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Publication
Journal: BMJ (Clinical research ed.)
June/21/1989
Abstract
OBJECTIVE
To investigate the effects of smoking, alcohol, and caffeine consumption and socio-economic factors and psychosocial stress on birth weight.
METHODS
Prospective population study.
METHODS
District general hospital in inner London.
METHODS
A consecutive series of 1860 white women booking for delivery were approached. 136 Refused and 211 failed to complete the study for other reasons (moved, abortion, subsequent refusal), leaving a sample of 1513. Women who spoke no English, booked after 24 weeks, had insulin dependent diabetes, or had a multiple pregnancy were excluded.
METHODS
Data were obtained by research interviewers at booking (general health questionnaire, modified Paykel's interview, and Eysenck personality questionnaire) and at 17, 28, and 36 weeks' gestation and from the structured antenatal and obstetric record. Variables assessed included smoking, alcohol consumption, caffeine consumption, and over 40 indicators of socio-economic state and psychosocial stress, including social class, tenure of accommodations, education, employment, income, anxiety and depression, stressful life events, social stress, social support, personality, and attitudes to pregnancy. Birth weight was corrected for gestation and adjusted for maternal height, parity, and baby's sex.
RESULTS
Smoking was the most important single factor (5% reduction in corrected birth weight). Passive smoking was not significant (0.5% reduction). After smoking was controlled for, alcohol had an effect only in smokers and the effects of caffeine became non-significant. Only four of the socioeconomic and stress factors significantly reduced birth weight and these effects became non-significant after smoking was controlled for.
CONCLUSIONS
Social and psychological factors have little or no direct effect on birth weight corrected for gestational age (fetal growth), and the main environmental cause of its variation in this population was smoking.
Publication
Journal: BMJ (Clinical research ed.)
October/11/1995
Abstract
OBJECTIVE
To examine the relation between preterm birth and socioeconomic and psychological factors, smoking, and alcohol, and caffeine consumption.
METHODS
Prospective study of outcome of pregnancy.
METHODS
District general hospital in inner London.
METHODS
1860 consecutive white women booking for delivery; 1513 women studied after exclusion because of multiple pregnancy and diabetes, refusals, and loss to follow up.
METHODS
Gestational age was determined from ultrasound and maternal dates; preterm birth was defined as less than 37 completed weeks. Independent variables included smoking, alcohol and caffeine consumption, and a range of indicators of socioeconomic status and psychological stress.
RESULTS
Unifactorial analyses showed that lower social class, less education, single marital status, low income, trouble with "nerves" and depression, help from professional agencies, and little contact with neighbours were all significantly associated with an increased risk of preterm birth. There were no apparent effects of smoking, alcohol, or caffeine on the length of gestation overall, although there was an association between smoking and delivery before 32 weeks. Cluster analysis indicated three subgroups of women delivering preterm: two predominantly of low social status and a third of older women with higher social status who did not smoke. Mean gestational age was highest in the third group.
CONCLUSIONS
Adverse social circumstances are associated with preterm birth but smoking is not, apart from an association with very early births. This runs counter to findings for fetal growth (birth weight for gestational age) in this study, where a strong effect of smoking on fetal growth was observed but there was no evidence for any association with psychosocial factors.
