Comparative Effects of Metformin and Insulin on Stereological Studies and Immunohistochemistry of Placenta
Condition: Diabetes Mellitus Arising in Pregnancy, Insulin-Requiring; Diabetes Mellitus in Pregnancy
MeSH terms: Pregnancy in Diabetics; Diabetes, Gestational; Diabetes Mellitus
Study type: Interventional

Summary: 
      Diabetes mellitus is a group of metabolic disorder characterized by high blood glucose level
      mainly due to defect in insulin secretion or resistance. In pregnancy, insulin resistance
      increases as the pregnancy advances, due to the placental hormones predisposing the female to
      gestational diabetes mellitus (GDM). Placenta is a vital organ as it provides nutrition to
      the fetus. It shows morphological changes in patients with GDM leading to feto-maternal
      complications. Insulin, a traditional treatment given for GDM is also known to cause intra
      uterine deaths, stillbirths and hypoglycemia in mothers and newborns. Insulin being anabolic
      hormone makes placenta larger in size and causes hypoxic changes with vascular insufficiency,
      infarctions and hemorrhages. In contrast to this, oral insulin sensitizing drug Metformin, is
      euglycemic in nature. It has been proven now that Metformin is a vasculo-protective agent,
      with better patient compliance and beneficial micro-vascular effects in type 2 diabetics.
      This study was designed to clearly visualize in detail if there are any unrevealed beneficial
      vascular effects of Metformin on placental tissues and also to compare these effects with
      Insulin and diet restriction therapy, by doing placental light microscopy, morphometric
      studies and immunohistochemistry.
    

Detailed description: 
      Diabetes mellitus is a group of metabolic disorder with relative or absolute deficiency of
      insulin. Pregnancy is a potentially glucose intolerant condition as insulin sensitivity
      decreases with the progress of pregnancy leading to the development of gestational diabetes
      mellitus (GDM). It is diagnosed in approximately 3-9% of pregnancies and is growing in
      prevalence. In Pakistan the recent prevalence of GDM is reported to be 3-3.45% but the
      complications are much higher due to poor glycemic control, lack of awareness and inadequate
      medical facilities. Placenta is an important feto-maternal organ which is responsible for
      nutrition of the fetus. It also provides the retrospective information regarding infant's
      prenatal development. Structurally, human placenta is a complex vascular organ that allows
      exchange of nutrients and chemicals between fetal and maternal blood. Proper development and
      maturity of placenta are strongly connected with fetal growth and survival.

      GDM produces anatomical and physiological alterations in placenta. This can be related to
      altered levels of fetal insulin and multiple growth factors such as placental vascular
      endothelial growth factor (VEGF), Insulin like growth factors (IGF and IGF binding proteins)
      which regulate the fetal and placental development. Morphologically, diabetic placentae are
      larger in size and volume. Microscopically, diabetic placenta shows degenerative alternations
      such as villous fibrinoid necrosis, chorangiosis, villous immaturity, calcification and
      syncytial knots formation which show intense hypoxia of the placental tissues.

      Nutritional therapy (diet control) is foremost important for achieving target glucose values
      during pregnancy but in uncontrolled cases pharmacological intervention is required. Parental
      Insulin is the traditional therapy in such circumstances, but is an expensive medication and
      is associated with high incidence of neonatal and maternal hypoglycemia, still births,
      neonatal morbidity and mortality. It is documented to produce many placental alterations such
      as immature villi, hemorrhages, edema, cystic changes and fibrinoid necrosis. It has been
      postulated that the reason behind all these hypoxic changes are the variation in the blood
      glucose level that occur in the maternal blood as sugar level suddenly dropped soon after
      Insulin injection and are at highest just before the next dose of Insulin.

      The use of oral anti-diabetic medications such as Metformin in the management of gestational
      diabetes has increased over the past several years. Recent studies has established that
      Metformin can be a better option for GDM as it well controls glycemia (produces euglycemic)
      with good pregnancy outcomes. Metformin is an oral anti-diabetic drug from biguanide group;
      work by improving insulin sensitivity, reducing hepatic gluconeogenesis and also by
      increasing peripheral glucose uptake and utilization. It is now been upgraded to category B
      drug as is not associated with teratogenic effects. But what are the effects of Metformin on
      stereological morphometric study and immunochemistry of placental tissues were left to be
      evaluated. Stereology provides practical measurements and significant approach for obtaining
      quantitative estimates of small structures on histological slides. In placental tissue it is
      performed to obtain unbiased quantitative estimates of placental components that inform about
      development and also estimate of structural parameters that have direct influence on
      placental functional capacity. Immunohistochemistry or immunofluorescence of tissue sections
      also provide valuable insight to placental structure and protein expression with
      three-dimensional spatial information, including morphology that cannot be obtained on
      microscopy.

      With this background knowledge, study was designed with the following objectives:

        1. To evaluate the placental gross and microscopic changes in normal, diet control,
           Metformin and Insulin treated in newly enrolled GDM females

        2. To evaluate stereological morphometric details of placenta in normal, diet control,
           Metformin and Insulin all enrolled females

        3. To evaluate immunohistochemistry of placental tissues in normal, diet control, Metformin
           and Insulin in all enrolled females

        4. To compare the placental morphology, stereology and immunohistochemistry with in the
           groups.

        5. To evaluate the fetal and maternal outcome in normal, diet control, Metformin and
           Insulin treated gestational diabetics.

        6. To correlate the placental morphology with the fetal and maternal outcome in Metformin
           and Insulin treated gestational diabetics
    

Intervention name(s): Metformin; Insulin
Intervention type(s): Drug; Drug
Intervention description(s): Euglycemic agent; Hypoglycemic agent
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: placenta; metformin; insulin; stereology; immunohistochemistry; morphometry