcomes were unscheduled deliveries with provided reasons, such as spontaneous labour onset or supervening complications, and any changes in the scheduled delivery date. Statistical analyses were according to intention-to-treat using Fisher’s exact test.
From March 2009 to June 2011 1,274 women were included. Median difference in gestational age at delivery was six days. Compared to the 38 weeks group, the women in the 39 weeks group were more likely to have an unscheduled caesarean section (15.2% vs. 9.3%; RR 1.64, 95% CI 1.21; 2.22), to deliver between 6 pm and 8 am (10 % vs. 6%; RR 1.68, 95% CI 1.14; 2.47), or to have the procedure rescheduled (36.7% vs. 23%; RR 1.6, 95% CI 1.34;1.90).
Scheduling caesarean section after 39 weeks leads to a 60% increase in unscheduled caesarean sections and a 70% increase in delivery outside regular work hours as compared to scheduling of the procedure prior to 39 weeks.
Trial Registration NCT00835003
PMCID: PMC3869904  PMID: 24376842
12.  Dietary Glycemic Index during Pregnancy Is Associated with Biomarkers of the Metabolic Syndrome in Offspring at Age 20 Years 
PLoS ONE  2013;8(5):e64887.
Growing evidence indicates that metabolic syndrome is rooted in fetal life with a potential key role of nutrition during pregnancy. The objective of the study was to assess the possible associations between the dietary glycemic index (GI) and glycemic load (GL) during pregnancy and biomarkers of the metabolic syndrome in young adult offspring.
Dietary GI and GL were assessed by questionnaires and interviews in gestation week 30 and offspring were clinically examined at the age of 20 years. Analyses based on 428 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, pre-pregnancy body mass index (BMI), education, energy intake, and the offspring’s ambient level of physical activity. In addition, possible confounding by gestational diabetes mellitus was taken into account.
Outcome Measures
Waist circumference, blood pressure, HOMA insulin resistance (HOMA-IR) and plasma levels of fasting glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and leptin were measured in the offspring.
Significant associations were found between dietary GI in pregnancy and HOMA-IR (the relative increase in HOMA-IR per 10 units’ GI increase was 1.09 [95% CI: 1.01, 1.16], p = 0.02), insulin (1.09 [95% CI: 1.02, 1.16], p = 0.01) and leptin (1.21 [95% CI: 1.06, 1.38], p = 0.01) in the offspring; whereas no associations were detected for GL.
Our data suggests that high dietary GI in pregnancy may affect levels of markers for the metabolic syndrome in young adult offspring in a potentially harmful direction.
PMCID: PMC3669023  PMID: 23741411
13.  Prenatal Exposure to Perfluorooctanoate and Risk of Overweight at 20 Years of Age: A Prospective Cohort Study 
Environmental Health Perspectives  2012;120(5):668-673.
Background: Perfluoroalkyl acids are persistent compounds used in various industrial -applications. Of these compounds, perfluorooctanoate (PFOA) is currently detected in humans worldwide. A recent study on low-dose developmental exposure to PFOA in mice reported increased weight and elevated biomarkers of adiposity in postpubertal female offspring.
Objective: We examined whether the findings of increased weight in postpubertal female mice could be replicated in humans.
Methods: A prospective cohort of 665 Danish pregnant women was recruited in 1988–1989 with offspring follow-up at 20 years. PFOA was measured in serum from gestational week 30. Offspring body mass index (BMI) and waist circumference were recorded at follow-up (n = 665), and biomarkers of adiposity were quantified in a subset (n = 422) of participants.
Results: After adjusting for covariates, including maternal pre-pregnancy BMI, smoking, education, and birth weight, in utero exposure to PFOA was positively associated with anthropometry at 20 years in female but not male offspring. Adjusted relative risks comparing the highest with lowest quartile (median: 5.8 vs. 2.3 ng/mL) of maternal PFOA concentration were 3.1 [95% confidence interval (CI): 1.4, 6.9] for overweight or obese (BMI ≥ 25 kg/m2) and 3.0 (95% CI: 1.3, 6.8) for waist circumference > 88 cm among female offspring. This corresponded to estimated increases of 1.6 kg/m2 (95% CI: 0.6, 2.6) and 4.3 cm (95% CI: 1.4, 7.3) in average BMI and waist circumference, respectively. In addition, maternal PFOA concentrations were positively associated with serum insulin and leptin levels and inversely associated with adiponectin levels in female offspring. Similar associations were observed for males, although point estimates were less precise because of fewer observations. Maternal perfluorooctane sulfonate (PFOS), perfluorooctane sulfonamide (PFOSA), and perfluorononanoate (PFNA) concentrations were not independently associated with offspring anthropometry at 20 years.
