The Lay of the Land
Oded Langer, MD, PhD
Be who you are and say what you feel, because those who mind don’t matter and those who matter don’t mind.
—Dr. Seuss
History is interim reports issued periodically. The story of diabetes mellitus is a remarkable narrative covering 3500 years of medical history that closely parallels the documented human story. Studying this disease over time reveals a jarring fact: the incidence of diabetes has increased dramatically, from an uncommon complaint in ancient times to one that may potentially affect the lives of more than 300 million people by the year 2025.
THE RECOGNITION OF DIABETES IN ANTIQUITY
The earliest descriptions of the symptoms of diabetes are to be found in the recorded observations of ancient physicians. Ancient Egypt was the first civilization known to have an extensive study of medicine and to have left behind written records that describe the nature of ailments, their origins, practices, and procedures. The first reference to diabetes mellitus is attributed to the Ebers Papyrus. A German Egyptologist, Georg Ebers, acquired this papyrus in 1872, and the document relates to the ancient Egyptian practice of medicine and mentions remedies “to eliminate urine which is too plentiful” (polyuria). The passage, written about 1550 BCE, provides evidence that its sources were many centuries older.1
Egyptian medicine has influenced medical practices, including those of ancient Greece. While the writing of Hippocrates, the father of Greek medicine, describes excessive urinary flow with wasting of the body, Galen, his disciple, referred to the ailment as “diarrhea of the urine” and “the thirsty disease.” Arataeus, Galen’s contemporary, was the first to use the term “diabetes,” meaning to pass through or to siphon, in connection with these symptoms. Arataeus described the afflicted patients as “never ceasing to make water and the discharge is an incessant sluice let off; the thirst is ungovernable.”1
In another part of the ancient world, the Hindu physicians Charaka, Susruta, and Vaghbata described polyuria and glycosuria. The Hindu medical writings of the sixth century refer to diabetes as honey urine. They noted the attraction of flies and ants to the sweet urine of ailing patients.2 In addition, the affliction was described as a “disease of the rich, brought about by gluttony or over-indulgence in flour and sugar.”3 Ancient Chinese and Japanese physicians likewise recognized the symptoms of diabetes. They bluntly described “the urine of diabetics was very large in amount and it was so sweet that it attracted dogs.”4
KNOWLEDGE OF DIABETES IN THE MIDDLE AGES AND THE RENAISSANCE
The practice of medicine in the Middle Ages until approximately 1450 CE was fundamentally a restatement and acceptance of Greek practices. The famous Arabian physician Avicenna (9801027) recorded further observations that maintained and extended the previous Greek knowledge of the disease. Avicenna observed that diabetic patients have an irregular appetite associated with thirst, mental exhaustion, and loss of sexual function. In fact, he described many of the symptoms and complications observed today, such as carbuncles and furuncles. In addition, he reported that diabetes probably affected the liver, causing its enlargement.2
Maimonides was a renowned medieval physician, rabbi, and philosopher. He claimed to have observed more than 20 cases while Galen, describing the condition as rare, documented having treated only two cases. Maimonides proposed that the sweet water of the Nile and the prevailing heat that spreads over the kidneys caused diabetes.4 No major progress in understanding diabetes was made until the sixteenth century. Physicians began thinking of possible causes and exploring these ideas. Renaissance physicians, such as Paracelsus, challenged the medical doctrines of the time and attempted to reform medical thinking. They questioned conventional thinking with a renewed spirit of curiosity, objectivity, and experimentation. This period of reawakening in all disciplines accomplished two major breakthroughs in the approach and practice of medicine: it questioned authority and began to reject dogma by reverting back to the Socratic method of attempting to provide responses with evidence; and it laid the foundation for an accurate knowledge of human anatomy.
