Introduction

Maternal–fetal medicine (MFM) is a multidisciplinary subspecialty dedicated to optimization of pregnancy and perinatal outcomes. The MFM emerged from a need to combine treatment of maternal high-risk pregnancies with diagnosis and treatment of fetal complications. Unfortunately, for various reasons, the focus of the MFM specialty has shifted over the years from maternal medicine toward ultrasound, diagnostic procedure, and fetal medicine. At the same time, the rates of maternal morbidity have been reported to increase, and attempts to decrease maternal mortality rates over the last few decades have failed. This has recently led to renewed efforts to reemphasize the M (maternal) component in the MFM specialty by means of educational changes and adjustment of health-care services to pregnant women. In the current article, we aim to further emphasize the importance of improving maternal health care by reviewing the strong interconnection between the M (maternal) and F (fetal) components of the MFM specialty. We also suggest new strategies to review novel technologies for diagnostics and treatments that can assist health-care organizations in achieving this goal and optimize obstetrical care and pregnancy outcome.

The reality – the neglected M in MFM

Although defined as maternal and fetal medicine, originally aiming to equally address fetal and/or maternal issues, in reality the main focus of MFM has been shifted from improving maternal outcome and preventing maternal short- and long-term complications to improving fetal and neonatal outcome. This change of focus is reflected by the disparity between maternal and fetal medicine in the perinatal care, which has become more focused on neonatal care. Availability of prenatal diagnosis of congenital and chromosomal anomalies, optional complex in utero treatments of fetal disorders and other advances in neonatal care have reduced the incidence of stillbirth and of preterm birth. As the advances in neonatal intensive care unit (NICU) treatments have led to reduced rates of morbidity and mortality even of very low-birth-weight infants, with the tendency to electively deliver neonates earlier and especially at late preterm (34–37 weeks).

At the same time, maternal morbidity rates have been reported to be rising, a rise that has been attributed to several reasons. The obesity epidemic has led to increasing rates of chronic diseases as hypertension and diabetes have a detrimental impact on pregnancy. The constant rise in the rates of cesarean delivery entail the risks of placenta accrete and hemorrhage . Taking advantage of using new artificial reproductive technologies opened the possibility for women of advanced age or with serious or chronic medical conditions to achieve pregnancy. Consequently, these women are at high risk for developing serious maternal complications during pregnancy and the postpartum period.

In 2010, M.E. D’Alton was the first to address the question: Where is the “M” in MFM . She urged to outline a specific plan to for clinical, educational, and research initiatives to put the “M” back in maternal fetal medicine. In 2012, a step forward was undertaken by the leading US authorities in obstetrics and gynecology that published their recommendations: to enhance education and training in maternal care for MFM fellows, to improve medical care and management of pregnant women, and to address critical research gaps in maternal medicine . It is now clear that multidisciplinary maternal care should have the ability to focus management on maternal metabolic disorders, hypertensive disorders, postpartum hemorrhage, prevention of venous thrombosis in pregnancy and postpartum, diagnosis and management of placenta accrete, and management of obesity and cardiac diseases in pregnancy .

In the current article, we aim to further emphasize the importance of improving maternal health care by reviewing the strong interconnection between the M (maternal) and F (fetal) components of the MFM specialty ( Fig. 1 ). We propose a resolution that will bridge the discrepancies by proposing to connect the leading hypotheses in MFM and in fetal medicine to those in maternal medicine. We also suggest new strategies review novel technologies for diagnostics and treatments that can assist health-care organizations in achieving this goal and optimize obstetrical care and pregnancy outcome.

Maternal fetal medicine.

The reality – the neglected M in MFM

Although defined as maternal and fetal medicine, originally aiming to equally address fetal and/or maternal issues, in reality the main focus of MFM has been shifted from improving maternal outcome and preventing maternal short- and long-term complications to improving fetal and neonatal outcome. This change of focus is reflected by the disparity between maternal and fetal medicine in the perinatal care, which has become more focused on neonatal care. Availability of prenatal diagnosis of congenital and chromosomal anomalies, optional complex in utero treatments of fetal disorders and other advances in neonatal care have reduced the incidence of stillbirth and of preterm birth. As the advances in neonatal intensive care unit (NICU) treatments have led to reduced rates of morbidity and mortality even of very low-birth-weight infants, with the tendency to electively deliver neonates earlier and especially at late preterm (34–37 weeks).

