Placenta-on-a-chip paves the path forward for easy drug screening during pregnancy

Courtesy: Penn State News Letter

Going forward with the concept of ‘organs-on-chip’ that mimic the physiological conditions in-vivo, researchers at the University of Pennsylvania’s School of Engineering and Applied Science have developed ‘placenta-on-a-chip’ to look at the placental barrier and drug transport in pregnancy.  

This is a real breakthrough to study the maternal-fetal drug transport across the placenta, as the placental barrier can never be exactly replicated in the lab and in-vivo studies in humans are not ethical. Pregnant women are not included as research subjects because of the risk of teratogenicity. Animal models are not exactly able to mimic human physiology.

We are all aware of the famous ‘Thalidomide’ disaster, in which a drug for morning sickness, crossed the placental barrier in humans and caused multiple birth defects, collectively known as ‘fetal thalidomide syndrome’ and deaths.

To address these issues, a team of researchers led by Dan Huh, Wilf Family Term Assistant Professor in Bioengineering at Penn and Cassidy Blundell, a graduate student in the Huh lab have developed a placenta-on-a-chip, using microfluidic channels in silicone casing.

The study was also published in the journal Advanced Healthcare Materials.

The two channels house human trophoblast cells on one side and endothelial cells on the other separated by a porous membrane. The unit mimics placental barrier and hence the permeability of the barrier to different drugs can be tested.

A blood-like fluid flows through the maternal side of the channel and the researchers can experiment by adding different drugs to the fluid and see the rate, amount of drug transferred to the fetal side of the channel.

“Ex vivo placental perfusion is a great method,” Huh said, “but it has a pretty high failure rate, and the experimental set-up is complicated: it’s prone to leaks and needs a high level of expertise. Most pharmaceutical companies are not going to be able to test their drugs using this method.”

Currently, to validate their model, the team has tested 2 drugs that they have already studied via ex vivo placental perfusion: heparin, an anticoagulant, and glyburide, used in the treatment of diabetes.

The placenta on the chip was able to simulate the drug transfer of these two drugs as it happens in human placenta and fetal interface. Heparin did not pass through the chip model as it is too large a molecule to breach the placental barrier and glyburide transfer was also limited as in real placenta to protect the fetus.

Huh further added, “We’re getting close, this study has given us confidence that the placenta-on-a-chip has tremendous potential as a screening platform to assess and predict drug transport in the human placenta.”

Besides its use by the pharmaceutical company to test various drugs, the ‘placenta-on-a-chip’ has tremendous potential in testing the transfer of supplements other than drugs like vitamins and nutritional supplement.

Penn State News Release

Abstract in Advanced Healthcare Materials

ACOG issues clinical practice guidelines for Gestational Diabetes Mellitus

Courtesy: YouTube.

The American College of Obstetricians and Gynecologists (ACOG) has issued clinical practice guidelines for the diagnosis and treatment of gestational diabetes mellitus (GDM).

Although prevalence of GDM is directly proportional to prevalence of type 2 DM in a given population, it is estimated that GDM accounts for 90% of cases diabetes in pregnancy. The prevalence of DM in pregnancy is around 6-9%.

The prevalence of GDM globally is on the rise because of increasing obesity, delayed childbearing and sedentary lifestyle.

The document provides a brief overview of GDM, one of the most common complication of pregnancy, identifies the disease process, its diagnosis and management based on current research and identifies the lacunae for future research.

Screening for GDM is done by various methods and there is still no standardized method. ACOG supports the two-step process most commonly used in USA. It involves first screening with the administration of a 50-g oral glucose solution followed by a 1-hour venous glucose determination. 

Women whose glucose levels meet or exceed an institution’s screening threshold then undergo a 100-g, 3-hour diagnostic OGTT. Gestational diabetes mellitus is most often diagnosed in women who have two or more abnormal values on the 3-hour OGTT.

Other institutions and private practitioners use International Association of Diabetes and Pregnancy Study Group (IADPSG) recommended one step, universal 75-g, 2-hour OGTT to diagnose GDM.

The summary of recommendations by ACOG:

Recommendations based on good scientific evidence (Level A):

All women diagnosed with GDM should first be treated with adequate nutritional and exercise counselling, before starting any pharmacological treatment.

If lifestyle modifications fail to control glucose levels, Insulin is the first line of drug for controlling blood sugar in pregnancy.

Recommendations based on limited or inconsistent scientific evidence (Level B):

All pregnant women should be screened for GDM with a laboratory based blood glucose level testing.

Women who refuse to take insulin, or who are unable to safely administer insulin, metformin is a reasonable second-line choice.

Glyburide is not be recommended as a first-line pharmacologic treatment because, in most studies, it does not yield equivalent outcomes to insulin.

All women should be counselled about limitations of safety data regarding oral hypoglycemic agents.

Women should also receive counselling regarding the risks and benefits of a scheduled cesarean delivery when the estimated fetal weight is 4,500 g or more.

Recommendations based primarily on consensus and expert opinion (Level C):

In the absence of clear evidence and comparative trials, no single value of blood glucose can be taken as cutoff over another for 1-hour glucose test nor one set of diagnostic criteria for the 3-hour OGTT can be clearly recommended over the other. Practitioners should select a single set of criteria and use it consistently with their patients.

Women should be advised dietary guidance and 30 minutes of moderate physical activity, 5 days a week or 150 minute/week.  

In women, whose GDM is well controlled by diet and exercise, delivery is not indicated before 39 weeks of gestation, in absence of other obstetric indication. She can be safely managed expectantly up to 40 6/7 weeks of gestation, with antepartum fetal surveillance.

In women, whose GDM is well controlled by medications, delivery is recommended at 39 0/7 to 39 6/7 weeks of gestation.