Conclusions: Our findings on the effects of low-dose developmental exposures to PFOA are in line with experimental results suggesting obesogenic effects in female offspring at 20 years of age.
PMCID: PMC3346773  PMID: 22306490
offspring obesity; overweight; perfluoroalkyl compounds; PFOA; pregnancy; prenatal exposure
14.  Presence of Antibodies Against Coxiella burnetii and Risk of Spontaneous Abortion: A Nested Case-Control Study 
PLoS ONE  2012;7(2):e31909.
Background and Aims
Q fever is a bacterial zoonosis caused by infection with Coxiella burnetii. It is well established that Q fever causes fetal loss in small ruminants. The suspicion has been raised that pregnant women may also experience adverse pregnancy outcome when the infection is acquired or reactivated during pregnancy. The purpose of this study was to assess the potential association between serologic markers of infection with C.burnetii and spontaneous abortion.
A nested case-control study within the Danish National Birth Cohort, a cohort of 100,418 pregnancies recruited from 1996–2002. Women were recruited in first trimester of pregnancy and followed prospectively. Median gestational age at enrolment was 8 weeks (25 and 75 percentiles: 7 weeks; 10 weeks). During pregnancy, a blood sample was collected at gestational week 6–12 and stored in a bio bank. For this study, a case sample of 218 pregnancies was drawn randomly among the pregnancies in the cohort which ended with a miscarriage before 22 gestational weeks, and a reference group of 482 pregnancies was selected in a random fashion among all pregnancies in the cohort. From these pregnancies, serum samples were screened for antibodies against C. burnetii in a commercial enzyme-linked immunosorbent assay (ELISA). Samples that proved IgG or IgM antibody positive were subsequently confirmatory tested by an immunofluorescence (IFA) test.
Among cases, 11 (5%) were C. burnetii positive in ELISA of which one was confirmed in the IFA assay compared to 29 (6%) ELISA positive and 3 IFA confirmed in the random sample.
We found no evidence of a higher prevalence of C.burnetii antibodies in serum samples from women who later miscarried and the present study does not indicate a major association between Q fever infection and spontaneous abortion in humans. Very early first trimester abortions were, however, not included in the study.
PMCID: PMC3283715  PMID: 22363769
15.  Infertility, infertility treatment, and mixed-handedness in children 
Early human development  2009;85(12):745-749.
Mixed-handedness, which may reflect atypical brain laterality, has been linked to a number of medical conditions as well as prenatal stress.
The aim of the study was to examine whether infertility or infertility treatment was associated with an increased risk of mixed-handedness in children.
Study design, subjects and outcome measures
We used data from three population-based birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984-1987), the Aarhus Birth Cohort (1990-1992) and the Danish National Birth Cohort (1996-2002) (N=7728, 5720 and 29486, respectively). Data on time to pregnancy and infertility treatment was collected during pregnancy. Handedness was reported in a follow-up questionnaire when the children were at least 7 years old. Children were categorized as mixed-handed if the mothers reported that they used both hands equally.
Children born after infertility treatment, particularly intrauterine insemination, had a higher risk of being mixed-handed compared to children of fertile couples with a time to pregnancy ≤12 months (odds ratio 1.41, 95% confidence interval 1.09-1.82). Children of couples with unplanned pregnancies, particularly after an oral contraceptives failure, were also more likely to be mixed-handed. There was no association between a long waiting time to pregnancy and mixed-handedness in children.
Children born after infertility treatment, particularly intrauterine insemination, and children exposed to oral contraceptives during early gestation may have a higher risk of being mixed-handed.
PMCID: PMC2788033  PMID: 19875254
Infertility; Infertility treatment; Mixed-handedness; Oral contraceptives; Time to pregnancy
16.  Handedness and time to pregnancy 
Non-right handedness, particularly mixed-handedness, has been associated with a number of medical conditions. We examined whether handedness was associated with fecundity, measured by time to pregnancy.