At the same time, maternal morbidity rates have been reported to be rising, a rise that has been attributed to several reasons. The obesity epidemic has led to increasing rates of chronic diseases as hypertension and diabetes have a detrimental impact on pregnancy. The constant rise in the rates of cesarean delivery entail the risks of placenta accrete and hemorrhage . Taking advantage of using new artificial reproductive technologies opened the possibility for women of advanced age or with serious or chronic medical conditions to achieve pregnancy. Consequently, these women are at high risk for developing serious maternal complications during pregnancy and the postpartum period.

In 2010, M.E. D’Alton was the first to address the question: Where is the “M” in MFM . She urged to outline a specific plan to for clinical, educational, and research initiatives to put the “M” back in maternal fetal medicine. In 2012, a step forward was undertaken by the leading US authorities in obstetrics and gynecology that published their recommendations: to enhance education and training in maternal care for MFM fellows, to improve medical care and management of pregnant women, and to address critical research gaps in maternal medicine . It is now clear that multidisciplinary maternal care should have the ability to focus management on maternal metabolic disorders, hypertensive disorders, postpartum hemorrhage, prevention of venous thrombosis in pregnancy and postpartum, diagnosis and management of placenta accrete, and management of obesity and cardiac diseases in pregnancy .

In the current article, we aim to further emphasize the importance of improving maternal health care by reviewing the strong interconnection between the M (maternal) and F (fetal) components of the MFM specialty ( Fig. 1 ). We propose a resolution that will bridge the discrepancies by proposing to connect the leading hypotheses in MFM and in fetal medicine to those in maternal medicine. We also suggest new strategies review novel technologies for diagnostics and treatments that can assist health-care organizations in achieving this goal and optimize obstetrical care and pregnancy outcome.

Maternal fetal medicine.

The neglected M is strongly interconnected to fetal health – bridging between maternal and fetal medicine – the MFM hypotheses

As discussed above, over the last few decades there seems to be lack of communication between the two subspecialties in MFM. However, it is now becoming clear that a segregation of the two disciplines is artificial in many aspects. It is also now well recognized that a communication between the M and F components is necessary since they are both strongly interconnected to each other. Maternal chronic conditions which traditionally fall under the M discipline are now known to have a major impact on the fetus (the subject of the F discipline) during early pregnancy, late pregnancy, neonatal life, as well as carry significant risk for long-term morbidity for the newborn. We demonstrate this concept by reviewing some of the leading hypotheses in maternal fetal medicine.

Effects of maternal conditions on the fetus throughout pregnancy – the Freinkel hypothesis (fuel-mediated teratogenesis)

Freinkel’s research focused on the intermediary metabolism in normal and diabetic pregnancy; specifically the mutual interplay between mother and fetus regarding metabolic changes during pregnancy. He perceived these changes as adaptations to facilitate the optimal development of the fetus.

It was demonstrated that a pattern (as he named) “accelerated starvation” characteristic of the transition from a status of overnight metabolic fasting to a prolonged fasting state or starvation . Clinical studies suggest that ketonemia/ketonuria above the normal levels during pregnancy may result in adverse effects on fetal development and subsequently adverse neurological outcomes . To avoid such dietary changes during pregnancy, the recommendation is a restriction of calorie or carbohydrate that may enhance ketogenesis. A delay until lunchtime or skipping of breakfast will initiate early metabolic changes (reduced concentration of plasma glucose and increase of free fatty acids (FFAs) and hydroxybutyrate). This state, if continued, may result in the metabolic state of accelerated starvation .

He studied altered nutritional metabolic states as obesity, diabetes, and malnutrition. Observation in normal pregnancy of adaptations to assure adequate nutrient delivery to the fetus he named “facilitated anabolism.” In pregnancy, insulin resistance plays a key role in initiating changes in the metabolism of carbohydrates, lipid, and amino acids that facilitate anabolism . A strong correlation between glycemia, aminoacidemia, lipids, and insulin sensitivity and secretion may explain the correlations between triglycerides and fetal birth weight or body composition and between maternal insulin sensitivity and fetal birth weight, he thus termed pregnancy a “tissue culture experience” .

Furthermore, he demonstrated that the metabolic alterations differ at specific times throughout pregnancy. Early in 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 behavioral, intellectual, or psychological damage in the offspring. During the third trimester, the abnormal proliferation of fetal adipocytes and muscle cells, together with hyperplasia of pancreatic β cells and neuroendocrine cells, may be responsible for the development of obesity, hypertension, and non-insulin diabetes mellitus later in life ( Fig. 2 ).

The Freinkel hypothesis – potential long-term effects upon the fetus of altered interactions in maternal fuels during pregnancy. Fuel-mediated teratogenesis as the basis for long-term anatomic and functional changes.