Publication
Journal: Reproductive Biology and Endocrinology
March/8/2005
Abstract
The onset of clinical assisted reproduction, a quarter of a century ago, required the isolation of motile spermatozoa. As the indication of assisted reproduction shifted from mere gynaecological indications to andrological indications during the years, this urged andrological research to understand the physiology of male germ cell better and develop more sophisticated techniques to separate functional spermatozoa from those that are immotile, have poor morphology or are not capable to fertilize oocytes. Initially, starting from simple washing of spermatozoa, separation techniques, based on different principles like migration, filtration or density gradient centrifugation evolved. The most simple and cheapest is the conventional swim-up procedure. A more sophisticated and most gentle migration method is migration-sedimentation. However, its yield is relatively small and the technique is therefore normally only limited to ejaculates with a high number of motile spermatozoa. Recently, however, the method was also successfully used to isolate spermatozoa for intracytoplasmic sperm injection (ICSI). Sperm separation methods that yield a higher number of motile spermatozoa are glass wool filtration or density gradient centrifugation with different media. Since Percoll as a density medium was removed from the market in 1996 for clinical use in the human because of its risk of contamination with endotoxins, other media like IxaPrep, Nycodenz, SilSelect, PureSperm or Isolate were developed in order to replace Percoll. Today, an array of different methods is available and the selection depends on the quality of the ejaculates, which also includes production of reactive oxygen species (ROS) by spermatozoa and leukocytes. Ejaculates with ROS production should not be separated by means of conventional swim-up, as this can severely damage the spermatozoa. In order to protect the male germ cells from the influence of ROS and to stimulate their motility to increase the yield, a number of substances can be added to the ejaculate or the separation medium. Caffeine, pentoxifylline and 2-deoxyadenosine are substances that were used to stimulate motility. Recent approaches to stimulate spermatozoa include bicarbonate, metal chelators or platelet-activating factor (PAF). While the use of PAF already resulted in pregnancies in intrauterine insemination, the suitability of the other substances for the clinical use still needs to be tested. Finally, the isolation of functional spermatozoa from highly viscous ejaculates is a special challenge and can be performed enzymatically to liquefy the ejaculate. The older method, by which the ejaculate is forcefully aspirated through a narrow-gauge needle, should be abandoned as it can severely damage spermatozoa, thus resulting in immotile sperm.
Publication
Journal: Paediatric and Perinatal Epidemiology
January/21/2010
Abstract
A woman's life style choices before and during pregnancy have important implications for her unborn child, but information on behaviour can be unreliable when data are collected retrospectively. In particular there are no large longitudinal datasets that include information collected prospectively before pregnancy to allow accurate description of changes in behaviour into pregnancy. The Southampton Women's Survey is a longitudinal study of women in Southampton, UK, characterised when they were not pregnant and again during pregnancy. The objective of the analyses presented here is to describe the degree to which women comply with diet and life style recommendations before and during pregnancy, and changes between these time points. The analyses are based on 1490 women who delivered between 1998 and 2003 and who provided information before pregnancy and at 11 and 34 weeks' gestation. At each time point a trained research nurse ascertained smoking status and assessed food and drink consumption using a food frequency questionnaire. We derived the proportions of women who complied with recommendations not to smoke, to eat five portions of fruit and vegetables per day and to drink no more than four units of alcohol per week and 300 mg of caffeine per day. There was a notable reduction in smoking when women became pregnant: before pregnancy 27% of women smoked, whereas in early pregnancy 15% smoked. Similarly there were significant reductions in alcohol consumption and intake of caffeinated drinks: before pregnancy 54% of women drank more than four units of alcohol per week and 39% had estimated intakes of caffeine in drinks of >300 mg per day, whereas comparable figures for early pregnancy were 10% and 16% respectively. However, there was little change in fruit and vegetable intake; the percentages of women who did not achieve the recommendation to eat at least five portions of fruit and vegetables per week were 47% before pregnancy and 46% in early pregnancy. Younger women and those with fewer educational qualifications were less likely to comply with public health recommendations. Overall, 81% of women in early pregnancy complied with at least three of the recommendations. Although there is encouraging evidence of changed health behaviours in pregnancy, young women and those with few educational qualifications may particularly benefit from targeted health initiatives.
Publication
Journal: Paediatric and Perinatal Epidemiology
July/19/2006
Abstract
Maternal diet may influence outcomes of pregnancy and childhood. Diet in the first trimester may be more important to development and differentiation of various organs, whereas diet later in pregnancy may be important for overall fetal growth as well as for brain development. To our knowledge, no studies have examined individual-level changes in food and nutrient intake from the 1st to 2nd trimester of pregnancy. The objective of this study was to examine changes in dietary intake from the 1st to 2nd trimester of pregnancy. As part of the ongoing US prospective cohort study, Project Viva, we studied 1543 women who completed food-frequency questionnaires that assessed dietary intakes during the 1st and 2nd trimester of pregnancy. For both foods and energy-adjusted nutrients, we examined changes in dietary intake from 1st to 2nd trimester. Reported mean energy intake was similar for the 1st (2046 kcal) and 2nd (2137 kcal) trimesters. Foods and energy-adjusted nutrients from foods whose overall mean intakes increased more than 5% from 1st to 2nd trimester were skim or 1% dairy foods (22%), whole-fat dairy foods (15%), red and processed meat (11%), saturated fat (6%) and vitamin D (7%). Intake of caffeinated beverages (-30%) and alcoholic beverages (-88%) decreased more than 5%. Because mean multivitamin intake increased by 35% from the 1st to 2nd trimester, total micronutrient intake increased appreciably more than micronutrient intake from foods only. Correlations across trimesters ranged from 0.32 for vitamin B12 to 0.68 for fruit and vegetables. In conclusion, for many outcomes of pregnancy and childhood, the incremental information obtained from assessing complete diet in both early and late pregnancy may not outweigh the burden to participants and investigators. However, investigators should assess caffeine, alcohol, and vitamin and supplement use in both the 1st and 2nd trimester, and consider doing so for foods and nutrients for which trimester-specific hypotheses are well substantiated.
