theobromine and Pregnancy studies

Theobromine: 3,7-Dimethylxanthine. The principle alkaloid in Theobroma cacao (the cacao bean) and other plants. A xanthine alkaloid that is used as a bronchodilator and as a vasodilator. It has a weaker diuretic activity than THEOPHYLLINE and is also a less powerful stimulant of smooth muscle. It has practically no stimulant effect on the central nervous system. It was formerly used as a diuretic and in the treatment of angina pectoris and hypertension. (From Martindale, The Extra Pharmacopoeia, 30th ed, pp1318-9)
theobromine : A dimethylxanthine having the two methyl groups located at positions 3 and 7. A purine alkaloid derived from the cacao plant, it is found in chocolate, as well as in a number of other foods, and is a vasodilator, diuretic and heart stimulator.

Pregnancy: The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH.

Research Excerpts

Excerpt	Relevance	Reference
"This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy."	9.22	Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites. ( Campbell, SC; Clark, EA; Schoen, K; Sherwin, CM; Spigarelli, MG; Stockmann, C; Tak, C; Varner, MW; Yu, T, 2016)
" A recent study found chocolate consumption during pregnancy, and, particularly, increasing cord serum concentration of theobromine (the primary methylxanthine alkaloid in chocolate), to be associated with reduced occurrence of preeclampsia."	7.75	Maternal serum theobromine and the development of preeclampsia. ( Klebanoff, MA; Levine, RJ; Zhang, C; Zhang, J, 2009)
"This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy."	5.22	Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites. ( Campbell, SC; Clark, EA; Schoen, K; Sherwin, CM; Spigarelli, MG; Stockmann, C; Tak, C; Varner, MW; Yu, T, 2016)
"We examined preconception and pregnancy caffeine exposure with DNAm alterations in neonate cord blood (n = 378)."	4.12	Maternal caffeine intake and DNA methylation in newborn cord blood. ( Guan, W; Mumford, SL; Polinski, KJ; Purdue-Smithe, A; Robinson, SL; Schisterman, EF; Schliep, KC; Silver, RM; Yeung, EH; Zhao, SK, 2022)
" A recent study found chocolate consumption during pregnancy, and, particularly, increasing cord serum concentration of theobromine (the primary methylxanthine alkaloid in chocolate), to be associated with reduced occurrence of preeclampsia."	3.75	Maternal serum theobromine and the development of preeclampsia. ( Klebanoff, MA; Levine, RJ; Zhang, C; Zhang, J, 2009)
" 1990) established that caffeine, when administered during pregnancy, significantly inhibited the differentiation of the seminiferous cords and subsequent Leydig cell development in the interstitium."	3.71	Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis. ( Locquet, O; Magre, S; Pollard, I; Solvar, A, 2001)
" The methylxanthines; caffeine, theophylline and theobromine, were administered via drinking water in the proportions occurring in tea, at a dose of 50, 1 and 2 mg/kg body-weight respectively to Wistar albino rats throughout pregnancy and for up to the 14th day of lactation."	3.68	The effect of methylxanthines on milk volume and composition, and growth of rat pups. ( Grimble, RF; Hart, AD, 1990)
"Caffeine disposition was studied over 24 h in rats on the 12th day of pregnancy given 80 mg/kg of drug as a single oral dose or in four divided doses every three hours."	3.67	Caffeine disposition after oral administration to pregnant rats. ( Bonati, M; Bortolotti, A; Gaspari, F; Jiritano, L, 1985)
"Relative risk of preeclampsia will be the primary measure of treatment effect."	2.49	Consumption of chocolate in pregnant women and risk of preeclampsia: a systematic review. ( Blanchet, C; Boivin, C; Bujold, E; Dodin, S; Lemieux, S; Mogollon, JA; Philippe, K; Turcotte, S, 2013)
" Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values."	1.27	Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits. ( Arnaud, MJ; Bonati, M; Bortolotti, A; Borzelleca, JF; Garattini, S; Gaspari, F; Jiritano, L; Latini, R; Tarka, SM; Traina, GL, 1984)
" The kinetic parameters of P rats were strikingly similar to NP rats at all TBR dosage levels employed."	1.27	Theobromine metabolism and pharmacokinetics in pregnant and nonpregnant Sprague-Dawley rats. ( Shively, CA; Tarka, SM, 1983)

