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.

Assessment of the biodegradability of selected sulfa drugs in two polluted rivers in Poland

Effects of seasonal variations, accidental contamination, turbidity and salinity

Up to 90% of consumed drugs enter the environment. This may have negative effects on wildlife, especially when the drugs take long periods to break down. This study assessed the breakdown of sulphonamides — a class of antibacterials — in samples from two rivers in Poland. The results showed that sulphamethoxazole, a common veterinary antibiotic, was the most persistent and that various factors inhibit degradation, including low temperatures, heavy metal pollution and low pH.

Highlights

  • Biodegradation rate of sulfonamides (SNs) in river water is variable.
  • Biodegradability of SNs depends on the growing season.
  • High concentration of salts in river water inhibits the SNs biodegradation.
  • Sulfamethoxazole could be classified as Persistent Organic Pollutant (POP).

Abstract

Which factors make drugs persistent? A look at sulphonamides in Polish rivers, Science for Environment Policy, 12 January 2017.

Assessment of the biodegradability of selected sulfa drugs in two polluted rivers in Poland: Effects of seasonal variations, accidental contamination, turbidity and salinity, science direct, August 2016.

Image credit Janusz Nowak.

The aim of our study was to assess the aerobic biodegradation of four selected sulfonamides (sulfanilamide, sulfamethoxazole, sulfadiazine and sulfathiazole) using water samples drawn from highly polluted rivers. Additionally, we aimed to identify the factors that have a significant effect on the process efficiency.

The 19 water samples were collected from Brynica and Czarna Przemsza rivers (in Poland) at the same location at approximately monthly intervals. A characteristic feature of the results is the presence of significant differences between the rates of sulfonamides biodegradation in particular samples.

The sulfonamide most resistant to biodegradation was sulfamethoxazole, whereas sulfathiazole was most biodegradable. Seasonal variations and related microbial population changes had the most significant effects on sulfonamides biodegradation, e.g., the studied process was highly inhibited during wintertime. A decrease in the biodegradation rate in the river water could be caused by an accidental water pollution by industrial wastewater with heavy metals, an increase in salinity and a decrease in pH, and turbidity.

Stibrol

Diethylstilbestrol Injection via Indiamart, India

image of stibrol
DES use for livestock “growth”, weight-gain …

DES was/is still sold under many names including Distilbène®, Stilbetin®, Stilboestrol-Borne®, Benzestrol®, Chlorotrianisene®, Estrobene® and Estrosyn® to name just a few.

Many different companies manufactured and marketed this drug under more than 200 different brand names.

This Stibrol Diethylstilbestrol Injection U.S.P. is sold by Kunj Pharma Private Limited, Chandni Chowk, New Delhi, Delhi, India.

DES Drugs Pictures
DES DiEthylStilbestrol Resources

Patient Education and Chronic Pain

Preventing the abuse of pain medication via proper patient education

As you may know, officials have reported that Ohio is on track to have over 10,000 overdose deaths this year, making the state the epicenter of the United States opioid epidemic. This alarming rate is higher than the total number of overdose deaths for the entire nation in 1990. Couple this with the fact that almost 72% of physicians say they have inadequate knowledge of pain treatment and opioid dependency management, and it becomes clear that something must change in the way our healthcare system approaches pain management.

Over 100 million Americans have chronic or persistent pain, meaning they are most likely being treated with conventional medications, surgery, injection, or physical therapy. What’s troubling is the fact that 75% of people with chronic pain who visited an emergency room reported a desire for information on pain treatment options, but only half reported actually receiving such information. 

This June 2017 infographic – Patient Education and Chronic Pain, by Regis Online health care programs – provides information on different strategies doctors can implement to best educate their patients and gain a better understanding of how pain affects their individual patients.

Enjoy our health infographics album on Flickr.

While 91 people per day die of opioid overdose…

Are drug policies at times exactly the opposite from what science-based policies would look like ?