Publication
Journal: CMAJ
December/21/2000
Abstract
BACKGROUND
A high prevalence of gestational diabetes mellitus and type 2 diabetes has been observed among the Cree of James Bay, Quebec. To address this problem, a diet and activity intervention during pregnancy, which was based on social learning theory, was initiated in 4 Cree communities.
METHODS
A prospective intervention compared dietary, weight and glycemic indicators for 107 control subjects and for 112 women who received the intervention during the course of their pregnancy. A control period in 4 communities (July 1995-March 1996) was followed by an intervention period (April 1996-January 1997) when subjects were offered regular, individual diet counselling, physical activity sessions and other activities related to nutrition.
RESULTS
The intervention and control groups did not differ at baseline regarding their mean age (24.3 years [SD 6.29] v. 23.8 years [SD 5.86]), mean prepregnancy weight (81.0 kg [SD 19.46] v. 78.9 kg [SD 17.54]) and mean gestational age at recruitment (17.1 weeks [SD 7.06] v. 18.5 weeks [SD 6.92]). The intervention did not result in differences in diet measured at 24-30 weeks' gestation, rate of weight gain over the second half of pregnancy (0.53 kg per week [SD 0.32] v. 0.53 kg per week [SD 0.27]) or plasma glucose level (50 g oral glucose screen) between 24 and 30 weeks (7.21 mmol/L [SD 2.09] v. 7.43 mmol/L [SD 2.10]). Mean birth weights were similar (3741 g [SD 523] v. 3686 g [SD 686]), as was maternal weight at 6 weeks post partum (88.1 kg [SD 16.8] v. 86.4 kg [SD 19.0]). The only changes in dietary intake were a reduction in caffeine (pregnancy) and an increase in folate (post partum).
CONCLUSIONS
This intervention had only a minor impact on diet; finding ways of encouraging appropriate body weight and activity levels remains a challenge.
Publication
Journal: Human Molecular Genetics
August/8/2011
Abstract
Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.
Publication
Journal: Current Opinion in Obstetrics and Gynecology
August/4/2009
Abstract
OBJECTIVE
To review the role of oxidative stress in the context of female fertility.
RESULTS
Oxidative stress is associated with decreased female fertility in animal and in-vitro models, but no studies to date have directly assessed the relationship in women. Exposures associated with oxidative stress and with evidence to influence the timing and maintenance of a viable pregnancy include pregnancy complications (e.g. preeclampsia), extremes of body weight, alcohol, tobacco, and caffeine intake. Intake of antioxidant nutrients, including use of multivitamins, impacts the generation of reactive oxygen species and may play a beneficial role in female fertility.
CONCLUSIONS
Infertility is a significant public health problem and diagnosis and treatment are stressful, invasive, and costly. The role of oxidative stress in female fertility is an understudied and compelling area for investigation. Identifying modifiable factors to decrease oxidative stress in the gynecologic environment may be an inexpensive and noninvasive therapy for increasing fertility.
Publication
Journal: Infant Behavior and Development
March/22/2011
Abstract
This review covers research on the negative effects of prenatal depression and cortisol on fetal growth, prematurity and low birthweight. Although prenatal depression and cortisol were typically measured at around 20 weeks gestation, other research suggests the stability of depression and cortisol levels across pregnancy. Women with Dysthymia as compared to Major Depression Disorder had higher cortisol levels, and their newborns had lower gestational age and birthweight. The cortisol effects in these studies were unfortunately confounded by low serotonin and low dopamine levels which in themselves could contribute to non-optimal pregnancy outcomes. The negative effects of depression and cortisol were also potentially confounded by comorbid anxiety, by demographic factors including younger age, less education and lower SES of the mothers and by the absence of a partner or a partner who was unhappy about the pregnancy or a partner who was depressed. Substance use (especially caffeine use) was still another risk factor. All of these problems including prenatal depression, elevated cortisol, prematurity and low birthweight and even postpartum depression have been reduced by prenatal massage therapy provided by the women's partners. Massage therapy combined with group interpersonal psychotherapy was also effective for reducing depression and cortisol levels. Several limitations of these studies were noted and suggestions for future research included exploring other predictor variables like progesterone/estriol ratios, immune factors and genetic determinants. Further research is needed both on the potential use of cortisol as a screening measure and the use of other therapies that might reduce prenatal depression and cortisol in the women and prematurity and low birthweight in their infants.
