• 1.
  

  a) F b) T c) T d) F e) T

Most studies have found significant histological differences between placentas from GDM and non-diabetic pregnancies. Macroscopic changes between GDM and non-diabetic placentas include higher weight and increased placental to fetal weight ratio which are proportional to the degree of hyperglycemia. While some studies have show more placental changes in poorly controlled diabetic pregnancies, others have equally demonstrated similar characteristics in placentas from well controlled diabetic pregnancies. Most studies have shown the described changes related to GDM. The main histological findings in GDM placentas are as described in e. Other changes such as the presence of nucleated red blood cells suggesting chronic hypoxia are also recognised.

• 2.
  

  a) F b) T c) T d) T e) F

Indeed, diabetic placentas are heavier than the non-diabetic ones. However, the increased placental to fetal ratio, even among AGA infants implies that the placenta grows first, perhaps as an attempt to “defend” the fetus from the overgrowth and only then contributes to accelerated fetal growth by increased glucose as well as other nutrient transfer. Villous immaturity can increase the distance between the intervillous space and fetal capillaries and therefore may alter placenta-fetal gas and nutrient exchange. Diabetic infants may compensate for such immaturity by increasing the placental exchange surface. GDM placentas have an increased incidence of vascular changes affecting the feto-placental circulation that can lead to the increased risk of pre-eclampsia in diabetic pregnancies. Since placental changes are also seen in well controlled GDM pregnancies placental changes cannot therefore necessarily be normalized by treatment, however, the consequences such as having large infants can be modulated.

• 3.
  

  a) F b) F c) F d) T e) F

As shown by clamp studies, during pregnancy there is a uniform decrease in insulin sensitivity in both normal and GDM pregnancies. In normal pregnancy, the fetus favours glucose as its main energy source. Maternal adaptive responses are aimed to allow this. Post prandial hyperglycemia, accelerated starvation and elevated free fatty acid all describe normal adaptive responses of the maternal compartment meant to favour transport of glucose to the fetus while allowing the use of fatty acids by the mother.

• 4.
  

  a) T b) T c) T d) F e) F

The term “The great obstetrical syndromes” was first described by Romero in 1996. The term relates to obstetric diseases that share placental involvement as part of their aetiology. These conditions are unified by multiple aetiologies causing normal adaptive responses of the materno-fetal unit to turn to pathological outcomes seen after a pre-clinical period as a defined disease. All conditions must therefore involve maternal and fetal compartments reflected by maternal and fetal adverse outcome.

• 5.
  

  a) F b) T c) T d) F e) T

Metabolomics offers a number of benefits compared with other ‘-omic’ strategies: close biological proximity to the phenotype of the system and hence the rapid observation of system perturbations in the metabolome. This is achieved by combining analytical chemistry, platform technology, MS, and NMR with sophisticated data analysis. This provides a foot-printing of biological systems, particularly useful for the non-invasive diagnosis of diseases. In the last ten years, several studies have been published about metabolomics in pediatric and neonatal age research, including: intrauterine growth restriction, perinatal transition, asphyxia, brain injury and hypothermia, maternal milk evaluation, postnatal maturation, bronchiolitis, sepsis, patent ductus arteriosus, respiratory distress syndrome, nephro-uropathies, metabolic diseases, antibiotic treatment, perinatal programming and long-term outcome in extremely low birth-weight infants. Metabolomics is an emerging branch of omic research. It attempts to systematically identify and quantify metabolites from a biological sample to detect changes in cell behavior and organ function. Metabolites are biological characteristics evaluated as indicators of normal biological and pathological processes or pharmacological responses to a therapeutic intervention Thus, the metabolic footprint of a biological systems provided by metabolomics can be used to monitor and measure the larger-scale physiological changes occurring in response to subtle changes in the environment, stress, drug discovery, toxicology, nutrition, genetic manipulation, and diseases. Scientists around the world are now beginning to realize that metabolic profiling will have a significant impact on the diagnosis, prediction, prevention and monitoring of many genetic, infectious and environmental diseases.