Thomas Willis, in 1674, was the first physician to rediscover and record the sweetness of the urine in diabetes referring to it as “the pissing evil.” He proposed that diabetes was primarily a disease of the blood and not the kidneys. He made the best qualitative urinalysis studies possible at the time.1 His work and Matthew Dobson’s experiments 100 years later conclusively established the diagnosis of diabetes in the presence of sugar in the urine and blood. Cullen, a prominent British clinician and educator, added the descriptive adjective “mellitus” (1769) from the Latin word for honey. Cullen wrote to Dobson, “You have done something in putting it beyond all doubt by your experiments....” Thereafter, diabetes was no longer considered a rare ailment.1,4
The Experimental Period
Experimental work as early as 1682 by Brunner demonstrated that the pancreas was the diseased organ in diabetic individuals.5 Experiments performed by Claude Bernard revealed that the liver releases a substance that affects blood sugar levels. In 1857, he isolated a starch-like substance, which he called “glycogen,” that was the precursor of glucose, “the internal secretion” of the liver. This observation established the role of the liver as a vital organ in diabetes.6 Langerhans, in his doctoral thesis presented in 1769, described small islands within the pancreas now known as the islets of Langerhans, even though he acknowledged at the time that he did not know the function of these ductless cells.7 Opie observed changes in the structure of the islet tissue of the pancreas of patients dying of diabetes. Minkowski’s (1889) removal of the pancreas from a dog unexpectedly resulted in uncontrolled polyuria and the progression towards diabetes. The observational work of Opie and the experiments of Minkowski began to link islet cell disease and diabetes.3,8 It was a major turning point in determining the endocrine function of the pancreas; it became clear that the substance secreted by the islet cells was inadequate in diabetic patients.
As with research in all diseases, many investigators concurrently work in different labs worldwide to find breakthroughs. Insulin was almost discovered in 1906 by Zuelzer in Berlin, in 1912 by Scott in Chicago, but was actually extracted by Paulesco in Romania in 1920. However, the world recognizes the definitive discovery and isolation of insulin to the Toronto group (1921-22), the collaborative work of Banting, Best, Collip, and Macleod.9
PREGNANCY AND DIABETES BEFORE THE DISCOVERY OF INSULIN
Diabetes was an affliction with a dismal prognosis. The dominant philosophy of the period before 1850 was that a successful pregnancy was virtually impossible when compromised by untreated diabetes. Pregnancy worsened the disease and shortened the lives of these women, many of whom died either during or shortly after the pregnancy. Blott wrote that “true diabetes is inconsistent with conception.”3 It was not until 1882 with Duncan’s description of 22 pregnancies that the prevailing philosophy was questioned.10 The trend, however, of high maternal and fetal mortality during or soon after pregnancy from uncontrolled diabetes persisted until the discovery of insulin. De Lee wrote that abortion and premature labor occurred in at least 33% of pregnancies of diabetic women. Perinatal mortality was close to 79%; maternal mortality about 30%, usually from diabetic ketoacidosis. In addition, diabetes was described as becoming progressively worse with each pregnancy.11 It is necessary to note that unrelated to diabetes, at this point in time, maternal and neonatal mortality was high for many reasons. Poor interventional obstetric care with increased risk of puerperal sepsis in addition to social and economic deprivations further compromised pregnancies. The link between congenital malformations and maternal diabetes in pregnancy is of more recent concern because not only are the historical records on the frequency of congenital malformations incomplete, but also they were not specifically identified as a result of diabetic pregnancies. The interrelationship of preeclampsia to diabetes is also difficult to trace before organized antenatal care.12
THE ADVENT OF INSULIN FOR PREGNANCIES COMPROMISED BY DIABETES
Up until this time, the only effective treatment for diabetes has been dietary. Restriction of food was known to ameliorate the symptoms of the disease. John Rollo’s work in 1797, as well as that of Allen in New York in 1919, documented a reduction in the symptoms of diabetes with a strict dietary regimen. Before the discovery of insulin, the work of Drs. Joslin of Boston and Laurence of London presaged the revolution in the treatment of diabetes and the potential for a positive pregnancy outcome for diabetic women. With the discovery and use of insulin, a new hope arose for diabetic women and their reproductive potential. With the introduction of insulin, maternal mortality fell dramatically but perinatal mortality decreased over time. However, the introduction of insulin did not ameliorate the problems of macro- somia and the associated traumatic injury to mother and fetus as well as continuing complications such as neonatal hypoglycemia, congenital malformations, preeclampsia, and infection.13