We used data on parental handedness and time to pregnancy from two regional birth cohorts in Denmark: the Aalborg-Odense Birth Cohort (1984–1987) and the Aarhus Birth Cohort (1990–1992) (N=5808 and 3426, respectively). We applied discrete-time survival analysis to assess fecundity in relation to handedness.
In both cohorts, we saw a slightly lower fecundity in individuals who reported being mixed-handed. Left handedness was not significantly associated with fecundity.
Our data showed a modest association between mixed-handedness and subfecundity, which suggests that these traits may share a common prenatal etiology.
PMCID: PMC2662690  PMID: 19057386
handedness; fecundity; time to pregnancy
17.  Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study 
Objective To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations.
Design Population based cohort study.
Participants 493 113 children born in Denmark, 1996-2003.
Main outcome measure Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005.
Results Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low—for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI.
Conclusion There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI.
PMCID: PMC2749925  PMID: 19776103
18.  Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study 
BMJ : British Medical Journal  2007;336(7635):85-87.
Objective To investigate the association between elective caesarean sections and neonatal respiratory morbidity and the importance of timing of elective caesarean sections.
Design Cohort study with prospectively collected data from the Aarhus birth cohort, Denmark.
Setting Obstetric department and neonatal department of a university hospital in Denmark.
Participants All liveborn babies without malformations, with gestational ages between 37 and 41 weeks, and delivered between 1 January 1998 and 31 December 2006 (34 458 babies).
Main outcome measures Respiratory morbidity (transitory tachypnoea of the newborn, respiratory distress syndrome, persistent pulmonary hypertension of the newborn) and serious respiratory morbidity (oxygen therapy for more than two days, nasal continuous positive airway pressure, or need for mechanical ventilation).
Results 2687 infants were delivered by elective caesarean section. Compared with newborns intended for vaginal delivery, an increased risk of respiratory morbidity was found for infants delivered by elective caesarean section at 37 weeks’ gestation (odds ratio 3.9, 95% confidence interval 2.4 to 6.5), 38 weeks’ gestation (3.0, 2.1 to 4.3), and 39 weeks’ gestation (1.9, 1.2 to 3.0). The increased risks of serious respiratory morbidity showed the same pattern but with higher odds ratios: a fivefold increase was found at 37 weeks (5.0, 1.6 to16.0). These results remained essentially unchanged after exclusion of pregnancies complicated by diabetes, pre-eclampsia, and intrauterine growth retardation, or by breech presentation.
Conclusion Compared with newborns delivered vaginally or by emergency caesarean sections, those delivered by elective caesarean section around term have an increased risk of overall and serious respiratory morbidity. The relative risk increased with decreasing gestational age.
PMCID: PMC2190264  PMID: 18077440
19.  Do inattention and hyperactivity symptoms equal scholastic impairment? evidence from three European cohorts 
BMC Public Health  2007;7:327.
Attention Deficit/Hyperactivity Disorder (ADHD) affects many children, adolescents, and adults and is associated with a number of impairments. Poor academic performance is related to ADHD in clinical samples. However, it is unclear to what extent core ADHD symptoms and scholastic impairment are related in non-referred school-aged children.
Data come from three population-based cohorts from Sweden, Denmark, and Finland, which are part of the Nordic Network on ADHD. The combined sample size was 13,087 children who were studied at ages 7–8 or 10–12 years. Teachers rated children on inattention and hyperactivity symptoms and reported children's scholastic performance on basic skills.
There was a significant association in all cohorts between core ADHD symptoms and scholastic impairment in reading, writing, and mathematics. Particularly, inattention was related to a two to tenfold increase in scholastic impairment. Prevalence of hyperactivity symptoms was similar across the three cohorts, but inattention was lowest among children from the Finnish cohort, after stratification on living conditions.
These results extend previous reports of scholastic impairment among children with clinically diagnosed ADHD to non-referred population samples from three European countries. Surveillance policies should be implemented in school systems to catch children in need of behavioral or scholastic support early.
PMCID: PMC2216016  PMID: 17999767
20.  Effect of reducing caffeine intake on birth weight and length of gestation: randomised controlled trial 
BMJ : British Medical Journal  2007;334(7590):409.
Objective To estimate the effect of reducing caffeine intake during pregnancy on birth weight and length of gestation.
Design Randomised double blind controlled trial.
Setting Denmark.
Participants 1207 pregnant women drinking at least three cups of coffee a day, recruited before 20 weeks' gestation.
