Antibiotics, PPIs/H2RAs increase obesity and allergy in kids

A couple of articles came out recently on the long-term adverse effects of early childhood use of antibiotics and acid suppression. 

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The 1^st looked at their  relationship with childhood obesity (see antibiotics kids obesity gutmicrobiota2018 in dropbox, or doi. org/ 10. 1136/ gutjnl- 2017- 314971).

Details:

--333 353 children from a cohort study of the US Military Health System database of TRICARE beneficiaries, born from 2006 -2013, who were exposed to prescription antibiotics, histamine-2 receptor antagonists (H2RAs), or to proton pump inhibitors (PPIs) in the 1^st 2 years of life

--241 502 (72.4%) children got an antibiotic, 39 488 (11.8%) an H2RA and 11 089 (3.3%) a PPI

-- there were a lot of co-prescriptions: 3700 received antibiotics and PPIs, 26 695 antibiotics and H2RAs, 877 PPIs and H2RAs, and 5868 were prescribed all three medications

-- obesity was defined as BMI greater than or equal to 95^th percentile for age and sex (they chose obesity as the target, as opposed to overweight, since previous studies have shown that obesity is a better marker of long-term health risk)

-- age BMI  last measured = 4 yo, 48% female, 26% had Cesarean section

-- Individual classes of antibiotics included penicillins, beta-lactam penicillins, cephalosporins, sulfonamides and macrolides

Results:

-- 46 993 (14.1%) developed obesity: 11% in kids not exposed to any of the study medications

-- antibiotic prescriptions were associated with a 26% increased risk of obesity, HR 1.26 (1.23 to 1.28), regardless of antibiotic class, and this increased with each additional class of antibiotic prescribed.

    -- For specific antibiotic classes, adjusted for Cesarean section, sex, other medication exposures:

        -- beta-lactam penicillin (72 809 exposed): 7% increase, HR 1.07 (1.04-1.09)

        -- penicillin (201 293 exposed): 11% increase, HR 1.11 (1.09-1.13)

        -- cephalosporin (83 207 exposed): 3% increase, HR 1.03 (1.01-1.06)

        -- sulfonamides (27 305 exposed): males 5% increase, HR 1.05 (1.01-1.10); females 19% increase, HR 1.19 (1.14-1.24)

        -- macrolides (84 578 exposed): 12% increase, HR 1.12 (1.10-1.15)

        -- other antibiotics (6052 exposed to fluoroquinolones, lincosamides, doxycycline, vancomycin, or linezolid): 24% increase, HR 1.24 (1.17-1.32)

--H2RA and PPI prescriptions were also associated with obesity, with an increasing association for each 30-day supply prescribed.

    -- PPI: 2% increase for each 30 day exposure, HR 1.02 (1.01-03)

    --H2RA: 1% increase for each 30 day exposure, HR 1.01 (1.004-1.02), though this increase was specifically in males

--the HR increased with exposure to each additional medication group prescribed, as compared to no medications:

    -- one medication: 21% increase, HR 1.21 (1.18-1.24)

    -- 2 medications: 31% increase, HR 1.31 (1.26-1.35)

    -- 3 medications: 42% increase, HR 1.42 (1.33 1.51)

-- review of their graph showed that the percent of obesity in those on antibiotics/acid suppressants was about 12% at age 4, but then increased to about 25% by age 8, and there was a consistent increased risk as the number of drug groups of meds given increased

-- they also found that those born by Cesarean section, as well as males, had an increased risk of developing obesity

Commentary:

-- prenatal, perinatal, and postnatal factors can affect the composition of the infants' intestinal microbiomes. This microbiome becomes more taxonomically diverse, reflecting the mature adult microbiome, within the 1^st 2 years of life, and is relatively stable, but susceptible to changes associated with certain diseases and exposures.

-- In particular, antibiotics and gastric acid suppressants do cause significant changes in the microbiome (see list of relevant prior blogs at end)

-- also, kids born by Cesarean section have an increased risk of obesity, potentially because of changes in the infant GI microbiome (eg, by bypassing exposure to the maternal vaginal microbiome). Though this sometimes may be confounded by the use of antibiotic prophylaxis prior to Cesarean deliveries

-- this was the largest retrospective study, though other studies have also found a relationship between antibiotic use during the first 6 months of life and weight; one found an increased risk of overweight children specifically in mothers with normal weight (in this study, there was no association with mothers who were overweight or obese, perhaps mitigating the role of genetic factors: see Ajslev TA Intl J Obesity 2011; 35: 522, or antibiotics overwt kids jintobesity 2011 in dropbox).

-- other changes in the gut microbiome are associated with obesity (see blogs at end), as farmers have learned in feeding antibiotics to their livestock

-- other studies have also found that acid suppressive medications decrease microbiome bacterial diversity and increase potentially pathogenic bacteria

-- twin studies have suggested that obesity in one twin is associated with a significant reduction in GI microbiome bacterial diversity

    -- in addition, the study authors note that acid suppressive medications “continue to be prescribed at high rates in children less than 1-year-old, despite limited evidence to support any clinically significant benefit”

-- this was a large retrospective study, and therefore cannot imply causality. Important information was missing in terms of parental socioeconomic status (though they did find that there was more obesity in kids born to junior and senior enlisted service members as compared to officers, with the lower rank of the former being a proxy for socioeconomic status). There is no information on the specifics of diet, smoking, breast-feeding, or medical comorbidities as well. The medications were only assessed by prescriptions given and not what medications were actually taken. Also no data on inpatient medication exposures.

