Gideon Koren

Selective Serotonin Reuptake Inhibitors during Pregnancy: Do We Have Now More Definite Answers Related to Prenatal Exposure?

Despite extensive studies, there still seems to be uncertainty as to the possible reproductive risk of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs) in pregnancy. We, therefore, assess the current data on the risk/benefit of SSRI use in pregnancy. As the neurodevelopmental effects of SSRIs are discussed in another paper in this issue, we will not address the possible neurodevelopmental effects. Special emphasis is given to the newer, large population‐based studies. Most studies have shown that the overall risk of major malformations is similar to that in unexposed children, except for some small increased risk for cardiac anomalies. Persistent pulmonary hypertension of the newborn has also been described with a low absolute risk of <1%, less than twice that observed in nonexposed newborns. Poor neonatal adaptation was described in up to 25% of exposed neonates. However, newer population‐based studies have also shown similarly high rates among offspring of women with untreated depression. There is a higher risk for psychiatric problems possibly related to the maternal psychiatric disease for which SSRIs were prescribed. Judging from the new population registry‐based studies with comparison to disease controls, there seems to be no demonstrable increase in the rate of major anomalies, prematurity, small for gestational age, or miscarriage. Therefore, the risk associated with treatment discontinuation (e.g., higher frequency of relapse, and postpartum depression) appears to outweigh the fetal and neonatal risks of maternal treatment. Thus, following appropriate explanation regarding possible risks, treatment should continue during pregnancy with minimal effective doses. Birth Defects Research 109:898–908, 2017.

Selective serotonin reuptake inhibitor use in pregnant women; pharmacogenetics, drug-drug interactions and adverse effects

ABSTRACT Introduction: Possible negative effects of selective serotonin reuptake inhibitors (SSRIs) in pregnancy relate to congenital anomalies, negative perinatal events and neurodevelopmental outcome. Many studies are confounded by the underlying maternal disease and by pharmacogenetic and pharmacokinetic differences of these drugs. Areas covered: The possible interactions of SSRIs and serotonin and norepinephrine reuptake inhibitors with other drugs and the known effects of SSRIs on congenital anomalies, perinatal and neurodevelopmental outcome. Expert opinion: SSRIs should be given with caution when combined with other drugs that are metabolized by cytochrome P450 enzymes. SSRIs apparently increase the rate of severe cardiac malformations, induce neonatal adaptation problems in up to 30% of the offspring, increase the rate of persistent pulmonary hypertension of the newborn and possibly slightly increase the rate of prematurity and low birth weight. Most neurodevelopmental follow up studies did not find significant cognitive impairments except some transient gross motor delay, slight impairment of language abilities and possibly behavioral changes. The literature on the possible association of SSRIs with autism spectrum disorder is inconsistent; if an association exists, it is apparently throughout pregnancy. The risk associated with treatment discontinuation seems to outweigh the risk of treatment, as severe maternal depression may negatively affect the child’s development. If needed, treatment should continue in pregnancy with the minimal effective dose.

Machine learning of big data in gaining insight into successful treatment of hypertension

Despite effective medications, rates of uncontrolled hypertension remain high. Treatment protocols are largely based on randomized trials and meta‐analyses of these studies. The objective of this study was to test the utility of machine learning of big data in gaining insight into the treatment of hypertension. We applied machine learning techniques such as decision trees and neural networks, to identify determinants that contribute to the success of hypertension drug treatment on a large set of patients. We also identified concomitant drugs not considered to have antihypertensive activity, which may contribute to lowering blood pressure (BP) control. Higher initial BP predicts lower success rates. Among the medication options and their combinations, treatment with beta blockers appears to be more commonly effective, which is not reflected in contemporary guidelines. Among numerous concomitant drugs taken by hypertensive patients, proton pump inhibitors (PPIs), and HMG CO‐A reductase inhibitors (statins) significantly improved the success rate of hypertension. In conclusions, machine learning of big data is a novel method to identify effective antihypertensive therapy and for repurposing medications already on the market for new indications. Our results related to beta blockers, stemming from machine learning of a large and diverse set of big data, in contrast to the much narrower criteria for randomized clinic trials (RCTs), should be corroborated and affirmed by other methods, as they hold potential promise for an old class of drugs which may be presently underutilized. These previously unrecognized effects of PPIs and statins have been very recently identified as effective in lowering BP in preliminary clinical observations, lending credibility to our big data results.

