The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

Childhood obesity with its growing prevalence worldwide presents one of the most important health challenges nowadays. Multiple mechanisms are involved in the development of this condition, as well as in its associations with various cardiometabolic complications, such as insulin resistance, diabetes, metabolic dysfunction-associated steatotic liver disease and cardiovascular diseases. Recent findings suggest that childhood obesity and associated dyslipidemia at least partly originate from epigenetic modifications that take place in the earliest periods of life, namely prenatal and perinatal periods. Hence, alterations of maternal metabolism could be fundamentally responsible for fetal and neonatal metabolic programming and consequently, for metabolic health of offspring in later life. In this paper, we will review recent findings on the associations among intrauterine and early postnatal exposure to undesirable modulators of metabolism, development of childhood obesity and later cardiometabolic complications. Special attention will be given to maternal dyslipidemia as a driven force for undesirable epigenetic modulations in offspring. In addition, newly proposed lipid biomarkers of increased cardiometabolic risk in obese children and adolescents will be analyzed, with respect to their predictive potential and clinical applicability.

OBJECTIVE: With increasingly prevalent folic acid consumption in early pregnancy, concerns about its potentially negative effect on maternal metabolism have been raised. Recent findings regarding folic acid levels in the first trimester and the risk of gestational diabetes mellitus have been inconclusive. The aim of this study was to investigate the association of folic acid status in early pregnancy with gestational diabetes mellitus as well as examine whether glucose levels can be modulated by folic acid status during the same first trimester.
METHODS: This was a retrospective cohort study based on 27 128 Chinese pregnant women who registered during their first prenatal visit from January 2015 to December 2019. Serum folic acid and fasting blood glucose concentrations were measured during the 9th to 13th gestational weeks. Binary logistic regression was applied to estimate the odds ratios of gestational diabetes mellitus by using the serum folic acid levels quartiles with adjustment for major confounders. To investigate the potential effect of modifying key risk factors for gestational diabetes mellitus, we established subgroups, in which analyses were stratified by age (<25, 25-29, 30-34, and ≥35 y), parity (nulliparous and parous), prepregnancy body mass index (< 18.5, 18.5-23.9, and ≥ 24 kg/m2), and family history of diabetes (yes and no).
RESULTS: The positive association between maternal folate concentrations and fasting blood glucose was observed: the risk for hyperglycemia was higher in those in the middle (Q3) and higher (Q4) quartiles compared with those in Q1 and Q2. A higher risk for gestational diabetes mellitus was found in hyperglycemia of early pregnant women with high folate concentrations (Q3: odds ratio = 5.63; 95% CI, 4.56-6.95, and Q4: odds ratio = 5.57; 95% CI, 4.68-6.64) compared with normal fasting glucose mothers with folate concentrations in Q1 and Q2 after accounting for multiple covariables. Similar patterns were observed for different subgroups. Restricted cubic spline plots had a positive correlation of serum folic acid level with fasting blood glucose concentration as well as risk of gestational diabetes mellitus in a nonlinear pattern, with 32.5 nmol/L as the cutoff point for folic acid level.
CONCLUSIONS: Our findings underscore the importance of maintaining an appropriate folic acid concentration for preserving a lower risk of gestational diabetes mellitus, especially in women with relatively higher blood glucose in early pregnancy. Additionally, folic acid concentration > 32.5 nmol/L may be considered a risk factor for gestational diabetes mellitus. This research suggested that folic acid levels should be monitored during the first trimester from the first prenatal checkup to prevent adverse effects of excessive folic acid intake.

BACKGROUND: Craniofacial microsomia (CM) is characterized by changes in the first and second branchial arches. It is a clinical condition whose etiology is still uncertain, but studies have shown that genetic, nutritional, and environmental factors can result in disorders of blastogenesis of the branchial arches. This study evaluates gestational aspects, focusing on possible risk factors associated with CM.
METHODS: This is a case-control study conducted with patients monitored at a medical genetics service and compared to a control group of patients without evidence of malformations, born in a mother and child hospital, both located in Porto Alegre, Southern Brazil. Mothers\' data were obtained using questionnaires and by reviewing medical records. The sample consisted of 43 patients with CM (cases) and 129 patients without evidence of malformations (controls), paired by sex, totaling three controls for each case. Data analysis was performed using the two-tailed Fisher\'s exact test, Pearson\'s chi-square test, and the t-test.
RESULTS: We identified several factors associated with the development of CM, including the use of abortion methods by the mothers of these babies (p = .001), maternal diabetes (p = .009), advanced maternal age (p = .035), and a history of vaginal bleeding (p < .001). Furthermore, these patients exhibited a tendency to be born prematurely (p = .027), with low birth weight (p = .007), and lower Apgar scores (p = .003) when compared to healthy infants. Using a multivariate model, the use of abortion methods (p = .003) and vaginal bleeding (p = .032) remained independently associated with craniofacial microsomia.
CONCLUSIONS: We have identified several risk factors for the development of CM, including a propensity for premature birth, low birth weight, and respiratory difficulties. Additionally, women of advanced maternal age and/or those who used abortion methods and/or have diabetes have a higher risk of giving birth to a baby with CM. This information can be valuable in clinical practice, especially for the prevention of future cases.

