Metformin vs. Insulin Treatment in Gestational Diabetes: Developmental Outcomes

Gestational diabetes has been primarily treated with insulin, which does not cross the placental barrier. However, the use of metformin, which does cross the placental barrier, to treat gestational diabetes is becoming increasingly more common. The researchers in this study aim to examine the offspring of these women treated with either insulin or metformin during their pregnancy, and compare the safety of these two treatment methods.

The study design was a prospective follow-up study, involving children whose mothers had been treated for gestational diabetes with either metformin for gestational diabetes. In the original trial, 751 women from either Australia or New Zealand were participants who were randomly assigned to either insulin or metformin to treat their gestational diabetes. 373 of these women were assigned to take metformin, while 378 were assignment to take insulin. The mothers in this study had consented to be contacted for follow-up after their child’s second birthday. The final number of children included in this follow-up study was 211. The children in the study were evaluated using the Bayley Scales of Infant Development (BSID-II), which consists of three different elements: the Mental Developmental Index (MDI), the Psychomotor Developmental Index and the Behaviour Rating Scale (BRS).

The results of this study concluded that there was no significant difference between the developmental outcomes of children whose mothers had been treated with insulin vs. those whose mothers had been treated with metformin for gestational diabetes. The researchers in the study acknowledge that long-term developmental outcomes have not been studied, and should be in order to get a better idea of the long-term safety of these medications for gestational diabetes.

This study is important because it offers a possible different treatment option for women with gestational diabetes. People typically don’t enjoy giving themselves injections, so with metformin as an option, they won’t have to deal with the needles associated with insulin.

Wouldes TA, Battin M, Coat S, Rush EC, et al. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch Dis Child Fetal Neonatal Ed. doi:10.1136/archdischild-2015-309602. (Published 24 February 2016).

Comparison of Incretin Based Drugs and Sulfonylureas and the Risk of Pancreatic Cancer in Diabetic Patients

Incretin based medications is an umbrella term for some newer antidiabetic agents including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists. These medications are approved to treat type 2 diabetes. Researchers in this study want to know if these medications are associated with an increased risk in pancreatic cancer compared to the sulfonylurea drug class. This study was conducted as a retrospective cohort study involving data from multiple countries. The researchers looked at 972,384 patients who were just beginning non-insulin antidiabetic therapy with the aforementioned medications. During the follow-up period, which ranged from 1.3 years to 2.8 years, 1221 patients were diagnosed with pancreatic cancer. The results concluded that there was no significant increased risk of pancreatic in incretin based drugs compared with sulfonylureas.

While this study was interesting, I think that more long term effects, included the incidence of pancreatic, should be studied in incretin based medications. This is still a relatively newer group of medications, so long term studies are necessary to determine their overall safety compared to other medications that have been used for longer periods of time. However, this study was definitely a great first step in determining the safety of incretin medications.

Azoulay L, Filion KB, Platt RW, et al. Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ. 2016;352:i581. (Published 17 February 2016). 


Proton Pump Inhibitors May Increase the Risk of Dementia in the Elderly Population

Proton pump inhibitors (PPIs) are a class of medications that are commonly used in the elderly population to remedy gastrointestinal problems. This prospective cohort study in German  looks at the possible association between these medications and dementia. For the study, the inclusion criteria was at least 75 years old and no diagnosis of dementia. They defined the use of a PPI as having one prescription per quarter of the following medications: omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole. Patients who only used PPIs occasionally were not included in the study.  This study also worked to analyze other factors that could contribute to the risk of dementia. Some of these factors were gender, the use of multiple prescription medications, stroke, and comorbid diagnosis with conditions such as depression, heart disease, or diabetes. The data analyzed was from 2004 – 2011.

A total of 73,679 people who met the inclusion criteria were analyzed in the study. The results of the study shows that the use of PPIs in the elderly is associated with an increased risk of dementia.  77.9% of patients who took PPIs regularly during this study had a “significantly increased risk of incident dementia”.  The study results also show that males had a higher risk of dementia with use of PPIs. The comorbid diagnosis of depression and stroke had a higher risk of dementia with the use of PPIs. Comorbid diagnosis with diabetes and the use of other prescription medication with PPIs showed a very slight increased risk of dementia. Patients using PPIs with heart disease actually had a slight decreased risk in developing dementia.