Personal clinical history predicts antibiotic resistance in urinary tract infections

The prevalence of antibiotic resistance in urinary tract infections (UTIs) often renders the prescribed antimicrobial treatment ineffective, highlighting the need for personalized prediction of resistance at time of care. Here, crossing a 10-year longitudinal dataset of over 700,000 community-acquired UTIs with over 6,000,000 personally-linked records of antibiotic purchases, we show that the resistance profile of infections can be predicted based on patient-specific demographics and clinical history. Age, gender, and retirement home residence had strong, yet differential and even non-monotonic, associations with resistance to different antibiotics. Resistance profiles were also associated with the patient’s records of past urine samples and antibiotic usage, with these associations persisting for months and even longer than a year. Drug usage selected specifically for its own cognate resistance, which led indirectly, through genetic linkage, also to resistance to other, even mechanistically unrelated, drugs. Applying machine learning models, these association patterns allowed good personalized predictions of resistance, which could inform and better optimize empirical prescription of antibiotics.

Poor Long-Term Adherence to Secondary Penicillin Prophylaxis in Children with History of Rheumatic Fever

OBJECTIVEnRecurrent episodes of acute rheumatic fever may contribute to the development or worsening of rheumatic heart disease. Secondary penicillin prophylaxis (SPP) has been found to significantly reduce the incidence of rheumatic heart disease. This study sought to evaluate adherence to oral and intramuscular SPP in pediatric patients with rheumatic fever using real-world data spanning 10 years.nnnMETHODSnThe study population included patients <18 years old insured by a 2.1-million-member health maintenance organization in Israel who were diagnosed with acute rheumatic fever between 1/1996 and 5/2015 and had purchased at least one monthly dose of oral or intramuscular penicillin by prescription. The mean proportion of days covered by SPP was calculated. The endpoint of the retrospective follow-up for therapy discontinuation was leaving the health maintenance organization, death, age 18 years, or end of follow-up.nnnRESULTSnThe cohort included 842 children: 734 treated with oral penicillin and 108 with intramuscular penicillin. The respective mean (SD) ages of the two groups at diagnosis were 8.6 (3.7) years and 10.9 (3.2) years, and the median (interquartile range) proportions of days covered by SPP were 8% (2%-33%) and 10% (3%-28%). Overall, the number of days covered decreased exponentially from 103 days in the first year of therapy to 20 days in the tenth year of follow-up.nnnCONCLUSIONnAdherence to SPP for rheumatic fever is poor. This renders this mode of long term prophylaxis futile. Although the IM route has been previously shown to be more effective, the oral route was more extensively used.

Clinical implications of selective serotonin reuptake inhibitors-selective serotonin norepinephrine reuptake inhibitors pharmacogenetics during pregnancy and lactation

Depression occurs during pregnancy in 3.9-12.8% of the women. The different serotonin reuptake inhibitors (SRIs) are metabolized in the liver by CYP450 enzymes. CYP2D6 metabolizes paroxetine, fluoxetine, duloxetine and venlafaxine, while CYP2C19 deactivates citalopram and escitalopram. Polymorphisms in these enzymes change the metabolic clearance and levels of these drugs. Higher metabolism of most SRIs in late pregnancy results in lower maternal levels, which could result in decreased efficacy. Very few studies have addressed the potential interaction between pregnancy-induced increase in 2D6 metabolism and specific genotypes of the women, suggesting that ultra-rapid and extensive metabolizers exhibit lower serum concentrations than the other slower genotypes. Preliminary studies suggest that some genotypes of the serotonin transporter (SLC6A4) promoter are associated and are linked to adverse effects in infants with SRI exposure during pregnancy. Presently, there are no clear clinical implications of SRI pharmacogenetic status in pregnancy and lactation. In late pregnancy, women may exhibit lower steady state concentrations of these drugs, necessitating increased doses but these are presently guided clinically and not through genotyping. Much more work is needed to define whether SRI genotype has clinical implications and predictive value for either mother or offspring.

Enhancing Earlier Diagnosis of Colorectal Cancer by Algorithmic Analysis of Trends in Complete Blood Counts

In this chapter we describe the evolution of a novel method for the detection of colorectal cancer, by analysis of changes in complete blood counts. In subjects who have not undergone screening with FOBT or colonoscopy, we document the ability to utilize a novel algorithm which calculates the risk of colorectal cancer from routine complete blood counts measurements, long before anemia is apparent. The results show values of sensitivity and specificity equivalent to, and even superior to the routine use of occult blood tests. This has created a unique opportunity to diagnose colorectal cancer cases before symptoms have emerged, when the disease is more likely to be curable. Large prospective studies are needed in different populations to validate these results.

