辅助生殖后孕妇妊娠期代谢性疾病的管理

通过辅助生殖技术妊娠后,若合并代谢性疾病可导致多种不良妊娠结局。尽早对患代谢性疾病的孕妇进行生活方式干预、孕早期筛查和评估,同时在孕期进行严密的监测管理,适时终止妊娠,有助于控制病情进展,减少母胎并发症的发生。     

Metabolic changes, hypothalamo-pituitary-adrenal axis and oxidative stress after short-term starvation in healthy pregnant women

AIM: To compare metabolic effects and oxidative stress in pregnant and non-pregnant women after 12 h of fasting. METHODS: Twenty-six healthy women with uncomplicated singleton pregnancies between the 24(th) and 28(th) gestational week were recruited. After an overnight fast, venous blood samples and urine samples were tested for metabolic parameters characteristic for starvation, cortisol and oxidative stress products. Healthy non-pregnant women matched by age, body mass index and length of fasting comprised the control group. RESULTS: The metabolic parameters beta-hydroxybutyrate and free fatty acids in blood and ketones in urine showed no differences in pregnant and non-pregnant women. However, the oxidative stress parameters, 8,12-iso-iPF(2alpha)-VI, isoprostanes and malondialdehyde were significantly higher in pregnant subjects, as was cortisol. CONCLUSION: Healthy pregnant women are exposed to oxidative stress and activation of the hypothalamo-pituitary-adrenal axis, but not to metabolic changes resembling starvation during short fasting periods in comparison to non-pregnant healthy women.     

高龄孕产妇慢性代谢性疾病的长期管理

目前高龄孕产妇的比例逐渐增加。随着年龄的增长,糖尿病、高血压、高脂血症、肥胖等代谢性疾病患病风险增加,而年龄往往是这些疾病的独立危险因素。因此,高龄孕产妇较年轻者将面临更大的风险,对高龄孕产妇的管理要求也更高。但目前对于高龄孕产妇代谢性疾病的关注点主要在于孕期,对于产后的管理与远期康复的关注度较为缺乏,孕期保健及治疗上仍存在不足及局限。为使孕产妇健康生活质量得到保障,现对高龄孕产妇产后常见慢性代谢性疾病的管理进行综述,增强产科医生对年龄因素的关注与重视。建议采用全局随访理念,加强对高龄孕产妇产后的规范管理,注意定期监测血糖、血脂、血压、体质量和腰围等,从而降低远期代谢性疾病的发病风险。     

Phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and maternal infection.

OBJECTIVE: Normal pregnancy has been proposed to be a state of physiologic activation of the innate limb of the immune response. Recent studies have concluded that normal pregnancy produces inflammatory changes in peripheral blood leukocytes akin to those of sepsis. This unexpected observation has implications that are critical to understanding the susceptibility of pregnant women to sepsis, the pathophysiology of preeclampsia, and the biology of normal pregnancy. This study was designed to examine the phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and in pregnant patients with acute infection. STUDY DESIGN: A cross-sectional study was conducted that included nonpregnant women (n = 20), normal pregnant women (n = 57), and pregnant women with a positive blood culture and/or pyelonephritis (n = 16). Phenotypic and metabolic characteristics of monocytes and granulocytes were studied with the use of flow cytometry and monoclonal antibodies against surface markers (CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR). Intracellular reactive oxygen species were measured at basal conditions and after stimulation (oxidative burst). The stimulation index (ratio of intracellular reactive oxygen species after oxidative burst over basal state) was calculated. Nonparametric statistics were used. A probability value of <.01 was considered statistically significant. RESULTS: Granulocytes from normal pregnant women had a higher median mean channel brightness for CD14 and CD64, but lower median mean channel brightness for CD16 and HLA-DR than granulocytes of nonpregnant women. Granulocytes of patients with acute infection had a higher median mean channel brightness for CD64 and CD66b than granulocytes of normal pregnant women. Monocytes from patients with acute infection had a higher mean channel brightness for CD11b, CD16, CD18, CD49d, CD64, and CD66b than monocytes of normal pregnant women. Baseline intracellular reactive oxygen species, oxidative burst, and stimulation index values were significantly higher in the granulocytes and monocytes of normal pregnant women than in the granulocytes and monocytes of nonpregnant women. Similarly, baseline intracellular reactive oxygen species, oxidative burst, and stimulation index values were higher in women with acute infections than in normal pregnant women. CONCLUSION: Normal pregnancy was associated with phenotypic and metabolic changes of granulocytes and monocytes; pregnant women with acute infection had more marked phenotypic and metabolic changes of leukocytes than normal pregnant women. These qualitative differences indicate that the innate limb of the immune response is not maximally activated during normal pregnancy.     