Maternal obesity has been associated with shorter breastfeeding duration, but little is known about mediating factors explaining this association. It is important to assess these relationships across diverse populations because breastfeeding is culturally patterned.
We investigated the association of prepregnancy maternal body mass index (BMI) with breastfeeding outcomes and potential mediators of this relationship in 3 culturally diverse international cohorts.
We analyzed 5120 singleton pregnancies from mother-child cohorts in Spain (INfancia y Medio Ambiente), Greece (Rhea), and the United States (Project Viva). Outcome variables were duration of any and exclusive breastfeeding. A priori hypothesized mediators in the association of maternal prepregnancy BMI with breastfeeding were birthweight (BW), maternal prenatal C-reactive protein (CRP), cesarean delivery, maternal dietary inflammatory index (DII) during pregnancy, gestational age at delivery, and gestational diabetes mellitus (GDM). We estimated the association between BMI and breastfeeding duration using linear regression adjusting for confounders. Mediation analysis estimated direct and indirect effects of maternal overweight/obesity on breastfeeding for each mediator.
Women with overweight and obesity had shorter duration of any and exclusive breastfeeding compared with normal-weight women (any: overweight β = -0.79 mo, 95% CI: -1.17, -0.40; obese β = -1.75 mo 95% CI: -2.25, -1.25; exclusive: overweight β = -0.30 mo, 95% CI: -0.42, -0.16; obese β = -0.73 mo, 95% CI: -0.90, -0.55). Significant mediators (% change in effect estimate) of this association were higher CRP (exclusive: 5.12%), cesarean delivery (any: 6.54%; exclusive: 7.69%), and higher DII (any: 6.48%; exclusive: 7.69%). GDM, gestational age, and BW did not mediate the association of maternal weight status with breastfeeding.
Higher prepregnancy BMI is associated with shorter duration of any and exclusive breastfeeding. Maternal dietary inflammation, systemic inflammation, and mode of delivery may be key modifiable mediators of this association. Identification of mediators provides potential targets for interventions to improve breastfeeding outcomes.

Gestational Diabetes Mellitus (GDM) carries an increased risk for adverse perinatal and longer-term cardiometabolic consequences in offspring. This study evaluated the utility of maternal anthropometric, metabolic and fetal (cord blood) parameters to predict offspring anthropometry up to 1 year in pregnancies with GDM.
In this prospective analysis of the MySweetheart study, we included 193/211 women with GDM that were followed up to 1 year postpartum. Maternal predictors included anthropometric (pre-pregnancy BMI, gestational weight gain (GWG), weight and fat mass at the 1st GDM visit), and metabolic parameters (fasting insulin and glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Quantitative insulin-sensitivity check index (QUICKI), HbA1c, triglycerides, and high-density lipoprotein (HDL) at the 1st visit and HbA1c at the end of pregnancy). Fetal predictors (N=46) comprised cord blood glucose and insulin, C-Peptide, HOMA-IR, triglycerides and HDL. Offspring outcomes were anthropometry at birth (weight/weight z-score, BMI, small and large for gestational age (SGA,LGA)), 6-8 weeks and 1 year (weight z-score, BMI/BMI z-score, and the sum of 4 skinfolds).
In multivariate analyses, birth anthropometry (weight, weight z-score, BMI and/or LGA), was positively associated with cord blood HDL and HbA1c at the 1st GDM visit, and negatively with maternal QUICKI and HDL at the 1st GDM visit (all p ≤ 0.045). At 6-8 weeks, offspring BMI was positively associated with GWG and cord blood insulin, whereas the sum of skinfolds was negatively associated with HDL at the 1st GDM visit (all p ≤0.023). At 1 year, weight z-score, BMI, BMI z-score, and/or the sum of skinfolds were positively associated with pre-pregnancy BMI, maternal weight, and fat mass at the 1st GDM visit and 3rd trimester HbA1c (all p ≤ 0.043). BMI z-score and/or the sum of skinfolds were negatively associated with cord blood C-peptide, insulin and HOMA-IR (all p ≤0.041).
Maternal anthropometric, metabolic, and fetal metabolic parameters independently affected offspring anthropometry during the 1st year of life in an age-dependent manner. These results show the complexity of pathophysiological mechanism for the developing offspring and could represent a base for future personalized follow-up of women with GDM and their offspring.

