Antidepressant use during pregnancy and psychiatric disorders in offspring

Danish nationwide register based cohort study, 2017

What is already known on this topic

  • Several studies have linked selective serotonin reuptake inhibitor use during pregnancy to autism spectrum disorder in offspring, although results have been conflicting
  • The potential explanation for this association is that selective serotonin reuptake inhibitors cross the placental barrier and affect the development of the fetal brain
  • If this holds true, in utero exposure to selective serotonin reuptake inhibitor and other classes of antidepressants may increase risk for various psychiatric disorders besides autism spectrum disorder

What this study adds

  • Antidepressant use during pregnancy was associated with increased risk for various diagnostic groups of psychiatric disorders in offspring
  • The observed associations may be attributable to the severity of underlying maternal psychiatric disorders in combination with in utero antidepressant exposure

Study Abstract

Objective
To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.

Design
Population based cohort study.

Setting
Danish national registers.

Participants
905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk.

Exposures for observational studies
Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).

Main outcome measure
First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.

Results
Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.

Conclusions
In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.

  • Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study, BMJ 2017;358:j3668, 06 September 2017.
  • Characteristics of study population according to maternal antidepressant use before and during pregnancy. Values are numbers (percentages) unless stated otherwise, featured image credit bmj.

Get Me Out

A History of Childbirth from the Garden of Eden to the Sperm Bank, by Randi Hutter

image of get me out book cover
Randi Hutter Epstein, M.D., M.P.H. is a medical writer, adjunct professor at Columbia University Graduate School of Journalism and a lecturer at Yale University.

From a witty, relentlessly inquisitive medical writer, an eye-opening history of pregnancy and birthing joys and debacles. Making and having babies—what it takes to get pregnant, stay pregnant, and deliver—has mystified women and men for the whole of human history. The birth gurus of ancient times told newlyweds that simultaneous orgasms were necessary for conception and that during pregnancy a woman should drink red wine but not too much and have sex but not too frequently. Over the last one hundred years, depending on the latest prevailing advice, women have taken morphine, practiced Lamaze, relied on ultrasound images, sampled fertility drugs, and shopped at sperm banks.

In Get Me Out, the insatiably curious Randi Hutter Epstein journeys through history, fads, and fables, and to the fringe of science, where audacious researchers have gone to extreme measures to get healthy babies out of mothers. The book has a full, good chapter on DES.

DES DiEthylStilbestrol Resources

Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth

When the human fetus is exposed to chemicals in the environment, fetal growth can be reduced

2017 Study Abstract

Background
Adverse effects of prenatal stress or environmental chemical exposures on fetal growth are well described, yet their combined effect remains unclear.

Objectives
To conduct a systematic review on the combined impact and interaction of prenatal exposure to stress and chemicals on developmental outcomes.

Methods
We used the first three steps of the Navigation Guide systematic review. We wrote a protocol, performed a robust literature search to identify relevant animal and human studies and extracted data on developmental outcomes. For the most common outcome (fetal growth), we evaluated risk of bias, calculated effect sizes for main effects of individual and combined exposures, and performed a random effects meta-analysis of those studies reporting on odds of low birthweight (LBW) by smoking and socioeconomic status (SES).

Results
We identified 17 human- and 22 animal-studies of combined chemical and stress exposures and fetal growth. Human studies tended to have a lower risk of bias across nine domains. Generally, we found stronger effects for chemicals than stress, and these exposures were associated with reduced fetal growth in the low-stress group and the association was often greater in high stress groups, with limited evidence of effect modification. We found smoking associated with significantly increased odds of LBW, with a greater effect for high stress (low SES; OR 4.75 (2.46–9.16)) compared to low stress (high SES; OR 1.95 (95% CI 1.53–2.48)). Animal studies generally had a high risk of bias with no significant combined effect or effect modification.

Conclusions
We found that despite concern for the combined effects of environmental chemicals and stress, this is still an under-studied topic, though limited available human studies indicate chemical exposures exert stronger effects than stress, and this effect is generally larger in the presence of stress.

Sources

Could taking Vitamin B3 prevent miscarriages and birth defects ?

Claims that niacin prevents miscarriages in humans grossly exaggerated

The “blockbuster breakthrough to prevent birth defects and miscarriages” releaseHistoric Discovery Promises to Prevent Miscarriages and Birth Defects Globally – describes a “double discovery” made by researchers at the Victor Chang Cardiac Research Institute in Australia that, theoretically, will greatly reduce the number of birth defects and miscarriages worldwide.