“We have an opioid epidemic that looks like it’s going to be deadlier than AIDS, but the criminal justice system handles drug addiction in almost exactly opposite of what neuroscience and other behavioral sciences would suggest,”

said Keith Humphreys, a professor of psychiatry and behavioral sciences and one of the leaders of the Stanford Neurosciences Institute’s Neurochoice Big Idea initiative.

Summary

With 1 in 8 deaths globally due to the use of tobacco, alcohol, and other drugs, the director-general of the World Health Organization recently called for more scientifically informed public policies regarding addiction.

In the United States, where an average of 91 people per day die of opioid overdose, a presidential task force is to present, on 27 June, policy recommendations to combat opioid addiction, although the House of Representatives passed an Affordable Care Act repeal bill that would withdraw health insurance from two million people with addictions.

Despite these urgent challenges, research on the brain and its interactions with the environment, which can help policymakers advance more effective and humane policies than some traditional approaches to addiction, has only occasionally been applied in public policy.

Sources and Press Releases

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.

More evidence about Duogynon dramatic side effects

A Scottish biologist examines the damaging effects of the Duogynon pregnancy drug

They were born with an open back, with heart defects and brain damage, shortened or missing limbs, deformed intestines, bladders or genitals. The cause for the malformations, among which hundreds of Germans and Britons born between the beginning of the 1950s and the middle of the 1970s, still today as adults, is given to a former drug of the Berlin pharmacy company Schering.

Mothers had received a drug from their doctors at the beginning of their pregnancy to determine if they really expected a child : named Duogynon in Germany, Primodos in the UK. Their content, a combination based on the female sex hormones gestagen and estrogen, was the same ; it could be swallowed or injected and was able to cause a menstrual bleeding.

If menstruation did not take place despite the hormone shock, the woman was considered pregnant. Urine test strips had not yet prevailed.

For the first time, the serious suspicions that are on the preparations of the past could be systematically examined by independent experts and at the present state of science. Neil Vargesson, professor of biology at the Scottish University of Aberdeen, researched on embryonic malformations for many years. He has worked with a team of his faculty to reproduce the Duogynon, Primodos, active ingredient and has already been tested in the laboratory for zebrafish embryos for its fruit-damaging effects.

“We were able to demonstrate that Primodos actually damages fish embryos, depending on both the stage of embryonic development and its dosage.”

Vargesson told the taz.

The Missing Proof

So far there have been indications, but no evidence for a causal link between the intake of Duogynon and the malformations. On the one reason being that clinical studies from the 1950s – when Schering brought the drug on the market – were not carried out in a way from which evidence could be derived. Another reason being that Duogynon has not been produced anymore for almost 40 years. Schering was taken over by Bayer AG in 2006, and they categorically excludes Duogynonas the cause of embryonic malformations“.

“The exact mechanism of action of Primodos / Duogynon on zebrafish is not yet known, but there are indications that the developmental stage of the blood vessels and the nerves play a key role in the nature and extent of embryonic damage”

said Vargesson.

“We could see enlarged hearts, open backs, damaged blood cells and damage to the nervous system. It is not just premature, but dubious, from these first results, to draw conclusions about possible damage to human embryos, I estimate that we will have to research at least three to five years in the lab and in very different animals”

said the scientist.

“Zebrafish, whose embryonic development is similar to those of higher vertebrate animals, and which develop completely and very quickly outside the mother’s body, are an important model organism for biologists. However, further experiments on rodents, fish and also sheep are essential in order to make assured statements. Research on pregnant women is prohibited for ethical reasons”

Vargesson said.

“You have to emphasize again and again that there is no such a thing as a natural malformation rate. Three per cent of all newborns are born with malformations, without apparent causes.”

added Vargesson.

New Hopes

The research approach of Neil Vargesson brings nevertheless new, great hope for the alleged Duogynon victims who have so far vainly struggled in the United Kingdom and in Germany as self-help groups for the recognition of their suffering by governments and parliaments and for a compensation fund based on the model of the foundation for contergan victims. Whether and how fast reliable results will be available, however, is also a matter of financing. The British parliament, which has been examining medical and scientific findings on Duogynon for one and a half years, has recently invited the Scottish biologists to a meeting. There were no concrete financial commitments so far.