Research

Studies (40)

Authors

Clinical Trials (2)

Trial Overview

Trial Outcomes

Abruption

Timeframe	Studies, this research(%)	All Research%
pre-1990	21 (52.50)	18.7374
1990's	5 (12.50)	18.2507
2000's	6 (15.00)	29.6817
2010's	6 (15.00)	24.3611
2020's	2 (5.00)	2.80

Authors	Studies
Polinski, KJ	1
Purdue-Smithe, A	1
Robinson, SL	1
Zhao, SK	1
Schliep, KC	2
Silver, RM	2
Guan, W	1
Schisterman, EF	2
Mumford, SL	2
Yeung, EH	1
Purdue-Smithe, AC	1
Kim, K	1
DeVilbiss, EA	1
Hinkle, SN	1
Ye, A	1
Perkins, NJ	1
Sjaarda, LA	1
Babar, A	2
Bujold, E	4
Leblanc, V	2
Lavoie-Lebel, É	2
Paquette, J	1
Bazinet, L	2
Lemieux, S	4
Marc, I	2
Abdous, B	1
Dodin, S	4
Buscicchio, G	1
Lorenzi, S	1
Tranquilli, AL	1
Mogollon, JA	2
Bourdages, M	1
Blanchet, C	3
Couillard, C	1
Noël, M	1
Boivin, C	1
Philippe, K	1
Turcotte, S	1
Yu, T	1
Campbell, SC	1
Stockmann, C	1
Tak, C	1
Schoen, K	1
Clark, EA	1
Varner, MW	1
Spigarelli, MG	1
Sherwin, CM	1
Girard, M	1
Poungui, L	1
Belkacem, A	1
Sidi, EL	1
Klebanoff, MA	1
Zhang, J	1
Zhang, C	1
Levine, RJ	1
BARBERI, M	1
LOMEO, AM	1
Chorostowska-Wynimko, J	2
Skopińska-Rózewska, E	2
Sommer, E	2
Rogala, E	1
Skopiński, P	2
Wojtasik, E	1
Grosso, LM	1
Triche, EW	1
Belanger, K	1
Benowitz, NL	1
Holford, TR	1
Bracken, MB	1
Patera, J	1
Słodkowska, J	1
Borowska, A	1
Wasiutyński, A	1
Martín, I	1
López-Vílchez, MA	1
Mur, A	1
García-Algar, O	1
Rossi, S	1
Marchei, E	1
Pichini, S	1
Nakatsuka, T	1
Hanada, S	1
Fujii, T	3
Tanaka, H	2
Nakazawa, K	2
Arima, M	2
Iwasaki, S	1
Tebbutt, IH	1
Teare, AJ	1
Meek, JH	1
Mallett, KA	1
Hawkins, DF	1
Shively, CA	2
White, DM	1
Blauch, JL	1
Tarka, SM	5
Latini, R	1
Bonati, M	2
Gaspari, F	2
Traina, GL	1
Jiritano, L	2
Bortolotti, A	2
Borzelleca, JF	3
Arnaud, MJ	1
Garattini, S	1
Berlin, CM	1
Wilkinson, JM	1
Pollard, I	2
Locquet, O	1
Solvar, A	1
Magre, S	1
Horning, MG	2
Nowlin, J	1
Butler, CM	1
Lertratanangkoon, K	1
Sommer, K	1
Hill, RM	2
Sommer, KR	1
Yovich, JM	1
Edirisinghe, WR	1
Cummins, JM	1
Yovich, JL	1
Hart, AD	2
Grimble, RF	2
Karymshakova, KK	1
Kucheriavenko, AN	2
Applebaum, RS	2
York, RG	1
Randall, JL	1
Scott, WJ	1
Bucher, HU	1
Gautschi, K	1
Nishimura, H	2