This study is important because PPIs are such a commonly used medication class, especially in the elderly population. If these medications are contributing to the onset of dementia, consideration should be given to avoid prescribing this medication in the elderly population. Additionally, this study could eventually lead to a clearer understanding of how disease states such as dementia or Alzheimer’s develop in the first place. From there, we could focus on developing medications that could help to prevent and treat these terrible conditions.

Gomm W, von Holt K, Thomé F, et al. Association of Proton Pump Inhibitors With Risk of Dementia. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791. (Published 15 February 2016).

Renin Angiotensin System Blockers are Not a Superior Class of Antihypertensives in Diabetic Patients

Renin angiotensin systems (RAS) blockers are any class of medication that interferes with the renin-angiotensin system. The two major classes of medications that target this system are angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARB). Previous guidelines suggested that RAS blockers were to be used as the first line treatment of hypertension in diabetic patients with impaired cardiovascular or renal function. These guidelines were based on clinical trials involving placebos. The goal of this meta-analysis study was to investigate these claim by comparing the use of RAS blockers to other antihypertensives in diabetic patients. The researchers used databases to search for research studies that met the following qualifications: a controlled randomized trial involving RAS blockers and another antihypertensive medication in patients with hyperglycemia or diabetes, and a sample size of 100 or more participants with a follow-up conducted at least a year later. Then, they established a set of outcomes for the participants in the studies. These included: death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, end stage renal disease, and major adverse drug effects.

Nineteen trials were analyzed, involving a total number of 25,414 participants with diabetes. Fifteen of the trials involved a comparison between RAS blockers and calcium channel blockers (CCBs), three involved a comparison between RAS blockers and a thiazide diuretic, and two involved comparison between RAS blockers and a beta-blocker. The RAS blocker of choice in fourteen of the studies was an ACE inhibitor, and in six of the studies it was an ARB. The results shows that RAS blockers had a  similar risk of death and similar outcomes as each of the other antihypertensive medications. One of the significant differences was that the use of RAS blockers has a decreased risk in heart failure compared to CCBs. Despite this observation, all other outcomes were associated with similar risks of adverse outcomes, whether the drugs used was a RAS blocker or another antihypertensive medication. This study concluded that the risk of death in diabetic patients using RAS blockers was roughly the same as those using other antihypertensives.

This study could be useful because it shows that these antihypertensive drugs did not have a significant difference in adverse outcomes in patients with diabetes. Therefore, patients can have more a choice in what they want to use to treat their hypertension. This could be especially helpful in low-income populations. Instead of going with a medication that was previously recommended for them based on certain guidelines, they may be able to go with one that has a cheaper copay.

Bangalore S, Fakheri R, Toklu B, et al. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016;352:i438. (Published February 11, 2016).

Surgical-Site Infection Prevention Following a Cesarean Delivery

Birth via cesarean delivery accounted for about one-third of the births in the United States in the year 2013. Although this is a common surgery, cesarean deliveries have a 5 to 12% rate of surgical site infections. The researchers in this study are looking to compare antiseptic agents that are used on the skin to prepare women for cesarean deliveries. Some of the exclusion criteria for this study included allergies to any of the antiseptic agent ingredients or those who have had a skin infection around the operative area. The study included a total of 1,147 female participants who all had very similar baseline characteristics.

The participants for this study were selected randomly to receive either a chlorhexidine-alcohol combination or a iodine-alcohol combination for antiseptic surgical preparation. The women were monitored in the hospital post-Cesarean delivery, and received a follow-up call 30 days after the surgery to determine if there were any complications or symptoms of skin infection. The results of the study showed that surgical-site infections were present in 7.3% of the patients who were treated with the iodine-alcohol combination, while only 4.0% of the patients treated with the chlorhexidine-alcohol combination had been diagnosed with a postoperative surgical site infection. This research concludes that the chlorhexidine-alcohol combination used for preoperative antisepsis had a lower risk of postoperative skin infection.