Interventions Caffeinated instant coffee (568 women) or decaffeinated instant coffee (629 women).
Main outcome measures Birth weight and length of gestation.
Results Data on birth weight were obtained for 1150 liveborn singletons and on length of gestation for 1153 liveborn singletons. No significant differences were found for mean birth weight or mean length of gestation between women in the decaffeinated coffee group (whose mean caffeine intake was 182 mg lower than that of the other group) and women in the caffeinated coffee group. After adjustment for length of gestation, parity, prepregnancy body mass index, and smoking at entry to the study the mean birth weight of babies born to women in the decaffeinated group was 16 g (95% confidence interval −40 to 73) higher than those born to women in the caffeinated group. The adjusted difference (decaffeinated group−caffeinated group) of length of gestation was −1.31 days (−2.87 to 0.25).
Conclusion A moderate reduction in caffeine intake in the second half of pregnancy has no effect on birth weight or length of gestation.
Trial registration Clinical Trials NCT00131690.
PMCID: PMC1804137  PMID: 17259189
22.  Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study 
BMJ : British Medical Journal  2003;326(7386):420.
To study the association between coffee consumption during pregnancy and the risk of stillbirth and infant death in the first year of life.
Prospective follow up study.
Aarhus University Hospital, Denmark, 1989-96.
18 478 singleton pregnancies in women with valid information about coffee consumption during pregnancy.
Main outcome measures
Stillbirth (delivery of a dead fetus at ⩾28 weeks' gestation) and infant death (death of a liveborn infant during the first year of life).
Pregnant women who drank eight or more cups of coffee per day during pregnancy had an increased risk of stillbirth compared with women who did not drink coffee (odds ratio=3.0, 95% confidence interval 1.5 to 5.9). After adjustment for smoking habits and alcohol intake during pregnancy, the relative risk of stillbirth decreased slightly. Adjustment for parity, maternal age, marital status, years of education, occupational status, and body mass index did not substantially change the estimates of association. There was no significant association between coffee consumption and death in the first year of life after adjustment for smoking habits during pregnancy.
Drinking coffee during pregnancy is associated with an increased risk of stillbirth but not with infant death.
What is already known on this topicResults from studies in monkeys suggest that high daily doses of caffeine in pregnancy increase the risk of stillbirth, but evidence from studies in humans has been lackingWhat this study addsPregnant women who drank eight or more cups of coffee a day had more than twice the risk of stillbirth compared with women who did not drink coffee during pregnancy
PMCID: PMC149440  PMID: 12595379
23.  Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy 
BMJ : British Medical Journal  1998;317(7157):505-510.
Objective: To examine the effect of alcohol consumption on the probability of conception.
Design: A follow up study over six menstrual cycles or until a clinically recognised pregnancy occurred after discontinuation of contraception.
Subjects: 430 Danish couples aged 20-35 years trying to conceive for the first time.
Main outcome measures: Clinically recognised pregnancy. Fecundability odds ratio: odds of conception among exposed couples divided by odds among those not exposed.
Results: In the six cycles of follow up 64% (179) of women with a weekly alcohol intake of less than five drinks and 55% (75) of women with a higher intake conceived. After adjustment for cycle number, smoking in either partner or smoking exposure in utero, centre of enrolment, diseases in female reproductive organs, woman’s body mass index, sperm concentration, and duration of menstrual cycle, the odds ratio decreased with increasing alcohol intake from 0.61 (95% confidence interval 0.40 to 0.93) among women consuming 1-5 drinks a week to 0.34 (0.22 to 0.52) among women consuming more than 10 drinks a week (P=0.03 for trend) compared with women with no alcohol intake. Among men no dose-response association was found after control for confounders including women’s alcohol intake.
Conclusion: A woman’s alcohol intake is associated with decreased fecundability even among women with a weekly alcohol intake corresponding to five or fewer drinks. This finding needs further corroboration, but it seems reasonable to encourage women to avoid intake of alcohol when they are trying to become pregnant.
Key messages As alcohol consumption is widespread and increasing in many countries, even a minor effect on fertility is of public health interest Some studies have found that women with high alcohol intake take longer to become pregnant, but none have found that moderate intake has an effect The probability of conception in a menstrual cycle decreased with increasing alcohol intake in women, even among those drinking five or fewer drinks a week Women who are trying to conceive should be encouraged to avoid intake of alcohol
PMCID: PMC28642  PMID: 9712595

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