During the 1940s, insulin had made pregnancy relatively safe for the diabetic mother. However, patients with severe diabetes who in the pre-insulin era would never have been pregnant were now being treated. During this period, several attempts were made to ameliorate fetal death due to diabetes. It was observed that there was a significant stillbirth rate beyond 36 weeks of gestation. As a result, diabetic patients were routinely delivered at or before 36 weeks by cesarean section or by induction of labor if fetal death had not already occurred or if maternal complications indicated an early delivery. Today, when cesarean section is being performed for more and more indications, some researchers during the 1940s cautioned against adding another indication. Shir wrote, “Cesarean section is still a dangerous operation and diabetes does not render it less so.”14
During this time, several clinics were organized in the United States and Europe for the care of pregnant women with diabetes using an interdisciplinary approach featuring the cooperation of diabetologists, obstetricians, and pediatricians. Pedersen15 in Denmark found that fetal mortality rate was significantly lower in patients who were followed throughout pregnancy in comparison to those who were first diagnosed with the disease at or about the time of delivery. There was an emerging philosophy that closer surveillance and more frequent patient visits improved fetal outcome. Thus, long-term management, frequent hospitalizations, and early delivery became the norm. At the Joslin Clinic in Boston under the leadership of Priscilla White,16 new clinical recommendations for the care of pregnant diabetic women consisted of strict glycemic control, long-term hospitalization, and sound obstetrical management.
During the 1950s, risk factors for the development of abnormal carbohydrate metabolism in pregnancy were defined. In addition, screening programs were proposed, and soon thereafter normal values for the interpretation of the glucose tolerance test (OGTT) were suggested.17-18
Gestational diabetes as a clinical entity Gestational diabetes (GDM), defined as “carbohydrate intolerance of varying severity with onset or first recognition during pregnancy,” is a fairly recent addition to our knowledge about diabetes in pregnancy. In the first recorded case, Bennewitz considered diabetes a symptom of the pregnancy, and since the symptoms and the glycosuria disappeared after two successive pregnancies, he had some evidence to support his views.19 Other studies conducted in the United States and Scotland during the
1940s reported that lesser degrees of maternal hyperglycemia were also a risk to pregnancy outcome.20-22 O’Sullivan first used the term gestational diabetes in 1961. In the United States, the emphasis was on establishing criteria for the 100-g oral glucose tolerance test in pregnancy as an index of the subsequent risk of the mother to develop diabetes; the well-known O’Sullivan criteria were derived from this foundation.23 At about the same time, Mestman reported increased perinatal mortality associated with abnormal oral glucose tolerance in the obstetric population of Los Angeles County Hospital. Most of the women were either Latino (60%) or African-American; few Caucasians were represented in this population.24 Gestational diabetes as a clinical entity was slow to win converts, partly because of the relatively short phase of hyperglycemia during the latter part of pregnancy and its disappearance after the delivery. It has become increasingly accepted as a disease not only for the immediate outcome of pregnancy but also for the long-term effects on child and mother (maternal development in later life of type 2 diabetes).19
MODERN ERA IN THE MANAGEMENT OF DIABETES IN PREGNANCY
Strong pressures were exerted by the medical community to develop methods to increase the rate of insulin release from its injection site so that control of blood sugar concentrations could be improved. Over the years, pharmaceutical laboratories have developed increasingly reliable and stable insulin preparations. Monomeric insulin preparations are now established in the repertoire of clinical therapies. Human insulin became widely available in the 1980s. This led to the availability of mutant insulin (insulin analogues) that was designed primarily to have improved pharmacokinetic features for subcutaneous administration.
