John L. Kitzmiller

Managing preexisting diabetes for pregnancy: Summary of evidence and consensus recommendations for care

This document presents consensus panel recommendations for the medical care of pregnant women with preexisting diabetes, including type 1 and type 2 diabetes. The intent is to help clinicians deal with the broad spectrum of problems that arise in management of diabetes before and during pregnancy, and to prepare diabetic women for treatment that may reduce complications in the years after pregnancy. A thorough discussion of the evidence supporting the recommendations is presented in the book, Management of Preexisting Diabetes and Pregnancy , authored by the consensus panel and published by the American Diabetes Association (ADA) in 2008 (1). A consensus statement on obstetrical and postpartum management will appear separately. The recommendations are diagnostic and therapeutic actions that are known or believed to favorably affect maternal and perinatal outcomes in pregnancies complicated by diabetes. The grading system adapted by the ADA was used to clarify and codify the evidence that forms the basis for the recommendations (2). Unfortunately there is a paucity of randomized controlled trials (RCTs) of the different aspects of management of diabetes and pregnancy. Therefore our recommendations are often based on trials conducted in nonpregnant diabetic women or nondiabetic pregnant women, as well as on peer-reviewed experience before and during pregnancy in women with preexisting diabetes (3–4). We also reviewed and adapted existing diabetes and pregnancy guidelines (5–10) and guidelines on diabetes complications and comorbidities (2,3,11–14). ### A. Organization of preconception and pregnancy care #### Recommendations

Pre-Conception Care of Diabetes, Congenital Malformations, and Spontaneous Abortions

As noted by many previous reviewers (1-4), major congenital malformations remain the leading cause of mortality and serious morbidity in infants of mothers with established diabetes (IDM). In addition to the associated human suffering, the malformations are very expensive in both shortand long-term health care costs. The purpose of this technical review is to provide the detailed background to the American Diabetes Associations Position Statement on clinical guidelines for pre-conception care of women with diabetes (5-7a). The review is organized to discuss several related topics.

Relationship of Fetal Macrosomia to Maternal Postprandial Glucose Control During Pregnancy

OBJECTIVE To determine the gestational ages at which maternal hyperglycemia is most closely related to fetal macrosomia; to determine whether macrosomia is related to elevations of fasting glucose, postprandial glucose, or both; and to assess the relationship of macrosomia to maternal insulin dose and caloric intake. RESEARCH DESIGN AND METHODS One hundred eleven consecutive pregnant women with Class B through RF diabetes were studied longitudinally from 13 to 36 wk gestation. Macrosomia was defined by birthweight > 90th percentile for gestational age based on California norms. Women who delivered macrosomic infants were compared with those without macrosomic infants on pre- and postprandial blood glucose, GHb, insulin dose, macronutrient intake, and several other maternal variables. RESULTS Macrosomia occurred in 32 (29%) cases, although several measures indicated reasonable glycemic control throughout pregnancy. Women delivering macrosomic infants did not differ from those without macrosomic infants in maternal age, prepregnant weight, duration of diabetes, White class, macronutrient intake, GHb, or fasting glucose. Macrosomia was associated with higher postprandial glucose levels up to 32 wk gestation and lower insulin doses from 29 to 36 wk gestation. In multiple logistic regression, macrosomia was significantly associated with postprandial glucose only between 29 and 32 wk gestation. Postprandial glucose values < 7.3 mM (< 130 mg/dl) were associated with a higher risk of small-for-gestational-age infants (18%) compared with values above this level (1%). CONCLUSIONS Because macrosomia was related to postprandial glucose but not fasting glucose, we conclude that postprandial glucose measurement should be a part of routine care for diabetes in pregnancy. A target 1-h postprandial glucose value of 7.3 mM (130 mg/dl) may be the level that optimally reduces the incidence of macrosomia without increasing the incidence of small-for-gestational-age infants.

Diabetic nephropathy and perinatal outcome

We studied the effect of diabetic nephropathy on the course of pregnancy, perinatal outcome, and infant development and determined the influence of pregnancy on maternal hypertension and renal function. Maternal proteinuria usually increased during pregnancy (greater than 3 gm/24 hours in 69%), and hypertension was present by the third trimester in 73%. The degree of proteinuria correlated with diastolic pressure and creatinine clearance. After pregnancy, proteinuria declined in 65% of the mothers, hypertension was absent in 43.5%, and the expected rate of fall in creatinine clearance was not accelerated. Among 35 patients, abortion occurred spontaneously or was performed electively in 25.7%, and 71% of the remainder underwent delivery before 37 weeks. Birth weight was related to maternal blood pressure and creatinine clearance. Neonatal morbidity was common, but the perinatal survival rate was 89%. Infants seen at follow-up without congenital anomalies had normal development at 8 to 36 months of age. We concluded that perinatal outcome has significantly improved for diabetic women with nephropathy.

Maternal—Fetal relation: II. Further characterization of an immunologic blocking factor that develops during pregnancy☆

Abstract An IgG blocking factor previously described to be present in the serum of normal multigravid women inhibits the production of macrophage migration inhibitory factor (MIF) by maternal lymphocytes responding to paternal antigens. In the present study, this blocking factor was detected in primigravid women during 12–26 weeks of gestation. The factor was found to block MIF production as well as lymphocyte proliferation induced by an allogeneic stimulus. Blocking activity was detected at about the same time during gestation when measured in either assay. In addition, IgG fractions isolated from placental eluates were found to suppress maternal MIF production to the same extent as serum blocking activity. Like serum blocking activity, the placental IgG suppressed MIF in a specific manner (autologous placental IgG suppressed MIF but not homologous placental IgG). In an attempt to study the antigenic nature of the trophoblast, we observed that solubilized trophoblast membranes were able to stimulate maternal mononuclear cells to produce MIF; MIF production in response to trophoblast membranes was antigen specific in that autologous but not homologous membranes were stimulatory. HLA-A,B,C and DR typing of normal gravid women and women with idiopathic spontaneous abortions revealed similar degrees of matching and mismatching in both groups of subjects for these antigens. There was no significant increase or decrease in any HLA-A,B,C, antigens in the group of chronic aborters. Thus, the biologic significance of an IgG antibody that develops during pregnancy has been further characterized and its role in the maintenance of normal-term pregnancy discussed.