Glucose kinetics in nondiabetic and diabetic women during the third trimester of pregnancy

Glucose kinetics were measured with 78% enriched D-[U-13C] glucose by the prime constant infusion technique during the third trimester of pregnancy in nine nondiabetic women, nine insulin-dependent diabetic women, six gestational diabetic women, and five control women (nonpregnant, nondiabetic) after an overnight fast. The patients not dependent on insulin were diagnosed as diabetic by oral glucose tolerance tests with the use of O'Sullivan and Mahan's criteria as modified by Carpenter and Coustan during the third trimester. The turnover studies were repeated post partum (6 weeks to 5 months after delivery) in 14 of the 24 pregnant subjects. All pregnant groups had a progressive fall in plasma glucose concentration during the study, but there was a steady state of plasma glucose concentration during the turnover period. In comparison to the control subjects, both the pregnant nondiabetic and pregnant insulin-dependent diabetic women had significantly higher plasma insulin concentrations throughout the study (p less than 0.05). There were no differences in the glucose turnover rate between any of the pregnant groups (1.7 +/- 0.2 mg . kg-1 min-1 in pregnant nondiabetic women; 1.5 +/- 0.2 mg . kg-1 min-1 in pregnant insulin-dependent diabetic women; and 2.1 +/- 0.4 mg . kg-1 min-1 in gestational diabetic women) and the control group of women (1.8 +/- 0.2 mg . kg-1 min-1) (mean +/- SEM). When the pregnant patients were studied post partum, the glucose turnover rate was similar when referenced to body weight; however, because of a 9.6% to 14.5% fall in weight post partum, the absolute values were higher in the pregnant women. We conclude that, in the basal state after an overnight fast, (1) both nondiabetic and diabetic patients accelerated their glucose turnover rate during pregnancy to provide for increased maternal and fetoplacental metabolic requirements, and (2) in the diabetic subjects the nearly normal plasma glucose and insulin concentrations and other metabolic parameters, as well as the glucose turnover rate, suggested good metabolic control during pregnancy in most of the insulin-dependent and in all of the gestational diabetic patients.     

Implications of abnormal liver function in pregnancy and non-alcoholic fatty liver disease

Elevated liver enzyme levels can sometimes be encountered in asymptomatic pregnant women. Similar to non-pregnant subjects, women with elevated gamma glutamyltransferase or alanine aminotransferase in early pregnancy have increased risk of subsequent complications, especially gestational diabetes mellitus. In non-pregnant subjects, the commonest cause of abnormal liver function currently is non-alcoholic fatty liver disease. Risk factors include obesity, diabetes, and the metabolic syndrome. It can progress to hepatocellular carcinoma through the development of steatohepatitis, and has become the leading cause for liver transplantation in women. Found in as many as 16–18% of pregnant women, it is associated with an increased risk of pregnancy complications and abnormal foetal growth, which predisposes the offspring to the same problem subsequently. This condition probably explains the majority of the cases of “idiopathic” abnormal liver function in pregnancy, and should be looked out for in high-risk women owing to its implications on their long-term health outcome.     

PPARγ、MMP-9在子痫前期合并代谢综合征的表达

目的:探讨过氧化物酶体增殖物受体γ(PPARγ)、基质金属蛋白酶-9(MMP-9)与子痫前期发病的关系。方法:用免疫组织化学法检测20例正常妊娠组、20例重度子痫前期不合并代谢综合征组和20例重度子痫前期合并代谢综合征组患者胎盘组织中PPARγ、MMP-9的表达。结果:(1)重度子痫前期组MMP-9阳性表达明显弱于正常组(P<0.05);(2)重度子痫前期组PPARγ表达明显弱于正常组(P<0.05),而重度子痫前期合并代谢综合征组PPARγ表达弱于重度子痫前期不合并代谢综合征组(P<0.05);(3)重度子痫前期合并代谢综合征组PPARγ和MMP-9表达呈正相关(r=1.0,P>0.01)。结论:重度子痫前期患者MMP-9、PPARγ表达下降,提示MMP-9、PPARγ可能与子痫前期发生密切相关。     

Plasma from women with preeclampsia has a low lipid and ketone body content--a nuclear magnetic resonance study.

