Use of antibiotics during pregnancy and the risk of major congenital malformations

Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to major congenital malformations

2017 Study Abstract

Introduction
Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed – population based cohort study, British Pharmacological Society, 19 July 2017 – to quantify the association between exposure to gestational antibiotic and the risk of MCMs.

Methods
Using the Quebec pregnancy cohort (1998 -2008), we included a total of 139,938 liveborn singleton alive whose mothers were covered by the “Régie de l’assurance maladie du Québec” drug plan for at least 12 months before and during pregnancy. Antibiotics exposure was assessed in the first trimester and MCMs were identified within the first year of life.

Results
After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95%CI, 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95%CI, 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95%CI, 1.04-3.16, 13 exposed cases).

Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95%CI ,1.21-4.67, 9 exposed cases; aOR 2.46, 95%CI, 1.21-4.99, 8 exposed cases; aOR 3.19, 95%CI, 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group.

Conclusions

  • Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ specific malformations.
  • Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs.

The feminist appropriation of pregnancy testing in 1970s Britain

Jesse Olszynko-Gryn, Department of History and Philosophy of Science, University of Cambridge, Cambridge, UK

Abstract

This article restores pregnancy testing to its significant position in the history of the women’s liberation movement in 1970s Britain. It shows how feminists appropriated the pregnancy test kit, a medical technology which then resembled a small chemistry set, and used it as a political tool for demystifying medicine, empowering women and providing a more accessible, less judgmental alternative to the N.H.S. While the majority of testees were young women hoping for a negative result, many others were older, menopausal women as well as those anxious to conceive. By following the practice of pregnancy testing, I show that, at the grassroots level, local women’s centres were in the vanguard of not only access to contraception and abortion rights, but also awareness about infertility and menopause.

… Many G.P.s also prescribed, on the N.H.S., Schering’s ‘Primodos,’ a ‘hormonal pregnancy test’ in tablet form that was less expensive and faster than ordering a urine test. The drug, which worked by inducing menstruation in non-pregnant women (a ‘negative’ result), was taken off the market in 1978 amidst concerns that it caused a variety of birth defects. Primodos Was a Revolutionary Oral Pregnancy Test: But Was It Safe?

  • … continue reading Jesse Olszynko-Gryn‘s full paper The feminist appropriation of pregnancy testing in 1970s Britain on tandfonline and/or download the PDF.
  • Featured image of the Pregnosticon Planotest credit tandfonline.

Sugar intake in pregnancy linked to childhood respiratory allergy, asthma in children

Maternal intake of sugar during pregnancy and childhood respiratory and atopic outcomes

Image credit mommywrites.

Pregnant women who consume high levels of free sugars during pregnancy are more likely to give birth to a child with allergy or allergic asthma, a study published in the European Respiratory Journal reported.

2017 Study Abstract

The possible role of maternal consumption of free sugar during pregnancy in the inception of respiratory and atopic diseases has not been studied. We aimed to study the relationship between maternal intake of free sugar during pregnancy and respiratory and atopic outcomes in the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children.

We analysed associations between maternal intake of free sugar in pregnancy (estimated by a food frequency questionnaire), and current doctor-diagnosed asthma, wheezing, hay fever, eczema, atopy, serum total IgE and lung function in children aged 7–9 years (n=8956 with information on maternal diet in pregnancy and at least one outcome of interest).

After controlling for potential confounders, maternal intake of free sugar was positively associated with atopy (OR for highest versus lowest quintile of sugar intake 1.38, 95% CI 1.06–1.78; per quintile p-trend=0.006) and atopic asthma (OR 2.01, 95% CI 1.23–3.29; per quintile p-trend=0.004). These associations were not confounded by intake of sugar in early childhood, which was unrelated to these outcomes.

Our results suggest that a higher maternal intake of free sugar during pregnancy is associated with an increased risk of atopy and atopic asthma in the offspring, independently of sugar intake in early childhood.

Postdischarge Opioid Use After Cesarean Delivery

Too Many Opioids After Cesarean Delivery

Doctors may be overprescribing opioids to women who have had cesarean sections, a new study found, and it’s not so simple as ‘just use less’, the lead author said:

”About a quarter of the women used all their pills and still reported they had pain”

2017 Study Abstract

OBJECTIVE
To characterize postdischarge opioid use and examine factors associated with variation in opioid prescribing and consumption.

METHODS
We conducted a prospective observational cohort study by recruiting all women undergoing cesarean delivery during an 8-week period, excluding those with major postoperative morbidities or chronic opioid use. Starting on postoperative day 14, women were queried weekly regarding number of opioid pills used, amount remaining, and their pain experience until they had stopped opioid medication. Demographic and delivery information and in-hospital opioid use were recorded. The state Substance Monitoring Program was accessed to ascertain prescription-filling details. Morphine milligram equivalents were calculated to perform opioid use comparisons. Women in the highest quartile of opioid use (top opioid quartile use) were compared with those in the lowest three quartiles (average opioid use).