Trial	Phase	Enrollment	Study Type	Start Date	Status
The Effects of Aspirin in Gestation and Reproduction: A Multi-center, Controlled, Double-blind Randomized Trial.[NCT00467363]		1,228 participants (Actual)	Interventional	2007-06-30	Completed
Assessment of Blood Pressure and Endothelial Function Pregnancy After Acute and Daily Consumption Flavanol-rich Chocolate Among Healthy Pregnant Women: a Pilot Randomized Controlled Trial[NCT01659060]	Phase 2	44 participants (Actual)	Interventional	2008-07-31	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Partial or complete abruption (ie, premature separation of the placenta) (NCT00467363)
Timeframe: until delivery

Clinically Recognized Pregnancy

Early Pregnancy Loss (EPL)

Ectopic Pregnancy

Fetal Pregnancy Loss

hCG Recognized Pregnancy

Live Birth

Intervention	participants (Number)
Aspirin	7
Placebo	5

Intervention	pregnancy (Number)
Aspirin	374
Placebo	346

Intervention	pregnancy (Number)
Aspirin	28
Placebo	27

Intervention	pregnancy (Number)
Aspirin	3
Placebo	3

Intervention	pregnancy (Number)
Aspirin	4
Placebo	6

Intervention	pregnancy (Number)
Aspirin	394
Placebo	363

Live birth was obtained prospectively by maternal report and abstraction from medical records by trained staff . (NCT00467363)
Timeframe: after delivery

Molar Pregnancy

Preeclampsia

Pregnancy Losses Occurring Less Than 10 Weeks

Intervention	livebirths (Number)
Aspirin	309
Placebo	286

Intervention	pregnancy (Number)
Aspirin	0
Placebo	0

Intervention	participants (Number)
Aspirin	32
Placebo	30

Includes preembryonic and embryonic losses (exclusive of implantation failures) (NCT00467363)
Timeframe: less than 10-weeks

Article	Year
Preconception caffeine metabolites, caffeinated beverage intake, and fecundability. The American journal of clinical nutrition, 2022, 04-01, Volume: 115, Issue:4 Topics: Adolescent; Adult; Caffeine; Carbonated Beverages; Coffee; Female; Fertility; Humans; Pregnancy; The	2022
Changes in endothelial function, arterial stiffness and blood pressure in pregnant women after consumption of high-flavanol and high-theobromine chocolate: a double blind randomized clinical trial. Hypertension in pregnancy, 2018, Volume: 37, Issue:2 Topics: Adult; Blood Pressure; Chocolate; Double-Blind Method; Endothelium, Vascular; Female; Humans; Pregna	2018
Blood pressure and endothelial function in healthy, pregnant women after acute and daily consumption of flavanol-rich chocolate: a pilot, randomized controlled trial. Nutrition journal, 2013, Apr-08, Volume: 12 Topics: Adolescent; Adult; Biomarkers; Blood Pressure; Cacao; Caffeine; Candy; Catechin; Double-Blind Method	2013
Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites. Journal of clinical pharmacology, 2016, Volume: 56, Issue:5 Topics: Adult; Caffeine; Cytochrome P-450 CYP1A2; Female; Humans; Pregnancy; Pregnancy Trimesters; Theobromi	2016
High-flavanol and high-theobromine versus low-flavanol and low-theobromine chocolate to improve uterine artery pulsatility index: a double blind randomized clinical trial. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 2017, Volume: 30, Issue:17 Topics: Adult; Chi-Square Distribution; Chocolate; Double-Blind Method; Female; Flavonols; Gestational Age;	2017
Influence of pentoxifylline in severe male factor infertility. Fertility and sterility, 1990, Volume: 53, Issue:4 Topics: Clinical Trials as Topic; Embryo Transfer; Female; Fertilization; Humans; Infertility, Male; Male; O	1990