Publication
Journal: PLoS ONE
March/6/2013
Abstract
Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.
Publication
Journal: BMC Medicine
July/16/2013
Abstract
BACKGROUND
Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA).
METHODS
This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves.
RESULTS
The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal-28 g, Skjaerven-25 g, Gardosi-21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day.
CONCLUSIONS
Coffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.
Publication
Journal: British Journal of Clinical Pharmacology
March/5/2013
Abstract
OBJECTIVE
Pregnant women are usually not part of the traditional drug development programme. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies.
METHODS
A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp® Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations.
RESULTS
The p-PBPK model predicted the PK changes of three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third trimester were predicted to be a 100% increase, a 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the nonpregnant women.
CONCLUSIONS
In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study.
Publication
Journal: Archives of Disease in Childhood: Fetal and Neonatal Edition
November/25/2004
Abstract
OBJECTIVE
To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects.
METHODS
A multicentre, randomised, double blind, clinical trial.
METHODS
Four tertiary neonatal units within Australia.
METHODS
Infants born less than 30 weeks gestation ventilated for more than 48 hours.
METHODS
Two dosing regimens of caffeine citrate (20 v 5 mg/kg/day) for periextubation management. Treatment started 24 hours before a planned extubation or within six hours of an unplanned extubation.
METHODS
Failure to extubate within 48 hours of caffeine loading or reintubation and ventilation or doxapram within seven days of caffeine loading.
RESULTS
A total of 234 neonates were enrolled. A significant reduction in failure to extubate was shown for the 20 mg/kg/day dosing group (15.0% v 29.8%; relative risk 0.51; 95% confidence interval (CI) 0.31 to 0.85; number needed to treat 7 (95% CI 4 to 24)). A significant difference in duration of mechanical ventilation was shown for infants of less than 28 weeks gestation receiving the high dose of caffeine (mean (SD) days 14.4 (11.1) v 22.1 (17.1); p = 0.01). No difference in adverse effects was detected in terms of mortality, major neonatal morbidity, death, or severe disability or general quotient at 12 months.
CONCLUSIONS
This trial shows short term benefits for a 20 mg/kg/day dosing regimen of caffeine citrate for neonates born at less than 30 weeks gestation in the periextubation period, without evidence of harm in the first year of life.
Publication
Journal: PLoS ONE
June/9/2014
Abstract
BACKGROUND
Lead is a widespread environmental toxin. The behaviour and academic performance of children can be adversely affected even at low blood lead levels (BLL) of 5-10 µg/dl. An important contribution to the infant's lead load is provided by maternal transfer during pregnancy.
OBJECTIVE
Our aim was to determine BLL in a large cohort of pregnant women in the UK and to identify the factors that contribute to BLL in pregnant women.
METHODS
Pregnant women resident in the Avon area of the UK were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) in 1991-1992. Whole blood samples were collected at median gestational age of 11 weeks and analysed by inductively coupled plasma dynamic reaction cell mass spectrometry (n = 4285). Self-completion postal questionnaires were used to collect data during pregnancy on lifestyle, diet and other environmental exposures. Statistical analysis was carried out with SPSS v19.
RESULTS
The mean±SD BLL was 3.67±1.47 (median 3.41, range 0.41-19.14) µg/dl. Higher educational qualification was found to be one of the strongest independent predictor of BLL in an adjusted backwards stepwise logistic regression to predict maternal BLL <5 or ≥5 µg/dl (odds ratio 1.26, 95% confidence interval 1.12-1.42; p<0.001). Other predictive factors included cigarette smoking, alcohol and coffee drinking, and heating the home with a coal fire, with some evidence for iron and calcium intake having protective effects.