RESULTS
Of 251 eligible patients, 246 (98%) agreed to participate. Complete follow-up data were available for 179 (71% of eligible). Most women (83%) used opioids after discharge for a median of 8 days (interquartile range 6-13 days). Of women who filled their prescriptions (165 [92%]), 75% had unused tablets (median per person 75 morphine milligram equivalents, interquartile range 0-187, maximum 630) and the majority (63%) stored tablets in an unlocked location. This amounts to an equivalent of 2,540 unused 5-mg oxycodone tablets over our study period. Women who used all prescribed opioids (n=40 [22%]) were more likely to report that they received too few tablets than women who used some (n=109 [61%]) or none (n=30 [17%]) of the prescribed opioids (33% compared with 4% compared with 5%, P<.001). The top quartile was more likely to be smokers than average users and consumed more opioid morphine milligram equivalents per hour of inpatient stay than average opioid users (1.6, interquartile range 1.1-2.3 compared with 1.0, interquartile range 0.5-1.4, P<.001).

CONCLUSION
Most women-especially those with normal in-hospital opioid use-are prescribed opioids in excess of the amount needed.

More Information
  • Postdischarge Opioid Use After Cesarean Delivery, The American College of Obstetricians and Gynecologists, doi: 10.1097/AOG.0000000000002095, June 06, 2017.
  • Too Many Opioids After Cesarean Delivery, nytimes, JUNE 14, 2017.

The BMJ Research looks at prenatal antidepressant use and risk of ADHD in children

Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study

Previous reports might have overestimated the association between gestational use of antidepressants and ADHD in offspring because they have failed to control for shared family factors. Although we cannot completely discount the possibility that gestational use of antidepressants is a causal factor, our findings raise the possibility that confounding by indication might at least partially explain the observed association. We propose that if a causal association exists, then the size of the effect is probably smaller than that previously reported. However, decision making about antidepressant use in pregnancy remains important and requires an assessment of the risks and benefits in the context of the individual woman and family.

What is already known on this topic

  • Whether to prescribe drugs for depression during pregnancy is a complex decision
  • Prenatal use of antidepressants is considered a risk factor for attention-deficit/hyperactivity disorder (ADHD) in children, but evidence is inconclusive
  • The negative consequences of untreated maternal depression might also affect childhood development

What this study adds

  • The risk of ADHD was similar between the offspring of mothers who used antidepressants during pregnancy and those who used before pregnancy only, whereas the risk was higher for offspring of mothers with psychiatric disorders irrespective of whether antidepressants were used
  • Evidence suggests that the association between prenatal antidepressant use and risk of ADHD may at least partially be explained by confounding by indication of antidepressants
  • If there was a causal association; then the size of the effect is probably smaller than what has been reported previously

2017 Study Abstract

Objective
To assess the potential association between prenatal use of antidepressants and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring.

Design
Population based cohort study.

Setting
Data from the Hong Kong population based electronic medical records on the Clinical Data Analysis and Reporting System.

Participants
190 618 children born in Hong Kong public hospitals between January 2001 and December 2009 and followed-up to December 2015.

Main outcome measure
Hazard ratio of maternal antidepressant use during pregnancy and ADHD in children aged 6 to 14 years, with an average follow-up time of 9.3 years (range 7.4-11.0 years).

Results
Among 190 618 children, 1252 had a mother who used prenatal antidepressants. 5659 children (3.0%) were given a diagnosis of ADHD or received treatment for ADHD. The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P<0.01) compared with non-use. After adjustment for potential confounding factors, including maternal psychiatric disorders and use of other psychiatric drugs, the adjusted hazard ratio was reduced to 1.39 (95% confidence interval 1.07 to 1.82, P=0.01). Likewise, similar results were observed when comparing children of mothers who had used antidepressants before pregnancy with those who were never users (1.76, 1.36 to 2.30, P<0.01). The risk of ADHD in the children of mothers with psychiatric disorders was higher compared with the children of mothers without psychiatric disorders even if the mothers had never used antidepressants (1.84, 1.54 to 2.18, P<0.01). All sensitivity analyses yielded similar results. Sibling matched analysis identified no significant difference in risk of ADHD in siblings exposed to antidepressants during gestation and those not exposed during gestation (0.54, 0.17 to 1.74, P=0.30).

Conclusions
The findings suggest that the association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication of antidepressants. If there is a causal association, the size of the effect is probably smaller than that reported previously.

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