Gestational diabetes after delivery : Short-term management and long-term risks

After the intensified treatment often required for treating gestational diabetes mellitus (GDM), clinicians may be tempted to relax after delivery of the baby. If it is assumed that no further management is needed, an excellent opportunity to improve the future health status of these high-risk women may be lost. There are special concerns for the early postpartum care of women with GDM. Encouragement and facilitation of exclusive breastfeeding is very important because of the profound short-term as well as long-term health benefits to the infant and the reduced risks for subsequent obesity and glucose intolerance demonstrated in many breastfeeding women. A method of contraception should be chosen that does not increase the risk of glucose intolerance in the mother. Some women with GDM will have persisting hyperglycemia in the days after delivery that will justify medical management for diabetes and perhaps for hypertension, microalbuminuria, and dyslipidemia. Treatment should be maintained according to the guidelines of the American Diabetes Association and other relevant organizations and adjusted for the needs of lactation. Treatment should be continued in adequate fashion to minimize risks to the early conceptus if there is a subsequent planned or unplanned pregnancy. Most women with GDM will not have severe hyperglycemia after delivery. This group should be followed for at least 6–12 weeks to determine their glucose status. Many studies over 3 decades on all continents of the globe demonstrate the high risk of subsequent diabetes in this female population. The degree of this risk is best assessed by glucose tolerance testing. Randomized controlled trials have proven that several interventions (diet and planned exercise 30–60 min daily at least 5 days per week and antidiabetic medications) can significantly delay or prevent the appearance of type 2 diabetes in the women with impaired glucose tolerance (IGT). The high-risk women can …

Experimental preeclampsia produced by chronic constriction of the lower aorta: validation with longitudinal blood pressure measurements in conscious rhesus monkeys.

OBJECTIVES Our goals were (1) to determine whether hypertension, proteinuria, and glomerular endotheliosis can be produced by chronic reduction of lower aortic pressure in pregnant rhesus monkeys and (2) to study the time course of the development of hypertension by means of longitudinal arterial blood pressure measurements in conscious, unrestrained pregnant rhesus monkeys. STUDY DESIGN Indwelling arterial catheters were placed at 103 +/- 4 days of gestation (term 160 days) for measurement of arterial pressure before and after reduction of lower aortic pressure. At 116 +/- 7 days lower aortic pressure was reduced by 24 +/- 11 mm Hg in 11 monkeys (experimental group) by a stricture on the aorta just below the renal arteries; six monkeys (controls) underwent a sham operation. Resting on the aorta just below the renal arteries; six monkeys (controls) underwent a sham operation. Resting pressures were measured three to five times per week by a tether-and-swivel system. RESULTS Baseline arterial pressure averaged 81 +/- 6 mm Hg. In the experimental group four monkeys had adverse outcomes (one maternal death with severe hypertension, one abruptio placentae with stillbirth, and two spontaneous preterm deliveries with hypertension). There was one preterm delivery in the control group. Of the seven monkeys with aortic stricture who continued to term, four developed sustained hypertension (mean pressure 18 +/- 6 mm Hg above baseline), proteinuria, and moderate-to-severe glomerular endotheliosis. None of the controls had hypertension or proteinuria, but two had endotheliosis. CONCLUSION These observations confirm that a syndrome resembling preeclampsia can be produced by a reduction of lower aortic pressure, and they demonstrate that the associated hypertension is not an artifact of anesthesia. This model may prove useful in studying the pathophysiologic mechanisms of preeclampsia.

Prenatal diagnosis of neural tube defects: VIII. The importance of serum alpha-fetoprotein screening in diabetic pregnant women☆

Maternal serum alpha-fetoprotein (AFP) screening of routine pregnancy is a valuable tool for the prenatal detection of neural tube defects (NTDs). Against our background experience with greater than 24,000 screened pregnancies, we have studied 411 pregnant insulin-dependent diabetic women. More than a tenfold increase (19.5/1,000) in the frequency of NTDs was observed in the offspring of these diabetic patients (p less than 0.000001). Serum AFP values were lower in diabetic than in nondiabetic women. Our data indicate that the normal standard of care for diabetic pregnancy should include serum AFP screening.

Cost-Benefit Analysis of Preconception Care for Women With Established Diabetes Mellitus

OBJECTIVE To determine whether the additional costs of preconception care are balanced by the savings from averted complications. Several studies have demonstrated the efficacy of preconception care in reducing congenital anomalies in infants born of mothers with pre-existing diabetes mellitus. RESEARCH DESIGN AND METHODS This study used literature review, consensus development among an expert panel of physicians, and surveys of medical care personnel to obtain information about the costs and consequences of preconception plus prenatal care compared with prenatal care only for women with established diabetes. Preconception care involves close interaction between the patient and an interdisciplinary health-care team as well as intensified evaluation, follow-up, testing, and monitoring. The outcome measures assessed in this study are the medical costs of preconception care versus prenatal care only and the benefit-cost ratio. RESULTS The costs of preconception plus prenatal care are

Prenatal diagnosis of neural tube defects

17,519/delivery, whereas the costs of prenatal care only are