I found this study to be interesting because I never really thought of antiseptic agents to play a role in whether or not patients have postoperative infections. If more studies are done to determine the safety and efficacy of the chlorhexidine-alcohol combination as a preoperative skin antiseptic agent, then it may become the new standard skin antiseptic used prior to Cesarean deliveries. The more widespread use of this agent may also reduce the number of surgical-site infections, which could possibly reduce the number of re-admittances to the hospital.

Tuuli MG, Liu J, Stout M, et. al A Randomized Trial Comparing Skin Antiseptic Agents at Cesarean Delivery. N Engl J Med. DOI: 10.1056/NEJMoa1511048. (Published 4 February 2016).


Increased Risk of Mortality in Patients Diagnosed with Obsessive-Compulsive Disorder

Obsessive-Compulsive Disorder (OCD) is a mental disorder that is characterized by intrusive thoughts or feelings which are accompanied by certain behaviors in attempt to relieve anxiety. This disorder is very debilitating, so researchers in Denmark set out to find if a diagnosis with OCD had an increased risk of mortality. This prospective cohort study looked at people born in Denmark between January 1, 1955 and November 31, 2006. The study included 3,270,650 people. Of the total population being studied, 10,155 people were diagnosed with OCD. The maximum age for any the cohort member was 57, because the researchers didn’t want to include older adults due to higher instances of mortality among that population. The researchers utilized a “follow-up” period, which began at January 1, 2002 and ended when the subjects either died, moved out of Denmark, or on December 31, 2011. The causes of death were placed into certain categories, such as deaths from physical conditions, deaths from external causes, and deaths from unnatural causes.

During the study follow-up period, 27,236 people died. Of these deaths, 110 of them were people who were diagnosed with OCD. The study also took into account how many of those people had received a comorbid diagnosis of another mental disorder; 82 of the 110 deaths were people with comorbid diagnosis. The results of the study concluded that people with diagnosed OCD had an increased risk of premature death in comparison to people that were not diagnosed with the disorder. Of these deaths, 40% of them were a result of unnatural causes, such as suicides, homicides, or accidents. Additionally, since 82 of the 110 deaths were people with comorbid mental disorder, the study suggests that comorbidity has a strong influence on mortality in people diagnosed with OCD.

I didn’t think the results of this study were very surprising, because the study starts out by saying that there are a number of mental disorders that are associated with an increased rate of mortality. OCD is considered to be one of the most debilitating mental disorders, so it comes as no surprise that it would have an effect on one’s life expectancy. Also, I think this article demonstrates the importance of increasing the awareness of mental illness. If caught early, sufferers of OCD have a better chance of living a more normal, functional life. On the other hand, the longer the disorder persists without treatment, the more debilitating the disorder ends up being. Therefore, consideration should be given to promoting the importance of mental health so that patients could have a increased chance of getting the proper treatment and medication for their disorder.

Meier SM, Mattheisen M, Mors O, et al. Mortality Among Persons With Obsessive-Compulsive Disorder in Denmark. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.3105. (Published 27 January 2016).

The Use of Oral Contraceptives in Pregnant Women and the Prevalence of Birth Defects

Oral contraceptives are the most common form of birth control around the world. Although they have a high rate of success, women who miss doses or take medications that decrease the effectiveness of birth control may be at an increased risk for pregnancy. Women are advised to discontinue oral contraceptives prior to trying to conceive, but what if a woman becomes pregnant while still taking the medication? Researchers in Denmark sought out to answer this question. The purpose of this study was to discover whether the use of oral contraceptives during the onset of pregnancy was correlated with a significantly elevated risk of birth defects. This prospective cohort study was conducted in Denmark, and included data on the use of oral contraceptives and 880,694 live births from January 1st, 1997 to March 31st, 2011.

