Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations via Epigenetic Modifications

Phthalates increase the risk of allergies among children

Phthalates, which are used as plasticizers in plastics, can considerably increase the risk of allergies among children. According to a new study, an increased risk of children developing allergic asthma exists if the mother has been particularly heavily exposed to phthalates during pregnancy and breastfeeding.

2017 Study Abstract

Background
Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children due to exposure to plasticizers like phthalates, findings of previous studies are inconsistent and lack mechanistic information.

Objective
We investigated the effect of maternal phthalate exposure on asthma development in the subsequent generations and their underlying mechanisms including epigenetic alterations.

Methods
Phthalate metabolites were measured within the prospective mother-child cohort LINA and correlated with asthma development in the children. A murine trans-generational asthma model was used to identify involved pathways.

Results
In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine trans-generational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by a BBP-induced global DNA hypermethylation in CD4 T cells of the offspring as treatment with a DNA demethylating agent alleviated exacerbation of allergic airway inflammation. 13 transcriptionally down-regulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor Zfpm1 emerged as a potential mediator of the enhanced susceptibility for Th2-driven allergic asthma.

Conclusion
These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in Th2 differentiation via epigenetic alterations.

Sources and Press Releases
  • Maternal Phthalate Exposure Promotes Allergic Airway Inflammation over Two Generations Via Epigenetic Modifications, jacionline, DOI: 10.1016/j.jaci.2017.03.017, 1 March 2017.
  • Phthalates increase the risk of allergies among children, medicalxpress, May 3, 2017.
  • Image credit: UFZ/André KünzelmannIn the course of the LINA mother-child cohort study, UFZ scientists investigated the lifestyle and environmental factors of pregnant women and their influence on the allergy risk of infants.

Antidepressant Use in Pregnancy and Preterm Birth, ASD, ADHD in Offspring

Is first-trimester maternal antidepressant use related to offspring birth problems, neurodevelopmental problems, or both?

1. Association Between Maternal Use of SSRI Medications and Autism in Their Children

In the February 2016 issue of JAMA Pediatrics, Boukhris and colleagues reported that in utero exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with a significantly increased risk for autism. The authors examined all pregnancies from 1998 to 2009 in the Québec Pregnancy/Children Cohort database that resulted in children with autism spectrum disorder (ASD) as the primary outcome. Among 145 456 full-term infants included in the analysis, 1054 children were diagnosed with ASD by the mean age of 6.2 years (SD, 3.2 years) at follow-up, including 1008 cases of ASD among 140 732 children (0.72%) who were not exposed to antidepressants, and 31 cases of ASD among the 2532 (1.2%) children who were exposed to SSRIs during the second or third trimester. Based on these results, the authors concluded that second- or third-trimester exposure to SSRIs was associated with increased risk for ASD (adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04).

2017 Study Abstract

Importance
The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.

Objective
To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.

Design, Setting, and Participants
We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145 456 singleton full-term infants born alive and whose mothers were covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.

Exposures
Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.

Main Outcomes and Measures
Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.

Results
During 904 035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).

Conclusions and Relevance
Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.

2. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

Key Points

Findings
In this retrospect cohort study of 1 580 629 Swedish offspring using multiple statistical and methodical approaches to adjust for confounding, first-trimester antidepressant exposure was significantly associated with preterm birth (odds ratio, 1.3 in a sibling comparison analysis) but not with risk of being born small for gestational age or later autism spectrum disorder or attention-deficit/hyperactivity disorder.

Meaning
After accounting for confounding factors, first-trimester antidepressant exposure, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

2017 Abstract

Importance
Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding.

Objective
To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems.

Design, Setting, and Participants
This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations.

Exposures
Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations.

Main Outcomes and Measures
Preterm birth (< 37 gestational weeks), small for gestational age (birth weight < 2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring.

Results
Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons.

Conclusions and Relevance
Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Image credit Jamie Campbell.

Questioning the Safety of the Hormonal Pregnancy Test Drugs

1978 London Programme

Greg Dyke and his team, at London Weekend TV, highlight and interview parents and children on the dangers which Primodos was causing to the unborn foetus.