Article	Year
Maternal caffeine intake and DNA methylation in newborn cord blood. The American journal of clinical nutrition, 2022, 02-09, Volume: 115, Issue:2 Topics: Adult; Caffeine; DNA Methylation; Epigenesis, Genetic; Female; Fetal Blood; Gestational Age; Humans;	2022
The effects of different concentrations of cocoa in the chocolate intaken by the mother on fetal heart rate. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 2013, Volume: 26, Issue:15 Topics: Adult; Cacao; Caffeine; Cardiotocography; Diet; Female; Fetal Movement; Gestational Age; Heart Rate,	2013
Maternal serum theobromine and the development of preeclampsia. Epidemiology (Cambridge, Mass.), 2009, Volume: 20, Issue:5 Topics: Adult; Case-Control Studies; Female; Humans; Odds Ratio; Pre-Eclampsia; Pregnancy; Theobromine; Unit	2009
[The action of a new soluble derivative of theobromine on various renal function indices in heart disease patients in pregnancy]. Minerva ginecologica, 1962, Jul-31, Volume: 14 Topics: Female; Heart Diseases; Humans; Kidney Function Tests; Pregnancy; Pregnancy Complications; Theobromi	1962
Multiple effects of theobromine on fetus development and postnatal status of the immune system. International journal of tissue reactions, 2004, Volume: 26, Issue:1-2 Topics: Angiogenesis Inhibitors; Animals; Animals, Newborn; Female; Fetus; Immune System; Lactation; Mice; M	2004
Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction. American journal of epidemiology, 2006, Jun-01, Volume: 163, Issue:11 Topics: Adult; Biomarkers; Caffeine; Chi-Square Distribution; Connecticut; Cytochrome P-450 Enzyme System; F	2006
Morphometric and functional abnormalities of kidneys in the progeny of mice fed chocolate during pregnancy and lactation. Folia histochemica et cytobiologica, 2006, Volume: 44, Issue:3 Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Animals, Suckling; Cacao; Creatinine; Female	2006
Neonatal withdrawal syndrome after chronic maternal drinking of mate. Therapeutic drug monitoring, 2007, Volume: 29, Issue:1 Topics: Beverages; Breast Feeding; Caffeine; Female; Humans; Ilex paraguariensis; Infant, Newborn; Neonatal	2007
Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice. Teratology, 1983, Volume: 28, Issue:2 Topics: Abnormalities, Drug-Induced; Animals; Antibiotics, Antineoplastic; Caffeine; Drug Synergism; Female;	1983
Caffeine and its dimethylxanthines and fetal cerebral development in rat. Brain & development, 1984, Volume: 6, Issue:4 Topics: Abnormalities, Drug-Induced; Animals; Brain; Caffeine; Female; Fetus; Maternal-Fetal Exchange; Pregn	1984
Caffeine, theophylline and theobromine in pregnancy. Biological research in pregnancy and perinatology, 1984, Volume: 5, Issue:4 Topics: Caffeine; Female; Humans; Pregnancy; Theobromine; Theophylline	1984
Dominant lethal testing of theobromine in rats. Toxicology letters, 1984, Volume: 20, Issue:3 Topics: Animals; Corpus Luteum; Dose-Response Relationship, Drug; Embryo Implantation; Female; Fetal Death;	1984
Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits. Toxicology, 1984, Apr-16, Volume: 30, Issue:4 Topics: Animals; Biological Availability; Dose-Response Relationship, Drug; Female; Kinetics; Male; Pregnanc	1984
Theobromine metabolism and pharmacokinetics in pregnant and nonpregnant Sprague-Dawley rats. Toxicology and applied pharmacology, 1983, Mar-15, Volume: 67, Issue:3 Topics: Animals; Female; Kinetics; Pregnancy; Pregnancy, Animal; Rats; Rats, Inbred Strains; Theobromine; Th	1983
Excretion of methylxanthines in human milk. Seminars in perinatology, 1981, Volume: 5, Issue:4 Topics: Adult; Beverages; Caffeine; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans;	1981
Accumulation of theophylline, theobromine and paraxanthine in the fetal rat brain following a single oral dose of caffeine. Brain research. Developmental brain research, 1993, Oct-15, Volume: 75, Issue:2 Topics: Animals; Biotransformation; Brain; Caffeine; Chromatography, High Pressure Liquid; Female; Pregnancy	1993
Reproductive toxicology. Theobromine. Environmental health perspectives, 1997, Volume: 105 Suppl 1 Topics: Animals; Birth Weight; Dose-Response Relationship, Drug; Female; Fertility; Litter Size; Liver; Male	1997
Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis. Reproduction, fertility, and development, 2001, Volume: 13, Issue:5-6 Topics: Animals; Caffeine; Cell Differentiation; Female; Gestational Age; Leydig Cells; Male; Maternal-Fetal	2001
Clinical applications of gas chromatograph/mass spectrometer/computer systems. Clinical chemistry, 1975, Volume: 21, Issue:9 Topics: Autoanalysis; Caffeine; Chromatography, Gas; Computers; Diazepam; Evaluation Studies as Topic; Femal	1975
Identification and quantification of drugs in human amniotic fluid. Research communications in chemical pathology and pharmacology, 1975, Volume: 12, Issue:3 Topics: Amniotic Fluid; Caffeine; Chromatography, Gas; Computers; Female; Fetal Blood; Humans; Mass Spectrom	1975
The effect of methylxanthines on milk volume and composition, and growth of rat pups. The British journal of nutrition, 1990, Volume: 64, Issue:2 Topics: Animals; Animals, Newborn; Body Weight; Caffeine; Fatty Acids; Female; Lactation; Milk; Pregnancy; R	1990
Effect of methylxanthines on lactational performance of rats. Annals of nutrition & metabolism, 1990, Volume: 34, Issue:5 Topics: Animals; Animals, Newborn; Body Weight; Caffeine; Drinking; Eating; Female; Lactation; Pregnancy; Ra	1990
[Effect of acute "altitude" hypoxia on the transport function of the placenta of the rat with placental insufficiency and its correction using trental]. Akusherstvo i ginekologiia, 1985, Issue:12 Topics: Altitude; Animals; Female; Maternal-Fetal Exchange; Pentoxifylline; Placenta; Placenta Diseases; Pla	1985
[Effect of trental on placental transport function and fetal development in hypotrophy]. Akusherstvo i ginekologiia, 1985, Issue:4 Topics: Animals; Biological Transport; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Pe	1985
[Effect of injections of parturients with trental on the transfer of exogenous glucose to the fetus]. Akusherstvo i ginekologiia, 1987, Issue:2 Topics: Female; Glucose; Humans; Maternal-Fetal Exchange; Obstetric Labor Complications; Pentoxifylline; Pre	1987
Evaluation of the teratogenic potential of cocoa powder and theobromine in New Zealand White rabbits. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 1986, Volume: 24, Issue:5 Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Cacao; Dose-Response Relationship, Drug; Femal	1986
Evaluation of the perinatal, postnatal and teratogenic effects of cocoa powder and theobromine in Sprague-Dawley/CD rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 1986, Volume: 24, Issue:5 Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Body Weight; Bone and Bones; Cacao; Dose-Res	1986
Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice. Teratology, 1986, Volume: 34, Issue:3 Topics: Abnormalities, Drug-Induced; Animals; Caffeine; Cleft Palate; Dose-Response Relationship, Drug; Fema	1986
[Detection of caffeine, theophylline and theobromine in the umbilical cord blood and breast milk]. Helvetica paediatrica acta, 1985, Volume: 40, Issue:2-3 Topics: Caffeine; Female; Fetal Blood; Humans; Infant, Premature; Kinetics; Maternal-Fetal Exchange; Milk, H	1985
The effect of caffeine ingestion on pharmacokinetics of caffeine and its metabolites after a single administration in pregnant rats. Journal of pharmacobio-dynamics, 1985, Volume: 8, Issue:3 Topics: Administration, Oral; Animals; Caffeine; Female; Injections, Intravenous; Kinetics; Pregnancy; Rats;	1985
Caffeine disposition after oral administration to pregnant rats. Xenobiotica; the fate of foreign compounds in biological systems, 1985, Volume: 15, Issue:12 Topics: Administration, Oral; Amniotic Fluid; Animals; Caffeine; Female; Fetus; Pregnancy; Rats; Theobromine	1985
Fetal hypoproteinemia associated with generalized edema caused by administration of methyl xanthines to the rat during late pregnancy. Japanese journal of pharmacology, 1973, Volume: 23, Issue:6 Topics: Animals; Blood Proteins; Body Water; Body Weight; Caffeine; Edema; Female; Fetal Diseases; Fetus; Ge	1973
Teratogenic actions of some methylated xanthines in mice. Okajimas folia anatomica Japonica, 1969, Volume: 46, Issue:4 Topics: Abnormalities, Drug-Induced; Animals; Caffeine; Female; Fetus; Injections, Intraperitoneal; Male; Mi	1969

theobromine and Pregnancy