The modern era in the management of diabetes in pregnancy began in the 1960s with the introduction of reliable chemical and/ or physical measures to assess gestational age, fetal well-being, and placental function: ultrasonography made early assessment of gestational age and accurate fetal growth determination possi- ble25; the biophysical profile became routine in the management of high-risk pregnancies26; antepartum fetal heart rate testing was introduced; and Gluck et al. proposed the determination of the lecithyin-to-sphingomyelin ratio in the amniotic fluid as a test for fetal lung maturity.27 With proper use and interpretation of these tests, two of the four causes of fetal loss were reduced: sudden intrauterine death and neonatal death caused by hyaline membrane disease. In addition, physicians were able to avoid unnecessary early delivery. Other advances included fetal blood-sampling techniques during labor, glucose monitoring, insulin pumps, and neonatal intensive care units.
In 1977, Karlsson and Kjellmer28 reported that there was a linear relationship between glycemic control and perinatal mortality. It was the advent of self-monitoring blood glucose that made possible strict blood sugar control from early pregnancy on and a resulting decline in adverse neonatal events. The results of this technology and other corroborating evidence led to intensified glucose management to as close to nondiabetic levels as possible; perinatal mortality began to decrease.29-30
Except for coronary artery disease, pregnancy has not been shown to be contraindicated in diabetic women with vascular complications. Perinatal outcome does not appear to be significantly different from other insulin-dependent diabetes when metabolic control is stringently maintained.31 Studies have suggested that congenital malformations are caused by derangement in metabolism during organogenesis.32 During the 1980s a major effort was mounted to control blood sugar before conception. The findings from Fuhrman’s study demonstrated that normalization of metabolism with tight glycemic control during preconception and the organogenesis period can reduce the incidence of congenital malformations.33 However, women become pregnant without having achieved established levels of glycemic control despite preconception counseling.
Scientific evidence demonstrates that self-management education with self-monitoring blood glucose is the cornerstone of care for all persons with diabetes. In pregnancy, human insulin is recommended since the use of insulin analogues has not been adequately tested. Data on insulin lispro and insulin aspart are limited. Studies have demonstrated an improvement in glycemic control, an increased patient satisfaction, and a decrease in hypoglycemic episodes; but there is scant data on maternal and neonatal outcomes.
Intensified therapy in the management of GDM and pregestational diabetes is an approach to achieving established levels of glycemic control. It involves memory-based, self-monitoring blood glucose (SMBG), multiple injections of insulin or its equivalent, control of diet, and an interdisciplinary practitioner effort. Regardless of the treatment modality used, insulin or oral anti-diabetic drugs, the purpose is to achieve the established level of glycemic control that diminishes the rate of hypoglycemia and ketosis and maximizes perinatal outcome. As suggested by Freinkel,34 “normalizing maternal- fetal metabolism throughout every day of pregnancy would result in healthy infants, with a potential of achieving normal intellectual and growth development.”
WHAT HAVE BEEN, AND CONTINUE TO BE, THE DILEMMAS ASSOCIATED WITH DIABETES IN PREGNANCY?
A dilemma refers to a difficult or persistent problem. Major life dilemmas are associated with ill health. “When health is absent, wisdom cannot reveal itself, art cannot become manifest, strength cannot be exerted, wealth is useless, and reason is powerless.” (Herophilus, an ancient Greek physician).
Pregnancy is a special time in a woman’s life when she is coping with the anxiety of the pregnancy, delivery, and welfare of the fetus. This waiting period becomes even more anxiety-producing if the pregnancy is complicated with diabetes. Diabetes constitutes one of the most common and significant complications of medicine in general and pregnancy in particular. Every pregnant woman needs and should expect high-quality, evidence-based medical care. We, as women’s health physicians, should be satisfied with providing nothing less.