CONCLUSIONS
The mean BLL in this group of pregnant women is higher than has been found in similar populations in developed countries. The finding that high education attainment was independently associated with higher BLL was unexpected and currently unexplained. Reduction in maternal lead levels can best be undertaken by reducing intake of the social drugs cigarettes, alcohol and caffeine, although further investigation of the effect of calcium on lead levels is needed.
Publication
Journal: Birth Defects Research Part B - Developmental and Reproductive Toxicology
August/14/2011
Abstract
A risk analysis of in utero caffeine exposure is presented utilizing epidemiological studies and animal studies dealing with congenital malformation, pregnancy loss, and weight reduction. These effects are of interest to teratologists, because animal studies are useful in their evaluation. Many of the epidemiology studies did not evaluate the impact of the "pregnancy signal," which identifies healthy pregnancies and permits investigators to identify subjects with low pregnancy risks. The spontaneous abortion epidemiology studies were inconsistent and the majority did not consider the confounding introduced by not considering the pregnancy signal. The animal studies do not support the concept that caffeine is an abortafacient for the wide range of human caffeine exposures. Almost all the congenital malformation epidemiology studies were negative. Animal pharmacokinetic studies indicate that the teratogenic plasma level of caffeine has to reach or exceed 60 µg/ml, which is not attainable from ingesting large amounts of caffeine in foods and beverages. No epidemiological study described the "caffeine teratogenic syndrome." Six of the 17 recent epidemiology studies dealing with the risk of caffeine and fetal weight reduction were negative. Seven of the positive studies had growth reductions that were clinically insignificant and none of the studies cited the animal literature. Analysis of caffeine's reproductive toxicity considers reproducibility and plausibility of clinical, epidemiological, and animal data. Moderate or even high amounts of beverages and foods containing caffeine do not increase the risks of congenital malformations, miscarriage or growth retardation. Pharmacokinetic studies markedly improve the ability to perform the risk analyses.
Publication
Journal: Drug Metabolism and Disposition
November/3/2013
Abstract
Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.
Publication
Journal: Frontiers in Psychiatry
August/15/2017
Abstract
Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.
Publication
Journal: Human Reproduction
December/14/2014
Abstract
OBJECTIVE
Are women's stress levels prospectively associated with fecundity and infertility?
CONCLUSIONS
Higher levels of stress as measured by salivary alpha-amylase are associated with a longer time-to-pregnancy (TTP) and an increased risk of infertility.
BACKGROUND
Data suggest that stress and reproduction are interrelated; however, the directionality of that association is unclear.
METHODS
In 2005-2009, we enrolled 501 couples in a prospective cohort study with preconception enrollment at two research sites (Michigan and Texas, USA). Couples were followed for up to 12 months as they tried to conceive and through pregnancy if it occurred. A total of 401 (80%) couples completed the study protocol and 373 (93%) had complete data available for this analysis.
METHODS
Enrolled women collected saliva the morning following enrollment and then the morning following their first observed study menses for the measurement of cortisol and alpha-amylase, which are biomarkers of stress. TTP was measured in cycles. Covariate data were captured on both a baseline questionnaire and daily journals.
RESULTS
Among the 401 (80%) women who completed the protocol, 347 (87%) became pregnant and 54 (13%) did not. After adjustment for female age, race, income, and use of alcohol, caffeine and cigarettes while trying to conceive, women in the highest tertile of alpha-amylase exhibited a 29% reduction in fecundity (longer TTP) compared with women in the lowest tertile [fecundability odds ratios (FORs) = 0.71; 95% confidence interval (CI) = (0.51, 1.00); P < 0.05]. This reduction in fecundity translated into a >2-fold increased risk of infertility among these women [relative risk (RR) = 2.07; 95% CI = (1.04, 4.11)]. In contrast, we found no association between salivary cortisol and fecundability.
CONCLUSIONS
Due to fiscal and logistical concerns, we were unable to collect repeated saliva samples and perceived stress questionnaire data throughout the duration of follow-up. Therefore, we were unable to examine whether stress levels increased as women continued to fail to get pregnant. Our ability to control for potential confounders using time-varying data from the daily journals, however, minimizes residual confounding.
CONCLUSIONS
This is the first US study to demonstrate a prospective association between salivary stress biomarkers and TTP, and the first in the world to observe an association with infertility.
BACKGROUND
This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3358). There are no conflicts of interest to declare.