“It’s also unusual to want to research a drug that is not there. My attention for Duogynon, came about by chance, almost as a by-product of my actual research interest.”

admited Vargesson.

Contergan was recommended to pregnant women in the 1960s against morning sickness and triggered one of the biggest drug scandal of the past century. The question of how the drug, can be used without harming unborns in the mother’s womb has been the focus for many years. Contergan is still of great therapeutic interest and use, said Vargesson, for the treatment of leprosy as well as certain types of cancer of the plasmatic cells.

Contergan Open Questions

​​Despite years of intensive research, it is still unclear as what exact building blocks of Contergan drug cause the malformations.

Vargesson does research on this, since he wants to know which molecules he has to forego completely, which he could change as well as which he should exchange, in order to make the medium safe and yet medically usable. Vargesson has recently patented several promising varieties of a slightly modified conteric.

Vargesson is optimistic:

“When I heard that another drug might also cause malformations in unborn babies, I had to look at the matter more closely.
Certain substances that were present in Duogynon are still found today in modified form in antibabies. There should be an interest in exploring possible undesirable side effects.
Whether it goes, and how, will depend above all on financial decisions.”

  • Original press release : FEHLBILDUNGEN DURCH DUOGYNON, on taz, 2.6.2017.
  • Translation via Google.
  • Image credit taz.

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.

Drugs stalled at FDA far more likely to have unpublished trials than licensed ones: 46% vs 10%

Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review

May 2017 Study Abstract

Objective
To evaluate nonpublication rates among trials of new successful and unsuccessful neurological drugs – A Systematic Review.

Methods
‘Licensed’ drugs consisted of all novel agents receiving FDA licensure 2005 to 2012 inclusive in seven neurological disorders. ‘Stalled’ drugs included all experimental agents tested in the same domains that had at least one completed phase III trial in the same timeframe but failed to receive FDA approval. Trials of these drugs were included in our sample if their primary outcome collection occurred before October 1, 2010. We determined the publication status of eligible trials using searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, sponsor websites, and direct electronic query of trial contacts and sponsors. The primary outcome was time to journal publication (or results reporting in other media) after study completion.

Results
The adjusted hazard ratio for publication was 1.79 (95% confidence interval 1.20 to 2.67) in favour of licensed drugs. Based on the criteria for nonpublication in this report, 14,092 and 33,882 volunteers participated in unpublished trials of licensed and stalled neurological drugs, respectively. Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively.

Interpretation
Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.

Nearly one-third of new drugs have safety concerns after FDA approval

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

How often are safety concerns raised about a drug after it’s been approved by the FDA?.

Nicholas Downing, MD, of the Department of Medicine at Brigham and Women’s Hospital, and colleagues have found that for drugs approved between 2001 and 2010, nearly 1 in 3 had a postmarket safety event.

The team defines postmarket safety events as those that lead to either withdrawal from the market due to safety concerns, a boxed warning or FDA issuance of a safety communication.

They found that of 222 novel therapeutics the FDA approved during this time period, three were withdrawn, 61 received boxed warnings and 59 elicited safety communications.

Key Points

Question
Are characteristics of novel therapeutics known at the time of US Food and Drug Administration (FDA) approval associated with postmarket safety events, including withdrawal, boxed warnings, and safety communications?

Findings
Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 (32.0%) were affected by a postmarket safety event. Postmarket safety events were more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval.

Meaning
Postmarket safety events are common after FDA approval, highlighting the importance of continuous monitoring of the safety of novel therapeutics throughout their life cycle.

2017 Study Abstract

Importance
Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

Objectives
To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.

Design and Setting
Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

Exposures
Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.

Main Outcomes and Measures
A composite of

  1. withdrawals due to safety concerns,
  2. FDA issuance of incremental boxed warnings added in the postmarket period,
  3. and FDA issuance of safety communications.

Results
From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).

Conclusions and Relevance
Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.