• 6.
  

  a) T b) F c) F d) F e) T

Experimental studies show that fetal malnutrition, both excessive and insufficient, may permanently alter the metabolic processes of the fetus and increase the risk of future chronic diseases. The first scholar who hypothesized the fetal origin of certain chronic diseases of the adult was Barker. This suggested that there was a relationship between low birth weight and the increased risk of contracting cardiovascular diseases. This theory is now accepted by most members of the academic community as several other studies have found an association between low birth weight and the risk of presenting a metabolic syndrome and type 2 diabetes in adulthood. However, some researchers have found that not only low birth weight, but also high birth weight, as in the case of diabetic mothers, is followed by an increased risk of developing type 2 diabetes in adulthood. Fetal malnutrition can expose a child to reduced carbohydrate tolerance that tends to persist not only during growth but also in adulthood, which consequently leads to a higher risk of developing pathologies such as obesity, type 2 diabetes and the metabolic syndrome.

• 7.
  

  a) T b) T c) F d) F e) T

The definition of the microbiome in a is that described by Hooper in 2001. That 90% are estimated as uncultivable is the great plate count anomaly, described by Dethlefsen in 2007. Metagenomics is studied by DNA sequencing. The 16S rRNA gene is generally used for PCR amplification due to its presence in all bacteria and its inclusion of both highly conserved and heterogenic sequences.

• 8.
  

  a) T b) F c) F d) F e) T

Both Ravel and Drell, in 2011 and 2013 respectively have shown that bacterial clusters are associated according to ethnic groups. Ravel’s observation that strictly anaerobic organisms, rather than Lactobacillus, dominated in one of the groups of bacterial clusters, indicates that dominance of Lactobacillus is not a necessary characteristic of a healthy vaginal flora. In addition to differences observed between ethnic groups and inter-individual differences, considerable intra-individual differences have been documented. A study of 32 healthy reproductive-age women over a 16-week period found bacterial community composition, time in the menstrual cycle, and sexual activity to be associated with deviations from the stability of bacterial vaginal communities. Li et al, in 2013, showed that the vaginal microbiome has a higher stability than other bodily habitats, namely the oral, skin, and distal gut.

• 9.
  

  a) F b) F c) T d) T e) T

Bacterial ascent from the vaginal tract to the uterus, possibly crossing the placental barrier, is recognized by both culture-dependent (Romero and Mazor, 1988) and culture-independent (DiGiulio, 2012) studies as the primary source of intrauterine infection. The finding that bacterial species common to the genital tract were among the most common bacteria detected in the uterine cavity supports this pathogenesis (Mendz 2013). Culture-independent technologies detected bacterial sequences in the fetal membranes of preterm deliveries and term deliveries, both with and without labour (Steel 2005, Fortner 2014), as well as in up to 70% of women undergoing elective Caesarean sections at term (Steel 2005), thus indicating that the presence of bacteria does not in itself cause preterm labour. The observations of a shorter amniocentesis-to delivery interval among women who were PCR positive, and a dose-response association between bacterial rDNA abundance and gestational age at delivery support the possibility of a causal relationship (DiGiulio 2008). In a recently published systematic review of women delivering before term, culture-independent techniques revealed intra-uterine bacterial infections in 349/761 (46%) (Mendz 2013). Investigation of bacteria from fetal membranes of women who delivered preterm or term, with or without labour, reported an association of increased bacterial presence with a thinner chorion, regardless of infection, gestational age, or labour status. This suggests that bacterial presence may lead to chorion thinning and ultimately to preterm premature rupture of membranes (PPROM) (Fortner 2014).

• 10.
  

  a) F b) F c) T d) T e) F

During the first trimester, intrauterine growth restriction and organ malformation can be primary factors leading to “fuel-mediated teratogenesis”. During the second trimester, metabolic alterations at the time of brain development and differentiation may lead to behavioural, intellectual or psychological damage in the offspring. During the third trimester, hypertension and non-insulin diabetes mellitus later in life can be set up by the abnormal proliferation of fetal adipocytes and muscle cells, together with hyperplasia of pancreatic β cells and neuroendocrine cells.