BACKGROUND
Not applicable.
Publication
Journal: Epidemiology
August/2/2009
Abstract
BACKGROUND
Many studies have examined whether caffeine, alcohol, or specific beverages containing these substances affect fertility in women. However, most of these studies have retrospectively collected information on alcohol and caffeine intake, making the results susceptible to biases.
METHODS
We followed 18,555 married women without a history of infertility for 8 years as they attempted to become (or became) pregnant. Diet was measured twice during this period and prospectively related to the incidence of ovulatory disorder infertility.
RESULTS
There were 438 incident report of ovulatory disorder infertility during follow-up. Intakes of alcohol and caffeine were unrelated to the risk of ovulatory disorder infertility. Comparing the highest to lowest categories of intake, the multivariate-adjusted relative risk, was 1.11 (95% confidence interval = 0.76-1.64; P for trend 0.78) for alcohol and 0.86 (0.61-1.20; 0.44) for total caffeine. However, intake of caffeinated soft drinks was positively related to ovulatory disorder infertility. Comparing the highest to lowest categories of caffeinated soft drink consumption, the RR was 1.47 (1.09-1.98; 0.01). Similar associations were observed for noncaffeinated, sugared, diet, and total soft drinks.
CONCLUSIONS
Our findings do not support the hypothesis that alcohol and caffeine impair ovulation to the point of decreasing fertility. The association between soft drinks and ovulatory disorder infertility seems not to be attributable to their caffeine or sugar content, and deserves further investigation.
Publication
Journal: Archives of Disease in Childhood
June/17/1992
Abstract
Caffeine, in the dose usually recommended (12.5 mg/kg loading dose and 3 mg/kg daily maintenance), and a higher dose regimen (25 mg/kg loading and 6 mg/kg daily maintenance), was compared with theophylline (7.5 mg/kg loading and 3 mg/kg thrice daily maintenance). The study was a randomised controlled trial in the treatment of a group of 44 infants of less than 31 weeks' gestation (mean gestational age 28.3 weeks) who were suffering from frequent apnoeic attacks. All three regimens produced a significant reduction in apnoeic attacks within 24 hours, but only the higher dose caffeine and theophylline groups showed a significant improvement in apnoea within eight hours. The use of caffeine for the treatment of neonatal apnoea is recommended, because a once daily dose is more easily administered, and because it was found that plasma concentrations were more predictable than those of theophylline. If used in very preterm infants, however, its is suggested that a higher dose regimen than that previously recommended be used to achieve a faster response.
Publication
Journal: Clinical Obstetrics and Gynecology
March/2/2009
Abstract
Cerebral palsy is the most prevalent cause of persisting motor function impairment with a frequency of about 1/500 births. In developed countries, the prevalence rose after introduction of neonatal intensive care, but in the past decade, this trend has reversed. A recent international workshop defined cerebral palsy as "a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain." In a majority of cases, the predominant motor abnormality is spasticity; other forms of cerebral palsy include dyskinetic (dystonia or choreo-athetosis) and ataxic cerebral palsy. In preterm infants, about one-half of the cases have neuroimaging abnormalities, such as echolucency in the periventricular white matter or ventricular enlargement on cranial ultrasound. Among children born at or near term, about two-thirds have neuroimaging abnormalities, including focal infarction, brain malformations, and periventricular leukomalacia. In addition to the motor impairment, individuals with cerebral palsy may have sensory impairments, cognitive impairment, and epilepsy. Ambulation status, intelligence quotient, quality of speech, and hand function together are predictive of employment status. Mortality risk increases incrementally with increasing number of impairments, including intellectual, limb function, hearing, and vision. The care of individuals with cerebral palsy should include the provision of a primary care medical home for care coordination and support; diagnostic evaluations to identify brain abnormalities, severity of neurologic and functional abnormalities, and associated impairments; management of spasticity; and care for associated problems such as nutritional deficiencies, pain, dental care, bowel and bladder continence, and orthopedic complications. Current strategies to decrease the risk of cerebral palsy include interventions to prolong pregnancy (eg, 17alpha-progesterone), limiting the number of multiple gestations related to assisted reproductive technology, antenatal steroids for mothers expected to deliver prematurely, caffeine for extremely low birth weight neonates, and induced hypothermia for a subgroup of neonates diagnosed with hypoxic-ischemic encephalopathy.
Publication