Part 1
Part 2
Part 3

More Information

Calls for Public Inquiry over Primodos Pregnancy Test Drug

Sky News investigation exposed Primodos pregnancy drug cover-up

March 2017 : MPs have welcomed a Sky investigation, which revealed how hormone pregnancy tests may have caused malformations and even deaths.

Around 1.5 million women in Britain in the 1960s and 1970s took Primodos in the early stages of pregnancy. Some say their pregnancies resulted in miscarriage or birth defects.

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News revealed how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

Primodos and Birth Defects : What was the Risk?

Sky News investigation exposes Primodos pregnancy drug cover-up

Around 1.5 million women in Britain in the 1960s and 1970s took Primodos in the early stages of pregnancy. Some say their pregnancies resulted in miscarriage or birth defects.

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News revealed how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

Primodos : The Secret Drug Scandal

Sky News investigation exposes Primodos pregnancy drug cover-up

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News reveals how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

Primodos Duogynon used for Abortions

Sky News investigation exposes Primodos pregnancy drug cover-up

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News reveals how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

  • Sky News March 2017 press releases:
    • Calls for public inquiry over Primodos pregnancy drug after Sky News documentary, Sky News, March 2017.
    • Primodos: Sky News exposes pregnancy drug cover-up on Sky News, March 2017.
    • ‘Taking Primodos caused me lifetime of regret‘: The story of mother Marie Lyon, Sky News, March 2017.
    • UK pregnancy test drug Primodos used for abortions in Germany, Sky News, March 2017.
  • Sign the petition : Expose cover up of Hormone Pregnancy Tests on 38degrees.
  • Our blog posts about the primodos pregnancy test drug.
  • Watch more videos about prescription drugs side-effects on YouTube.

Primodos Pregnancy Drug Cover-Up

Sky News investigation exposes Primodos pregnancy drug cover-up

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News reveals how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

  • Sky News March 2017 press releases:
    • Calls for public inquiry over Primodos pregnancy drug after Sky News documentary, Sky News, March 2017.
    • Primodos: Sky News exposes pregnancy drug cover-up on Sky News, March 2017.
    • ‘Taking Primodos caused me lifetime of regret‘: The story of mother Marie Lyon, Sky News, March 2017.
    • UK pregnancy test drug Primodos used for abortions in Germany, Sky News, March 2017.
  • Sign the petition : Expose cover up of Hormone Pregnancy Tests on 38degrees.
  • Our blog posts about the primodos pregnancy test drug.
  • Watch more videos about prescription drugs side-effects on YouTube.

Primodos Pregnancy Test Linked to Child’s Death

Sky News investigation exposes Primodos pregnancy drug cover-up

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News reveals how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

  • Sky News March 2017 press releases:
    • Calls for public inquiry over Primodos pregnancy drug after Sky News documentary, Sky News, March 2017.
    • Primodos: Sky News exposes pregnancy drug cover-up on Sky News, March 2017.
    • ‘Taking Primodos caused me lifetime of regret‘: The story of mother Marie Lyon, Sky News, March 2017.
    • UK pregnancy test drug Primodos used for abortions in Germany, Sky News, March 2017.
  • Sign the petition : Expose cover up of Hormone Pregnancy Tests on 38degrees.
  • Our blog posts about the primodos pregnancy test drug.
  • Watch more videos about prescription drugs side-effects on YouTube.

Primodos and Gestest Drugs Use Linked to Horrific Birth Defects

Sky News investigation exposes Primodos pregnancy drug cover-up

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal is presented by senior political correspondent Jason Farrell, who has been investigating it for six years.

Sky News reveals how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

  • Sky News March 2017 press releases:
    • Calls for public inquiry over Primodos pregnancy drug after Sky News documentary, Sky News, March 2017.
    • Primodos: Sky News exposes pregnancy drug cover-up on Sky News, March 2017.
    • ‘Taking Primodos caused me lifetime of regret‘: The story of mother Marie Lyon, Sky News, March 2017.
    • UK pregnancy test drug Primodos used for abortions in Germany, Sky News, March 2017.
  • Sign the petition : Expose cover up of Hormone Pregnancy Tests on 38degrees.
  • Our blog posts about the primodos pregnancy test drug.
  • Watch more videos about prescription drugs side-effects on YouTube.