Measuring the success of treatment is based on the evaluation of the outcome in a given complication. The Saint Vincent’s Declaration (October, 1989) targeted the achievement of pregnancy outcomes in diabetic women to approximate those of nondiabetic women within the forthcoming 5-year period. This was not only the summary statement of the meeting organized by WHO and the IDF, but also a challenge to all clinicians and researchers interested in diabetes in pregnancy. A difference, in order to be a difference, must make a difference. Today, almost 25 years later, morbidity and mortality data in both GDM and pre-existing diabetes remain relatively unchanged.35-36 The debate of the past few decades over whether gestational diabetes is a clinical entity37-39 has been resolved, demonstrating that treatment can improve pregnancy outcome. Yet, in both medical forums and academic research, the diabetes in pregnancy community of clinicians and researchers has been too engrossed in fine-tuning diagnostic criteria and not more vigorously invested in pregnancy outcome. If we want to change our minds, we have to change our exposure. Changing our fixed ideas or positions doesn’t happen quickly—it is often a slow and tedious process. Integration and relationship-building by people (clinicians and researchers) talking to the peers they trust who represent the change in question is the route to sounder medical practice with fewer turf wars. The focus for the next decade is to respond to the outcome dilemma by seeking the means to uphold the Saint Vincent’s Declaration. Worldwide collaboration and dissemination of information is still the cornerstone for stimulating ideas and encouraging creative, evidence-driven research. This focus may help make the content of the St. Vincent’s Declaration a reality.
“Measurement is the first step that leads to control and improvement. If you can’t measure something, you can’t understand it. If you can’t understand it, you can’t control it. If you can’t control it, you can’t improve it” (H. James Harrington). What to test and how to test in diabetes management remains another unresolved dilemma, especially with the introduction of new technology: that is, self-monitoring blood glucose, continuous blood glucose insulin pumps, and continuous blood glucose monitoring. Another dilemma in need of resolution is an efficient and efficacious means to analyze the data generated by these technologies in order to enhance diabetes management. Still another significant dilemma involves the as yet not well defined threshold that needs to be targeted to initiate and maintain glucose control.
To date, there are numerous logarithmic formulae for estimating fetal weight, but there is a lack of uniformity and accuracy in measurement. Virtually all EFW (estimated fetal weight) formulae systematically overestimate birth weight. The imprecision of the formulae to account for fat deposits in fetuses and difficulties in measuring the abdominal circumference (AC) of fetuses of diabetic mothers may provide another explanation for the inaccuracies in EFW. However, most formulae are better at predicting macrosomia than are predictions based on gestational age alone. In infants of women with poorly controlled diabetes, there is characteristic enlargement of the majority of the organs but not of the brain. Increased weight of insulin-sensitive tissues including liver, pancreas, heart, lungs, and adrenals has been demonstrated in the infants of diabetic mothers (e.g., an increase in liver size of 179%). On the basis of this finding, it was suggested that morphometry be used to measure fetal liver length.
It was found that the increase in liver length was evident as early as the 18th week of gestation and became more marked with increased duration of pregnancy. Furthermore, individual liver length measures did not always remain constant when they were followed serially throughout pregnancy. This approach may provide an early fetal marker in addition to maternal markers (level of glycemia) for initiation of pharmacological therapy. Neonatal fat contributes approximately 12-14% of total birth weight; it accounts for about 50% of the variance. However, the amount of fetal fat in the subcutaneous locations used in anthropometric models may account for 40-80% of total fetal fat.40
The evaluation of the fetus of a diabetic mother should include in the first trimester a transvaginal ultrasound examination to rule out gross congenital abnormalities and CRL (crown rump length) measurements for dating. A complementary abdominal ultrasound examination for congenital malformations needs to be performed at approximately 20-23 weeks’ gestation. AC (abdominal circumference), fetal weight estimation, body composition, and cardiac evaluation (echocardiography) will enhance identification of the constitutionally large or small infants. During the third trimester, serial sonographic measurements need to be performed in order to assist in the selection of the treatment modality and the detection of deviant fetal growth.41
For pre-existing diabetes, preconception care is a major dilemma if we seek to adequately address the problem of congenital malformation. To date, the majority of women attend the first prenatal visit after organogenesis. For GDM (gestational diabetes mellitus), the window of opportunity for affecting outcome is narrow, that is, 8 to 12 weeks. Criteria for the assignment of treatment modality are lacking; that is, should treatment be based on diet alone, diet and exercise, insulin, or oral hypoglycemic agents? Furthermore, there is no benchmark for altering therapy when the desired glycemic results have not been achieved. We clinicians and researchers agree that early diagnosis, adequate treatment, and close follow-up are essential in order to minimize and often eliminate many of the diabetes-related complications. In our zeal to diagnosis and treat, however, we have not established universal criteria that enable a fluid, less controversial, less error- prone route towards enhanced perinatal and maternal outcome.