The premise rests on the discovery that genetic mutations causing a deficiency in one type of molecule (Nicotinamide adenine dinucleotide, or NAD) can lead to birth defects in humans. The researchers then tested the impact of vitamin B3 (or niacin) supplements on mouse models engineered to have the same mutations who were deficient in NAD. They found that the mice who had higher levels of niacin were less likely to have offspring with birth defects.

The news release hid the fact that the vitamin supplements (referring only to “preclinical models”) were tested in mice, and not humans. But most worrying was the use of extremely sensationalist language prevalent throughout the release. The language was so overblown that it could give false hope to women without properly describing the limits of the research.

continue reading Claims that niacin prevents miscarriages in humans grossly exaggerated, healthnewsreview, August 14, 2017.

  • NAD Deficiency, Congenital Malformations, and Niacin Supplementation, N Engl J Med 2017; 377:544-552, DOI: 10.1056/NEJMoa1616361, August 10, 2017.
  • Vitamin profile of 563 gravidas during trimesters of pregnancy, Journal of the American College of Nutrition, NCBI PubMed PMID: 11838885, 2002 Feb.
  • Featured image credit @HealthNewsRevu.

Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic drugs

The BMJ investigates in utero co-exposure to psychotropic medications-opioids and neonatal drug withdrawal

In the US, about every 25 minutes an infant is born with signs of drug withdrawal.

Prescriptions for opioid analgesics in the US have increased more than threefold over the past two decades, and this rise also extends to prescriptions to pregnant women. About 14-22% of pregnancies in the US are complicated by exposure to prescription opioid medications.

A strong increase in the prescription of opioids has also been observed in most European countries (such as Germany, Italy, Spain, Scandinavia, UK, the Netherlands) and Australia, though the number of prescriptions and defined daily doses remains much lower than in the US and Canada Data from a population based registry in Norway showed that 6% of pregnant women filled at least one opioid prescription in 2004-06.

Neonatal abstinence syndrome (NAS) is a well recognized complication of intrauterine exposure to opioid analgesics, with manifestations ranging from difficulties with feeding and sleeping to more severe complications including impaired thermoregulation, seizures, failure to thrive, and respiratory distress. From 2000 to 2012, hospital charges for this syndrome increased from about $190m (about £150m; €170m) to $1.5bn.

2017 Study Abstract

Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study, BMJ 2017;358:j3326, 02 August 2017.

Image credit @bmj_latest.

Objectives
To assess the impact of in utero co-exposure to psychotropic medications and opioids on the incidence and severity of neonatal drug withdrawal.

Design
Observational cohort study.

Setting
Nationwide sample of pregnancies in publicly insured women in the US, nested in the Medicaid Analytic eXtract (2000-10).

Participants
201 275 pregnant women with public insurance who were exposed to opioids around the time of delivery and their liveborn infants.

Interventions
In utero exposure to psychotropic medications, in particular antidepressants, atypical antipsychotics, benzodiazepines, gabapentin, and non-benzodiazepine hypnotics (Z drugs), with prescriptions filled within the same time window as prescriptions for opioids.

Main outcome measure
Diagnosis of neonatal drug withdrawal in infants exposed in utero to opioids and psychotropic medications compared with opioids alone.

Results
The absolute risk for neonatal drug withdrawal ranged from 1.0% in infants exposed in utero to prescription opioids alone to 11.4% for those exposed to opioids co-prescribed with gabapentin. Among neonates exposed in utero to prescription opioids, the relative risk adjusted for propensity score was 1.34 (95% confidence interval 1.22 to 1.47) with concomitant exposure to antidepressants, 1.49 (1.35 to 1.63) with benzodiazepines, 1.61 (1.26 to 2.06) with gabapentin, 1.20 (0.95 to 1.51) with antipsychotics, and 1.01 (0.88 to 1.15) with Z drugs. In utero exposure to two or more psychotropic medications along with opioids was associated with a twofold increased risk of withdrawal (2.05, 1.77 to 2.37). The severity of the withdrawal seemed increased in neonates exposed to both opioids and psychotropic medications compared with opioids alone.

Conclusions
During pregnancy, the use of psychotropic medications in addition to prescription opioids is common, despite a lack of safety data. The current findings suggest that these drugs could further increase the risk and severity of neonatal drug withdrawal.

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.