• 11.
  

  a) T b) F c) T d) T e) T

In the first trimester, an improvement in maternal carbohydrate tolerance was observed lasting 2–3 months. In the third trimester, a decrease in tolerance lasting for an average of two months led to diabetic pre-coma, acute acidosis or required raising insulin dosages.

• 12.
  

  a) T b) T c) F d) T e) T

A reduced transfer of amino acids and glucose, due to decreased maternal IGF (Insulin-like growth factors) will indeed eventually lead to reduced rates of fetal growth. Mortality rates from ischaemic heart disease later in life were 2 fold higher in those in the smallest category who weighed <2.5 kg at birth compared to the largest who weighted >4.3 kg at birth. Thin or stunted and small trunk babies were born due to different adaptations to in-utero under nutrition, hypoxia and other changes, these in turn led to different consequential long-term diseases.

• 13.
  

  a) T b) T c) F d) F e) T

A combination of maternal characteristics with measurement of mean arterial pressure, uterine artery Doppler and biochemical tests at 11–13 weeks can aid in determining the prediction of future development of PET in up to 60% of pregnancies. Maternal factors and biomarkers at 11 to 13 weeks have the potential to identify the subsequent development of GDM in about 75% of pregnancies with a false positive rate of 20%. Using maternal biophysical and biochemical markers as early as 11–13 weeks can also identify a higher tendency for deviant fetal growth, and especially small for gestational age fetuses, in up to 75% of pregnancies.

• 14.
  

  a) F b) F c) T d) T e) F

First trimester predictive models for hypertension are effective in describing the risk for early onset pre-eclampsia but are not very efficient in describing risk for either late onset pre-eclampsia or gestational hypertension. The models include multiple parameters and different groups have published data related to the screening efficacy of varying combinations of markers. Risk algorithms often define an a priori risk based on demographic factors. Measured markers include maternal mean arterial blood pressure and the uterine (not umbilical) artery Doppler. Although some groups have published data purely related to maternal serum markers these algorithms appear to be less effective than those that include biophysical parameters.

• 15.
  

  a) F b) T c) T d) F e) F

There are several meta-analyses that suggest that Aspirin has a role in reducing the prevalence of pre-eclampsia. Internationally, the WHO advise that women deemed to be at high risk of pre-eclampsia should take Aspirin during their pregnancy. Treatment only seems to be effective if started <16 weeks gestation. Treatment is also only effective in reducing the prevalence of disease that has an early onset, leading to delivery <34 weeks’ gestation. A number of trials have been performed since the 1990s giving variable low doses of Aspirin, but there is evidence that a significant proportion of women taking very low doses are more likely to be resistant to therapy. Similarly, there is evidence that Aspirin has its best effect when taken at night. Some RCTs have raised the issue of an increase in the rate of placental abruption in women who are treated with Aspirin in pregnancy; more recent meta-analyses suggest that this risk is confined to women who start treatment >16 weeks. There is no evidence of an increase in other maternal complications.

• 16.
  

  a) T b) T c) T d) T e) F

Gestational diabetes (GDM) is becoming more prevalent in all ethnic groups. Recent changes to guidelines for the diagnosis of GDM may also lead to an increase in rates of diagnosis, and this is the basis of controversy over the international adoption of these guidelines in clinical practice. The long term impact of GDM is being recognised – both to the mother (with increasing prevalence of type II diabetes) and the infant (with increasing prevalence of metabolic syndrome). The ACHOIS trial showed that a diagnosis of GDM is associated with a number of obstetric complications; this has become the rationale for intervention during the antenatal period in many centres. The ‘gold standard’ for testing is currently a formal oral glucose tolerance test at 26–28 weeks gestation.

• 17.
  

  a) F b) F c) F d) T e) F

The IADPSG advises that ‘high risk’ women are offered early testing for gestational diabetes. Assessment of risk is currently based on demographic risk factors; this does not include primigravidity. Most research studies looking at universal screening have performed poorly; with sensitivities in the order of 60–70% for a 20% screen positive rate. There appears to be more success in using algorithms that involve multiple parameters, but these are still in the research rather than the clinical domain. A glucose challenge test does not appear to perform well enough to be recommended as a universal screening tool at 12 weeks.