The consequences of metabolic intrauterine changes are dependent on the gestational stage the exposure occurs, these in turn may affect the neurobehavioral development, development of adipose tissue and obesity, cell function, and impaired glucose homeostasis in the offspring of diabetic mothers. Thus, indicating an increased risk for obesity and type 2 diabetes in late childhood, due to the increased exposure to the intrauterine environment of DM during mid- and/or late gestation .

The effect of maternal conditions on the fetus in late pregnancy – the Pedersen hypothesis – fetal hyperinsulinemia

Pedersen researched treatments and prognosis in diabetic mothers and their fetuses and also other problems to elucidate the complex and serious pathogenetic, pathoanatomic, metabolic, and endocrine problems. He postulated that in two critical periods during pregnancy, diabetic alterations took place: in the first trimester and at the third trimester. 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 2 months led to diabetic precoma, acute acidosis, or required raising insulin dosage . His clinical studies showed that in unplanned pregnancies of type 1 diabetic mothers, the rate of pregnancy complications and preterm deliveries, severe congenital malformations, and fetal mortality were increased remarkably compared to planned pregnancy in women treated with insulin ( Fig. 3 ). These observations demonstrated the importance for constant care for diabetic women both at the preconceptional period and during pregnancy. Hyperinsulinism in the fetus consists of the presence of adequate supplies of glucose, which lasts only until birth explaining adverse fetal outcomes . The Pedersen theory is used for the classification of preconceptional diabetic mothers based on various factors, particularly the diabetes severity and vascular complications, which may be predictors for pregnancy and fetal complications and fetal mortality .

The Pedersen hypothesis – the effect of maternal conditions on the fetus in late pregnancy .

The effect of maternal conditions on the fetus during adult life – the Barker hypothesis (fetal origins of adult disease – programming and imprinting in utero)

Barker’s first studies demonstrated the relationship between low weight at birth and during infancy to high risk for coronary heart disease in adulthood. He postulated this implies that a limited transfer of nutrients from mothers to their fetuses at critical periods of development causes permanent metabolic, physiologic, and structure change. These “programed changes” have been shown in Barker’s later studies to be the origins of diseases later in life, as increased risk of hypertension, ischemic heart disease, stroke, and type 2 diabetes. These findings led him to construct the “Fetal Origins Hypothesis” ( Fig. 4 ) while this hypothesis is also strongly supported by animal studies .

The Barker hypothesis – fetal origins of adult disease – programming and imprinting in utero.

Maternal medicine meets fetal medicine; the vicious cycle – NCD epidemic the great obstetrical syndromes – obesity, diabetes, hypertension, metabolic syndrome, and pregnancy.

Metabolic and endocrine changes

The immediate metabolic adaptation to undernutrition of the human fetus is catabolism, self-consuming its substrates for energy supplies. Prolonged fetal undernutrition also causes endocrine changes as reduced concentration of fetal growth hormones, effecting the hormonal and metabolic interactions between the fetus and mother via the placental transfer. A reduced transfer of amino acids and glucose, due to decreased maternal insulin-like growth factors (IGF) will eventually lead to reduced rates of fetal growth .

Coronary heart disease

Ischemic heart disease studies linking to fetal development were based on birth records with documentation of birth weight and growth in infancy, from three large databases following 16,000 individuals born in Britain in the early twentieth century. Mortality rates from ischemic heart disease later in life were twofold 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. Increased mortality rates following coronary heart disease were found in men who had a low ratio of birth weight or of placental weight to head circumference .

Type 2 diabetes mellitus

Further studies explored the mechanisms underlying the association between early fetal and placental growth to the risk of coronary heart disease and stroke. He found similar trends in two of the major ischemic risk factors, hypertension, and type 2 diabetes mellitus (T2DM) . The prevalence of T2DM and impaired glucose tolerance later in life was threefold higher in the smallest babies who weighed <2.5 kg as compared to the largest who weighed >4.3 kg at birth . There is evidence that deficiency in insulin production and insulin resistance are both determined in utero. Low-birth-weight babies had high prevalence of “insulin resistance syndrome” in which the same patient has impaired glucose tolerance, hypertension, and high concentrations of triacylglycerol . A Dutch study of individuals who were in utero during the Dutch famine of 1944–1945 provides evidence linking fetal undernutrition to programming insulin resistance and type 2 diabetes. Their glucose tolerance tests when over 50 years of age were all higher than in those conceived before or after the famine .

Blood pressure and hypertension

A multitude of studies have found a trend in which each 1 kg increase in birth weight is associated with a fall of around 3.5 mmHg in blood pressure in adult life . The associations between low birth weight and higher blood pressure are generally as strong as those between thinness, stunting, and below average head circumference to higher blood pressure and the risk of hypertension in adult life .