The study looked at four groups of women: those who had never taken oral contraceptives (21% of women), those who quit taking oral contraceptives at least 3 months before pregnancy onset (69% of women), those who took oral contraceptives from 0-3 months before pregnancy onset (8% of women), and those who took oral contraceptives after the onset of pregnancy (1% of women). The results of the study looked at the number of major birth defects that were present per 1,000 live births per group of women. These numbers were 25.1, 25.0, 24.9, and 24.8, respectively. The research concluded that there is no significant risk of birth defects in women who were exposed to oral contraceptives after the onset of pregnancy, versus women who had never used oral contraceptives or who had discontinued use greater than three months prior to the onset of pregnancy.

I think this study is important because the results offers relief to women who may have become pregnant as a result of missing a dose of their oral contraceptive, and they’ve been continuing their medication up until they realize that they are pregnant. The results tell them that their child is not more likely to have a major birth defect. It is definitely reassuring to let the expecting mother know that they haven’t put their unborn child at risk. This is also an important teaching point for pharmacists who counsel women who are taking oral contraceptives. I think an interesting point to explore would be if other forms of contraception that are used during the onset of pregnancy are associated with the risks of birth defects.

Charlton BM, Mølgaard-Nielsen D, Svanström H, et al. Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. BMJ. 2016;352:h6712. (Published 06 January 2016).


Effects of Oral Fluconazole Exposure in Pregnant Women

The purpose of this study was to research the possible correlation between pregnant women in contact with fluconazole and the occurrence of miscarriages and stillbirths. Fluconazole is a medication that is used to treat vaginal candidiasis. Typically, this medication is used topically, however an oral formulation can be used in certain cases. Pregnant women have a higher risk of contracting these yeast infections, and therefore may end up being prescribed an oral formulation of fluconazole.

The authors of this article conducted a retrospective cohort study of all pregnancies in Denmark between January 1, 1997 to December 31, 2013 that resulted in either a single live birth, stillbirth, miscarriage, or other form of abortion.  The study looked at pregnant women who were exposed to fluconazole between the gestational weeks of 7 weeks to birth. Specifically, the study was broken down into two two subcategories: pregnant women exposed to fluconazole between gestational week 7 and week 23, and pregnant women exposed to fluconazole between gestational week 7 to birth. Gestational week 23 was an important marker, because a pregnancy loss after this week was considered a stillbirth. The different doses of fluconazole that were prescribed to these women were also taken into account and were assessed in the study. Additionally, topical formulations of fluconazole prescribed to pregnant women were also compared to the prevalence of spontaneous abortions and stillbirths.

In total, 1,495,663 pregnancies were included in this study. Steps were taken to match pregnancies of women who were unexposed to fluconazole versus those who were exposed to fluconazole during their pregnancy. The women were matched via an algorithm based on factors such as their age and the gestational age, and only matches with a standardized difference of 10% or less were considered viable. The study concluded that women who took an oral formulation of fluconazole while pregnant had a higher risk of having a spontaneous abortion between gestational week 7 through week 22 compared to women who had used a topical formulation of fluconazole or had been unexposed. There was no significantly increased risk of a pregnancy ending in a stillbirth as a result of an exposure to oral fluconazole, although the rarity of this event could have resulted in inaccurate representation. The authors of this study recognize that there are additional factors that they could not necessarily account for. For example, they could not count spontaneous abortions that occurred prior to gestational week 6, because “many vary early pregnancy loss are not recognized clinically.” The authors also mention that severe cases of vaginal candidiasis could possibly result in pregnancy loss, so these losses may not have been due to the use of fluconazole.

Although the authors admit that more research should be done on this matter, the evidence presented in this study is enough to convince me that oral fluconazole should not be prescribed to pregnant women. Research like this is important because further studies can hopefully help to prevent the loss of pregnancies. It is also interesting to see how different formulations of the same medication can have different effects: the oral formulation had a significant increased risk of miscarriage, while the topical formulation was not associated with any higher risk that a women who had been unexposed to oral fluconazole.

Mølgaard-Nielsen D, Svanström H, Melbye M, et al. Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. doi:10.1001/jama.2015.17844 (published 5 January 2016)