• 18.
  

  a) F b) T c) F d) F e) F

The criteria are derived from a cohort study conducted in the late 1950s and not from a randomized trial. The criteria were derived because they were predictive of the later risk of diabetes in a separate cohort of pregnant women who also underwent glucose tolerance testing in pregnancy. These criteria, in particular the requirement for 2 abnormal values for a GDM diagnosis are widely used in the USA, but only sporadically in most other areas of the world. The original cohort comprised 752 women. HbA1c is not generally recommended for the diagnosis of GDM as it shows weaker associations with adverse pregnancy outcomes.

• 19.
  

  a) F b) F c) F d) T e) T

Both studies used composite endpoints. In the Crowther study, the composite endpoint was significantly improved by treatment of GDM, whereas the Landon study did not show a significant improvement in a (different) composite endpoint. The Landon study excluded women with elevated fasting glucose levels, but required two elevated post load values for inclusion and the mean glycaemic levels in Landon’s study were much higher. Quality of life improved with GDM diagnosis and treatment in the Crowther study. It was not assessed in the Landon trial. Pre-eclampsia was decreased by active treatment in both studies. The Landon study also assessed body composition in the neonates and found that fat mass was reduced with active treatment of GDM.

• 20.
  

  a) F b) T c) F d) T e) F

Screening is only relevant when treatment is offered. On this basis evaluations only focusing on the screening process, will not allow you to decide whether GDM screening and treatment is worthwhile. GDM might predispose to a wide range of both neonatal and maternal complications. The outcome measure QALY can incorporate the utility (or disutility) of the different health states that GDM can predispose to. QALY is therefore suitable for the purpose if not just focusing on the effectiveness. Permanent brachial plexus injury is only one among the severe neonatal and maternal complications associated with GDM. Focusing on this outcome, will give you input to decide whether screening is worthwhile to prevent this serious injury only. However, other outcomes important to a clinical setting are not considered. GDM predisposes to a wide range of both neonatal and maternal complications. A composite outcome combining neonatal and maternal morbidity and mortality can address all these complications at the same time and would therefore be suited for the purpose. Putting things into monetary units requires quite refined and time consuming techniques. From a pragmatic point of view, conducting a CBA would therefore be too much of an objective.

• 21.
  

  a) T b) T c) F d) T e) F

The outcome found cases of GDM is necessary for an economic evaluation. Using QALY can take into account GDM complications and incorporate the utility (or disutility) of these into the outcome measure. The outcome permanent brachial plexus injury is too narrow for as an outcome measure. The composite outcome combining neonatal and maternal morbidity and mortality is much broader and therefore appropriate. From a pragmatic point of view, conducting a CBA would be overkill as the objective of the evaluation is priority within the healthcare sector.

• 22.
  

  a) T b) F c) T d) T e) T

Going from risk-based to universal screening will markedly increase the screening population and thus increase the need of resources for personnel, materials, laboratory facilities, space and overheads. Lowering the diagnostic threshold will not affect resources used for screening, but increase the number of women being diagnosed with GDM. Thus, lowering will only increase the costs for the GDM intervention program offered to the women who meet the diagnostic criteria. Expanding risk factor criteria will increase the screening population though not as dramatically as if going to universal screening. However, the need for personnel, materials and laboratory facilities will still increase. If the duration of the test is increased, resources for personnel to operate the clinic will increase along with need for space and overheads. Hourly blood sampling as opposed to one final blood sample will increase the need for resources as above.

• 23.
  

  a) F b) F c) F d) F e) F

Quenching refers to any process which decreases the fluorescence intensity of a given substance. MicroRNAs are endogenous small non-coding RNAs (about 22 nt in size) that play pivotal post-transcriptional regulatory roles in normal physiological functions by targeting messenger RNAs (mRNA) for cleavage or translational repression. Ubiquitination is post-translational where ubiquitin is attached to a substrate protein, leading to its degradation by the proteasome. Methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. It typically occurs in CpG islands.