Pregnancy and postpartum are periods of intense changes in women\'s metabolism. The knowledge of the metabolites and maternal factors underlying these changes is limited.
We aimed to investigate the maternal factors that could influence serum metabolome changes from late pregnancy to the first months of postpartum.
Sixty-eight healthy women from a Brazilian prospective cohort were included. Maternal blood and general characteristics were collected during pregnancy (28-35 wk) and postpartum (27-45 d). A targeted metabolomics approach was applied to quantify 132 serum metabolites, including amino acids, biogenic amines, acylcarnitines, lysophosphatidylcholines (LPC), diacyl phosphatidylcholines (PC), alkyl:acyl phosphatidylcholines (PC-O), sphingomyelins with (SM) and without hydroxylation [SM(OH)], and hexoses. Metabolome changes from pregnancy to postpartum were measured as log2 fold change (log2FC), and simple linear regressions were employed to evaluate associations between maternal variables and metabolite log2FC. Multiple comparison-adjusted P values of < 0.05 were considered significant.
Of 132 metabolites quantified in serum, 90 changed from pregnancy to postpartum. Most metabolites belonging to PC and PC-O classes decreased, whereas most LPC, acylcarnitines, biogenic amines, and a few amino acids increased in postpartum. Maternal prepregnancy body mass index (ppBMI) showed positive associations with leucine and proline. A clear opposite change pattern was observed for most metabolites across ppBMI categories. Few phosphatidylcholines were decreased in women with normal ppBMI, while an increase was observed in women with obesity. Similarly, women with high postpartum levels of total cholesterol, LDL cholesterol, and non-HDL cholesterol showed increased sphingomyelins, whereas a decrease was observed for women with lower levels of those lipoproteins.
The results revealed several maternal serum metabolomic changes from pregnancy to postpartum, and the maternal ppBMI and plasma lipoproteins were associated with these changes. We highlight the importance of the nutritional care of women prepregnancy to improve their metabolic risk profile.

The energy and metabolic state of sows will alter considerably over different phases of gestation. Maternal metabolism increases dramatically, particularly in late pregnancy. This is accompanied by the development of an increase in oxidative stress, which has a considerable negative effect on the maternal and the placenta. As the only link between the maternal and the fetus, the placenta is critical for the maternal to deliver nutrients to the fetus and for the fetus\' survival and development. This review aimed to clarify the changes in energy and metabolism in sows during different pregnancy periods, as well as the impact of maternal oxidative stress on the placenta, which affects the fetus\' survival and development.

Higher maternal body mass index (BMI) and abnormal glucose metabolism during early pregnancy are associated with congenital heart defects in the offspring, but the exact mechanisms are unknown.
We evaluated the association between maternal first trimester metabolic profile and transposition of the great arteries (TGA) in the offspring in a matched case-control study with 100 TGA mothers and 200 controls born in Finland during 2004-2014. Cases and controls were matched by birth year, child sex, and maternal age and BMI. Serum samples collected between 10- and 14-weeks of gestation were analyzed for 73 metabolic measures. Conditional logistic regression was used to assess the risk for TGA in the offspring, and a subgroup analysis among mothers with high BMI was conducted.
Higher concentrations of four subtypes of extremely large very-low-density lipoprotein (VLDL) particles and one of large VLDL particles were observed in TGA mothers. This finding did not reach statistical significance after multiple testing correction. The pooled odds ratio (OR) of the all metabolic variables was slightly higher in TGA mothers in the subgroup with maternal BMI over 25 (OR 1.25) and significantly higher in the subgroup with maternal BMI over 30 (OR 1.95) compared to the original population (OR 1.18).
Our findings indicate that an abnormal maternal early pregnancy metabolic profile might be associated with TGA in the offspring, especially in obese mothers. A trend indicating altered VLDL subtype composition in TGA pregnancies warrants further research.

High-flavonoid cocoa consumption has been associated with beneficial properties. However, there are scarce data concerning the effects of maternal cocoa intake on dams and in their progeny. Here, we evaluated in rats whether maternal supplementation with a high-flavan-3-ol cocoa extract (CCX) during lactation (200 mg.kg-1.day-1) produced beneficial effects on dams and in their normoweight (STD-CCX group) and cafeteria-fed obese (CAF-CCX group) adult male offspring. Maternal intake of CCX significantly increased the circulating levels of adiponectin and decreased the mammary gland lipid content of dams. These effects were accompanied by increased energy expenditure and circulating free fatty acids, as well as by a higher expression of lipogenic and adiponectin-related genes in their mammary glands, which could be related to a compensatory mechanism to ensure enough lipid supply to the pups. CCX consumption programmed both offspring groups towards increased plasma total adiponectin levels, and decreased liver weight and lean/fat ratio. Furthermore, CAF-CCX progeny showed an improvement of the inflammatory profile, evidenced by the significant decrease of the monocyte chemoattractant protein-1 (MCP-1) circulating levels and the mRNA levels of the gene encoding the major histocompatibility complex, class II invariant chain (Cd74), a marker of M1 macrophage phenotype, in the epididymal white adipose tissue. Although further studies are needed, these findings can pave the way for using CCX as a nutraceutical supplement during lactation.