High risk for neural tube defects; the role of arsenic in drinking water and rice in Asia

BACKGROUNDnNeural tube defects (NTDs) affect >300,000 children annually worldwide. The incidence of NTDs in Northern India (7.7/1000), is tenfold higher than in the US (0.7/1000). Higher rates were previously reported in Northern China. The causes of these trends have not been elucidated. Arsenic is a teratogen shown in animals to induce NTDs. The main potential sources for environmental arsenic exposure, groundwater and rice as a staple food, are high in India and China.nnnOBJECTIVESnTo discuss the possible association between high environmental arsenic exposure through drinking water and rice with the high NTDs rates in these regions.nnnDISCUSSIONnArsenic contamination of groundwater is the main source of environmental arsenic exposure. The locations of toxic arsenic regions in China and India correspond in most cases to the northern regions where the NTDs rates were high. Rice, the staple food in India and China, can absorb up to 10 times more arsenic than other crops, such as wheat and might further increase arsenic exposure.nnnCONCLUSIONSnWe hypothesize that this NTD-arsenic in drinking water and rice association may explain why these areas in the northern regions of both countries have the highest incidence of NTDs. If proven true, this has major public health implications.

The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplementation during pregnancy: A nested case–control study

BACKGROUND AND RATIONALEnSeveral studies have suggested that the incidence of infantile hypertrophic pyloric stenosis (IHPS) has decreased in recent decades. This decrement is controversial and not fully explained. Concurrently, there has been a major increase in folic acid consumption by pregnant women to prevent neural tube defects. We aimed to describe IHPS incidence in Israel in recent years and to assess its potential association with folic acid consumption.nnnMETHODSnUsing the electronic medical database of a 2.1 million member health organization in Israel, we identified all cases (nu202f=u202f1899) of IHPS occurring between 1999 and 2015. Cases were individually matched with up to 5 controls (nu202f=u202f7350) by birth date, sex, and region. Odds ratios and 95% confidence intervals by tertiles of cumulative dose of supplemented folic acid between three months prior to pregnancy and up to birth of index child were calculated using conditional logistic regression.nnnRESULTSnDuring the study period IHPS incidence declined from 4.3 in 1999 to 2.1 per 1000 live births in 2015(pu202f<u202f0.0001). No significant (pu202f=u202f0.81) association was observed between folic acid intake during pregnancy and risk of IHPS incidence. Preterm birth and infants use of macrolides during first 3 postnatal months were significantly (pu202f<u202f0.01) associated with increased risk of IHPS.nnnCONCLUSIONSnSimilar to other countries, IHPS incidence in Israel has decreased in recent years. The decrement cannot be explained by increased use of folic acid.nnnTYPE OF STUDYnCase Control Study.nnnLEVEL OF EVIDENCEnLevel III.nnnSUMMARYnUsing linkage to a large electronic patient database, this study investigated the association between the decrease in infantile hypertrophic pyloric stenosis and maternal exposure to folic acid during pregnancy.

Environmental exposures and fetal growth: the Haifa pregnancy cohort study

BackgroundThe developing fetus is susceptible to environmental insults. Studying the effects of environmental exposures on fetal growth is essential for understanding the causal pathway between prenatal exposures and pregnancy outcomes. Here we describe the Haifa Pregnancy Cohort Study (HPCS) and discuss challenges and opportunities in applying “big data” paradigm.MethodsMaccabi Healthcare Services (MHS), is the second largest Israeli health maintenance organization (HMO) providing care services to two million beneficiaries. The HPCS cohort potentially includes ~750,000 newborns born between 1998 and 2017. We will estimate daily exposures to air pollutants, temperature and greenness, using satellite-based data and models. We hypothesize that residents of Haifa have higher exposures to environmental pollutants and that in pregnant women this higher exposure is associated with poorer fetal growth. We will evaluate outcomes such as birth-weight, head-circumference and gestational age at birth. We will adjust for pregnancy complications such as pre-eclampsia and gestational diabetes and parental variables, such as maternal weight, age and smoking habits as potential confounders. In addition, we will conduct a multi-tiered field study, nested within this population, among 150 pregnant women residing in two geographical regions-one in the polluted Haifa area, and one in a relatively unpolluted area in central Israel. Blood and urinary samples will be collected, as well as personal and indoor exposure to air pollution.DiscussionEvaluating environmental exposures of pregnant women and assessing in utero growth over the course of the pregnancy during different exposure windows, is of great scientific and public health interest. Recent advances in data collection and analysis pose great promise to provide insights into contribution of environment to the health of the developing fetus, but also pose major challenges and pitfalls, such as data management, proper statistical framework and integration of data in the population-based study and selectiveness in the nested field study. Yet the continuing follow-up of the study cohort, integrating data from different services, health-promotion, and eventually, application later in real life of our main promises. Our study aims to meet these challenges and to provide evidence of the environmental exposures associated with fetal growth.