• 24.
  

  a) F b) F c) T d) F e) F

Human placenta exhibits a specific microRNA expression pattern that dynamically changes during pregnancy. More than 130 microRNAs have been reported to be dysregulated in pre-eclampsia, out of which only 20 are named in at least two independent studies. Variation in microRNA expression may be due to relative small study sizes (up to 30 patients), intrinsic patient variations, different definitions of pre-eclampsia, inclusion criteria and variability in the methodologies, e.g. in the RNA extraction protocols, statistical analyses or other.

• 25.
  

  a) T b) T c) T d) T e) T

MiR-210 does appear to be the most highly expressed microRNA in trophoblast cells and in placental tissue. There is good evidence that miR-210 is involved in the control of trophoblast proliferation and invasion. Up-regulation of miR-210 in the plasma of pre-eclampsia patients was noticed, with a greater increase in more severe pre-eclampsia than in milder forms. Ectopic expression of miR-210 has been shown to inhibit the migration and invasion capability of cultured trophoblast cells in a transwell assay.

• 26.
  

  a) F b) F c) T d) T e) F

Cff DNA levels rise in pathologies involving ischemia/hypoxia such as pre-eclampsia. Amniotic fluid insulin and C-peptide in early amniocentesis have been tested without disease predicting value. The connection between microRNAs, adipose tissue and insulin resistance was seen in several experiments and may have a role in GDM pathophysiology. MiR-29a and miR-222 are significantly decreased in GDM women with respect to controls of similar gestation. MicroRNAs may have the potential to be used as biomarkers, as they are relatively stable, are tissue specific and can be detected in maternal blood. Detection of placental-expressed microRNAs in the maternal plasma suggests their potential use in non-invasive prenatal diagnostics and form the basis for therapeutic strategies.

• 27.
  

  a) F b) T c) T d) F e) F

Depending on studies, different cut-offs to define macrosomia have been proposed: a BW between 4000–4500g, >3500g, or above the 90th percentile for gestational age. Maternal diabetes can have an impact on fetal growth. It mainly results in a macrosomic fetus, with an established relationship between maternal glycaemic levels and the risk of macrosomia. Macrosomia, regardless of its cause, is by itself associated with adverse neonatal outcomes such as asphyxia, perinatal death, shoulder dystocia and birth injury, respiratory distress and hypoglycemia. Maternal obesity and diabetes are the main factors for macrosomia. Macrosomia is a risk factor for long term adverse outcomes in the offspring, such as obesity and metabolic syndrome.

• 28.
  

  a) T b) T c) F d) F e) T

The rate of fetal malformation is slightly increased in cases of GDM compared to the general population (ORs between 1.1 and 1.3). RDS is a major cause for admission in neonatal intensive care units in diabetic pregnancy. The principal mechanism is due to altered lung surfactant synthesis due to fetal hyperinsulinism. The risk of RDS is higher in preterm infants when GA is between 36–37 weeks. The burden of neonatal complications is higher in developing countries, because of the high incidence of maternal hyperglycemia and the absence of screening and treatment of maternal diabetes, as well as the scarcity of neonatal care. Infants born to diabetic mothers are prone to develop non-communicable diseases such as hypertension, type-2 diabetes and metabolic syndrome later in life.

• 29.
  

  a) F b) T c) T d) F e) T

Normal-grown infants of mothers with diet-controlled GDM should not be monitored. Early and frequent breastfeeding remains key in preventing hypoglycemia. Infants with excessive size at birth are more likely to develop hyperinsulinemia and hypoglycemia. In mildly or moderately symptomatic infants with low blood glucose levels, sustained breastfeeding, or eventually formula supplements should be tried first. Breastfeeding has beneficial effects on the risk of long-term obesity.

• 30.
  

  a) T b) T c) T d) F e) T

Only carotid atherosclerotic plaques have not been documented in this situation.