All women with GDM should be screened at 4–12 weeks postpartum to identify women with diabetes, impaired fasting glucose levels, or impaired glucose tolerance, with an appropriate referral to medical practitioner.

The American Diabetic Association (ADA) and ACOG recommend repeat testing every 1–3 years for women who had a pregnancy affected by GDM and normal postpartum screening test results.

Full Text 

Gestational Diabetes Mellitus Revisited

Gestational Diabetes Mellitus Revisited 

Today is world diabetes day. The International Diabetes Federation has released new data in support of its campaign against Diabetes quoting that “1 in 7 births is affected by gestational diabetes” and “One quarter of all births are affected by high blood glucose during pregnancy in South-East Asia.”

 This article is based on The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care.

• The International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy.

• While 16% of these cases may be due to diabetes in pregnancy (either preexisting diabetes—type 1 or type 2—which antedates pregnancy or is first identified during testing in the index pregnancy), the majority (84%) is due to gestational diabetes mellitus (GDM).

• The definition of GDM is still evolving.

• Hyperglycemia first detected at any time during pregnancy should be classified either as diabetes mellitus in pregnancy (DIP) or GDM.

• When the level of hyperglycemia first detected by testing at any time during the course of pregnancy meets the criteria for diagnosis of diabetes in the nonpregnant state, the condition is called DIP. Those criteria are:

      1) Fasting plasma glucose ≥7.0 mmol/L (126 mg/dL); and/or

      2) 2-hour plasma glucose ≥11.1 mmol/L (200 mg/dL) following a 75-g oral glucose load; or

      3)Random plasma glucose ≥11.1 mmol/L (200 mg/dL) in the presence of diabetes   symptoms.

• DIP may either have been pre-existing diabetes (type 1 or type 2) antedating pregnancy, or diabetes first diagnosed during pregnanc.

• When hyperglycemia detected during routine testing in pregnancy (generally between 24 and 28 weeks) does not meet the criteria of DIP it is called GDM.

            To address the global burden of GDM, FIGO recommendations:

• Universal testing-- All pregnant women should be tested for hyperglycemia during pregnancy using a one-step procedure and FIGO encourages all countries and its member associations to adapt and promote strategies to ensure this.

• As per the recommendation of the IADPSG (2010) and WHO (2013), the diagnosis of GDM is made using a single-step 75-g OGTT when one or more of the following results are recorded during routine testing specifically between weeks 24 and 28 of pregnancy or at any other time during the course of pregnancy:

     1)Fasting plasma glucose 5.1−6.9 mmol/L (92−125 mg/dL);

     2)1-hour post 75-g oral glucose load ≥10 mmol/L (180 mg/dL);

     3)2-hour post 75-g oral glucose load 8.5–11.0 mmol/L(153−199 mg/dL)

• Asian Indians are considered to be at the highest risk of gestational diabetes. Based on studies from India and keeping in mind the already high burden and rising prevalence of diabetes and the realities of resource constraints within the health system in India, as well as the high rate of deliveries (27 million each year), the Diabetes in Pregnancy Study Group in India (DIPSI) developed the following guideline for diagnosis of GDM in the community. This guideline has been endorsed by the Ministry of Health, Government of India, the Federation of Obstetrics and Gynecological Societies of India (FOGSI), and the Association of Physicians of India (API)
• For Asian Indians Testing for GDM is recommended twice during prenatal care. The first testing should be done during first prenatal contact as early as possible in pregnancy. The second testing should be done ideally during 24−28 weeks of pregnancy if the first test is negative. If women present beyond 28 weeks of pregnancy, only one test is to be done at the first point of contact.

• The management of GDM should be in accordance with available national resources and infrastructure even if the specific diagnostic and treatment protocols are not supported by high-quality evidence, as this is preferable to no care at all.

• Life style modification is the corner stone in management of DIP and GDM.

• Nutritional therapy includes an individualized food plan to optimize glycemic control. Medical nutritional therapy in pregnancy can be described as “a carbohydrate-controlled meal plan that promotes adequate nutrition with appropriate weight gain, normoglycemia, and the absence of ketosis.

• Daily energy intake of approximately 2050 calories (minimum of 175 g carbohydrates/day) in all BMI categories in women with GDM was reported to reduce weight gain, maintain euglycemia, avoid ketonuria, and achieve average birth weights of 3542 g.

• Oral antidiabetic agents  Insulin, glyburide, and metformin are safe and effective therapies for GDM  during the second and third trimesters, and may be initiated as first-line treatment after failing to achieve glucose control with lifestyle modification. Among OADs, metformin may be a better choice than glyburide.

• Insulin should be considered as the first-line treatment in women with GDM who  are at high risk of failing on OAD therapy, including some of the following factors

       • Diagnosis of diabetes <20 weeks of gestation

             • Need for pharmacologic therapy >30 weeks

       • Fasting plasma glucose levels >110 mg/dL

       • 1-hour postprandial glucose >140 mg/dL

       • Pregnancy weight gain >12 kg

• The postpartum period is crucial, not only in terms of addressing the immediate perinatal problems, but also in the long term for establishing the basis for early preventive health for both mother and child, who are at a heightened risk for future obesity, metabolic syndrome, diabetes, hypertension, and cardiovascular disorders.

• Progression to diabetes is more common in women with a history of GDM compared with those without a GDM history. 
• Both “intensive lifestyle” and metformin have been shown to be highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.

• The current EBCOG proposal is to screen women with a history of GDM at 6−12 weeks postpartum using the 2-hour 75-g OGTT with nonpregnancy diagnostic criteria. Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years.

     References:

• http://www.ijgo.org/article/S0020-7292%2815%2930033-3/pdf

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