In light of extended life expectancy and adequate diabetic management for both the pregnant and nonpregnant patient, we need to address the diabetes epidemic worldwide when the number of known and undiagnosed individuals (approximately 9% for type 2 in the United States alone) is reaching staggering proportions. The double medical offensive of diabetes and obesity, that is, “diabesity,” with their short- and long-term complications contributes an additional dilemma of how to maximize maternal care before pregnancy. We, as women’s healthcare practitioners, are responsible for women throughout the life cycle and not solely during pregnancy.
The goal of the second edition of this textbook is to provide a forum to mitigate the dilemmas caused by diabetes in pregnancy by offering evidence-based responses by world-renowned clinicians and researchers often working and writing together in pursuit of this goal. The above-described dilemmas in no way seek to minimize the significance of basic science research in pathophysiology, immunology, and metabolic pathways associated with diabetes in pregnancy. Perhaps mapping of the human genome, which marks a new era in scientific research in the twentyfirst century, will provide the next chapter to be written in the history of diabetes.
I, and my distinguished group of expert contributors, have sought to provide a comprehensive approach to a very important topic. The book will be of interest and of help not only to obstetricians and gynecologists, but also to endocrinologists, internists, and primary care physicians. Every health professional who cares for women of reproductive age must be concerned with issues of gestational and pregestational diabetes. These include fetal mac- rosomia, congenital malformations, spontaneous abortions, and also complications arising as a result of obesity, hypoglycemia, hypertension, including retinopathy and nephropathy. A comprehensive understanding and firm foundation in the knowledge of the potential disease complications will positively alter the success rate for both mother and infant.
Women with diabetes want to have children and want to deliver them healthy while addressing the complications of their own disease. To the extent that this text advances student, faculty, and practitioners’ capacity to understand, conceptualize, and apply the information relevant to the needs of the pregnant diabetic and her fetus, I believe that we may contribute to the quality of life and care of these persons. We the authors hope that the information and the recommendations offered in this text will advance this mission.
REFERENCES
1. Barach J. Historical facts in diabetes. Ann Med History. 1928; 10:387.
2. Frank L. Diabetes in the texts of old Hindu medicine. Am J Gastroenterol. 1957; 27:76.
3. Peel J. A historical review of diabetes and pregnancy. Obstet Gynecol Br Comm. 1972; 79:385-95.
4. Ballard J. A descriptive outline of the history of medicine from its earliest days of 600 BC. Ann Med Hist. 1924; 6:53.
5. Brunner J. Experiments Nova Circa Pancreas. Amsterdam: H Weststenium, 1683.
6. Young F. Claude Bernard and the discovery of glycogen: A century of retrospect. Br Med J. 1957; 22(5033):1431-7.
7. Langerhans P. Beitrage zue mikroskopischen Anatomie der Bauchspeicheldruse [doctoral dissertation]. Berlin, Buchduckerei von Gustav Lange, 1869.
8. Opie E. On the relation of chronic interstitial pancreatitis to the islands of Langerhans and to diabetes mellitus. J Exp Med. 19001901; 5:397.
9. Bliss M. The Discovery of Insulin. Paul Harris Publishing: Edinburgh, 1983; 20-58.
10. Duncan G. Diabetes Mellitus: Principles and Treatment. Philadelphia: WB Saunders, 1951.
11. De Lee J. The Principles and Practice of Obstetrics, 3rd edition. Philadelphia: WB Saunders, 1920.
12. Hadden D. History of diabetic pregnancy. In: Textbook of Diabetes and Pregnancy. Hod M, Jovanovic L, De Renzo GC, de Leiva A, Langer O, eds. London: Dunitz, 2003; 1-12.