-- One positive of the study is that there is universal access to health care in the military, decreasing the likelihood of the bias from unequal access (oh, that the rest of us would be so lucky to have universal access…)

Another article from the same group found an association between the use of acid suppressive medications or antibiotics during the 1^st 6 months of life and increased allergic diseases in early childhood (see antibiotics kids allergic dz jamaped2018 in dropbox, or doi:10.1001/jamapediatrics.2018.0315) . In brief,

Details:

--395 215 children of whom 60 209 (7.6%) got H2RA, 13 687 (1.7%) a PPI, and 131 708 (16.6%) an antibiotic during the first 6 months of life

--followed a median of 4.6 years

Results:

For acid suppressant medications, HRs (adjusted for Cesarian delivery, sex, the other drug classes):

--Food allergy

    --H2RAs: HR 2.18 (2.04-2.33)

    --PPIs: HR 2.59 (2.25-3.00)

--medication allergy:

    -- H2RAs: HR 1.70 (1.60-1.80)

    -- PPIs: HR 1.84 (1.56-2.17)

--anaphylaxis:

    -- H2RAs: HR 1.51(1.38-1.66)

    -- PPIs: HR 1.45 (1.22-1.73)

--allergic rhinitis

    -- H2RAs: HR 1.50 (1.46-1.54)

    -- PPIs: HR 1.44 (1.36-1.52)

--asthma

    -- H2RAs: HR 1.25 (1.21-1.29)

    -- PPIs: HR 1.41 (1.31-1.52)

For antibiotics in the 1^st 6 months of life:

    --asthma: HR 2.09 (2.05-2.13)

    --allergic rhinitis: HR 1.75 (1.72-1.78)

    --anaphylaxis: HR 1.51(1.38-1.66)

    --allergic conjunctivitis: HR 1.42 (1.34-1.50)

Commentary:

--the association of antibiotics and acid suppressants with allergic symptoms is quite impressive, with quite high hazard ratios as noted above. 

--several of the blogs below go into other studies confirming a relationship; some of review the overuse of antibiotics, others the "hygiene hypothesis" whereby asthma and some other allergic problems are associated with lack of exposure to certain microorganisms/parasites.

So, these two articles reinforce several points from prior articles:

-- there clearly are potent effects from antibiotics and acid suppressant medications on the microbiome and that these may well have long-term profound health effects, many of them adverse

-- this article, yet again, brings up the limitations of our conceptual models of disease, ones we all develop based on our experience and knowledge, and morph as we accumulate more of these (these models are the necessary consequence of integrating huge amounts of information into a seemingly coherent and applicable picture). But, these models also may limit (or confine) our need to challenge them, at least until we reach a threshold of new information leading us to totally change our models (eg: old model: bacteria are bad; new model: some bacteria are good)

    --Western medicine in general focuses on short-term benefits over the unknown potential long-term risks. for example, if there is GERD or an infection (or most chronic conditions), we tend to give a med, knowing that this condition is likely to respond

    --though antibiotics certainly have a role in treating serious infections, we should always be very circumspect in using them judiciously, only when clearly appropriate, and using those with the narrowest, most targeted spectrum of activity (and, therefore, the fewest overall adverse effects in the body, and specifically on the microbiome). Or, as another example, to me it makes sense to use GLP-1 agonists in diabetics (which seem very targeted) vs DPP-4 inhibitors, which increase GLP-1 levels but also poison several other enzyme systems.

    --and in general we are all better off if we can make adjustments in our lives instead of using medications which typically are not highly targeted and often affect many other parts of our body (creating their adverse effects). These lifestyle changes include diet, exercise, weight loss when appropriate, stopping smoking/drinking, decreasing stress, etc.  And these benefits often have collateral positive effects (diet and exercise may benefit blood pressure, but also decrease cancer risk/dementia/….)

http://gmodestmedblogs.blogspot.com/2018/04/microbiome-change-and-weight-loss.html , which notes that positive microbiome changes is associated with weight loss, and refers to articles of adverse microbiomes being associated with weight gain

http://gmodestmedblogs.blogspot.com/2017/01/artificial-sweeteners-microbiome1.html  , finding that artificial sweeteners are associated with glucose intolerance, weight gain and associated microbiome changes (where in mice, transplanting the altered microbiome from those given these sweeteners into normal germ-free mice recreates the development of glucose intolerance)

http://gmodestmedblogs.blogspot.com/2017/01/microbiome2-overview.html notes the broad effects of the microbiome on human health

http://gmodestmedblogs.blogspot.com/2015/10/gi-microbiome-in-little-kids-and.html another article on the association of microbiome changes in little kids and development of asthma

http://gmodestmedblogs.blogspot.com/2016/08/microbiome-and-type-1-diabetes-etc.html  looks at studies on the “hygiene hypothesis” of allergy/asthma, finding that the method of farming affects the incidence of allergic problems, in Hutterites of South Dakota/Amish and farmers in North Karelia Finland

http://gmodestmedblogs.blogspot.com/2016/01/antibiotic-overprescribing-and-acute.html for several studies on antibiotic overprescribing

geoff​

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