13. Papaspyros N. The History of Diabetes Mellitus, 2nd edition. Stuttgart: Thieme, 1952.
14. Shir M. Diabetes in pregnancy with observations in 28 cases. Am J Obstet Gynecol. 1938; 1032-5.
15. Pedersen J, Brandstrup E. Fetal mortality in pregnant diabetics. Lancet.1956; 27:607-10.
16. White P. Pregnancy complicating diabetes. Am J Med. 1949; 609-16.
17. Moss J, Mulholland H. Diabetes and pregnancy with special reference to the pre-diabetic state. Ann Intern Med. 1951; 34:678-91.
18. Wilkerson H, Remain Q. Studies of abnormal metabolism in pregnancy. Diabetes. 1957; 6:324-9.
19. Hadden D. The development of diabetes and its relation to pregnancy: The long-term and short-term historical viewpoint. In: Sutherland HW, Stowers JM, Pearson DWM, eds. Carbohydrate Metabolism in Pregnancy and the Newborn II. Springer-Verlag: London, 1989; 1-8.
20. Miller H. The effect of the pre-diabetic state on the survival of the fetus and the birth weight of the newborn infant. N Engl J Med. 1945; 233:376-8.
21. Hurwitz D, Jensen D. Carbohydrate metabolism in normal pregnancy. N Engl J Med. 1946; 234:327-9.
22. Gilbert J, Dunlop D. Diabetic fertility, maternal mortality and fetal loss rate. Br Med J. 1949; i:48-51.
23. O’Sullivan J, Mahan C. Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964; 13:278-85.
24. Mestman J, Anderson G, Barton P. Carbohydrate metabolism in pregnancy. Am J Obstet Gynecol. 1971; 109:41-5.
25. Campbell S. An improved method of fetal cephalometry by ultrasound. J Obstet Gynecol Br Commonw. 1968; 75:568-76.
26. Ray M, Freeman R, Pine S, et al. Clinical experience with the oxytocin challenge test. Am J Obstet Gynecol. 1972; 114:1-9.
27. Gluck L, Kulovich M, Borer R, et al. Diagnosis of the respiratory distress syndrome by amniocentesis. Am J Obstet Gynecol. 1971; 109:440-5.
28. Karlsson K, Kjellmer I. The outcome of diabetic pregnancies in relation to the mother’s blood sugar level. Am J Obstet Gynecol. 1972; 112:213.
29. Pedersen J, Molsted-Pedersen L, Andersen B. Assessors of fetal perinatal mortality in diabetic pregnancy. Diabetes. 1974; 23: 302.
30. Walford S, Gale E, Allison S, et al. Self-monitoring of blood glucose: Improvement of diabetic control. Lancet. 1978; 1:732-5.
31. Coustan D, Berkowitz R, Hobbins J. Tight metabolic control of overt diabetes in pregnancy. Am J Med. 1980; 68:845.
32. Miller E, Hare J, Cloherty J, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med. 1981; 304:1331.
33. Fuhrman K, Reiher H, Semmler K, et al. The effect of intensified conventional insulin therapy before and during pregnancy on the malformation rate of offspring of diabetic mothers. Exp Clin Endocrinol. 1984; 83:173.
34. Freinkel N. Banting Lecture 1980: Of pregnancy and progeny. Diabetes. 1980; 29:1023-35.
35. Langer O. Type 2 diabetes in pregnancy: Exposing deceptive appearances. J Mat Fetal Neonatal Med. 2008; 21(3):181-9.
36. Colstrup M, Mathiesen R, Ringholm L. Pregnancy in women with type 1 diabetes: Have the goals of St. Vincent’s Declaration concerning fetal and neonatal complications? J Mat Fetal Neonatal Med. 2013 PMID23570252.
37. Landon M, Spong C, Thorn E, et al. A multicenter randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009; 361:1339-48.
38. Crowther C, Hiller J, Moses J, et al. Australian carbohydrate intolerance study in pregnant women (ACHOIS) trial group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477-86.
39. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005; 192:989-97.
40. Langer O. Ultrasound biometry evolves in the management of diabetes in pregnancy. Ultrasound Obstet Gynecol. 2005; 26: 585-595.
41. Nicolaides K. Turning the pyramid of prenatal care. Fetal Diag Ther. 2011; 29:183-196.