OBJECTIVE: Using (1)H-nuclear magnetic resonance spectroscopy and chemometrics, we sought to establish the metabolic profile for preeclampsia and to identify biomarkers that would permit a distinction between women with a normal pregnancy and those suffering from preeclampsia. METHODS: Plasma samples from 11 normotensive pregnant women and 11 women with preeclampsia were analyzed. Principal component analysis was applied to differentiate between the two groups of patients. RESULTS: Lipid concentrations were found to be significantly lower in the plasma of patients suffering from preeclampsia than those in normotensive pregnant women (p = 0.031). There is also evidence to suggest that ketone body constituents may contribute to the discrimination. CONCLUSION: (1)H-nuclear magnetic resonance-based metabolic profiling can detect patients with preeclampsia.     

PPAR-gamma2 Pro12Ala polymorphism is associated with weight gain in women with gestational diabetes mellitus

OBJECTIVE: The polymorphisms of peroxisome proliferator-activator receptor-gamma2 (PPAR-gamma2) have been suggested to affect glucose metabolism and weight gain. Both conditions show great variations during pregnancy that makes pregnancy a suitable condition to detect any metabolic abnormalities related to PPAR-gamma2 polymorphisms. The objective of this study is to investigate the prevalence and metabolic impacts of PPAR-gamma2 polymorphism in control pregnant women and in patients with gestational diabetes mellitus (GDM). METHODS: In this case-control study, anthropometric and metabolic variables of 100 non-diabetic pregnant women and of 62 women who were diagnosed as having GDM according to 100 g oral glucose tolerance test (OGTT) were compared on the basis of PPAR-gamma2 polymorphism by univariate analysis of covariance. RESULTS: There were no statistically significant differences in baseline characteristics and the mean 50 g glucose challenge test values of pregnant women in both groups on the basis of PPAR-gamma2 genotype, although patients with Pro12Ala polymorphism were significantly taller in GDM group. The Pro12Ala polymorphism had no effect on 100 g OGTT results of patients with GDM. However, patients with GDM who had Pro12Ala polymorphism gained significantly more weight during their pregnancy. CONCLUSION: The PPAR-gamma2 Pro12Ala polymorphism was observed to have no effect on glucose metabolism in normal pregnant women and women with GDM. However, only the patients with GDM who had this polymorphism gained significantly more weight during their pregnancy. It seems that Pro12Ala polymorphism plays a dynamic and interactive role in the regulation of BMI and glucose homeostasis.     

Metabolic syndrome in normal and complicated pregnancies

OBJECTIVE: To evaluate the prevalence of metabolic syndrome and its components in normal and complicated pregnancies. STUDY DESIGN: Setting: university hospital, tertiary referral centre. Subjects: 90 pregnant women in four groups: 20 women with preeclampsia, 20 women with gestational hypertension, 30 women with late-onset gestational diabetes and 20 healthy pregnant women as a control group. Intervention: peripheral insulin resistance was measured by using the insulin tolerance test. Glucose, triglycerides, high-density lipoprotein cholesterol, blood pressure and body mass index were analysed. Comparisons were done by Chi-squared test, one-way analysis of variance and the Bonferroni's test. Prevalence of the metabolic syndrome was calculated by adapting both the WHO and the NCEP definitions of the metabolic syndrome to pregnancy. RESULTS: There were no cases of metabolic syndrome in the control group according to any of the adapted definitions. The prevalence of this syndrome was 3.3% and 10% in the late-onset gestational diabetes group, 35% and 20% in the gestational hypertension group and 30% and 30% in the preeclampsia group for the WHO and the NCEP definitions, respectively. CONCLUSIONS: Metabolic syndrome is present in about one-third of women with pregnancy-induced hypertension but only in 10% of women with late-onset gestational diabetes.     

子痫前期对氧磷酶1活性和代谢综合征变量变化的临床研究

目的:研究子痫前期患者血清对氧磷酶1(PON-1)活性及代谢综合征变量的变化和发生情况。方法:选择年龄、孕周、产次相匹配的轻度子痫前期患者38例(MPE组),重度子痫前期患者45例(SPE组),正常孕妇63例(对照组)为研究对象,测定其血清PON-1活性、丙二醛(MDA)、血脂及空腹血糖水平等指标。结果:子痫前期患者(MPE组+SPE组)血清MDA、总胆固醇、甘油三酯、低密度脂蛋白水平(LDL)均明显高于对照组(P<0.05),而血清PON-1活性及高密度脂蛋白(HDL)较对照组明显降低(P<0.05);SPE组空腹血糖较MPE组和对照组明显升高(P均<0.05)。子痫前期患者血清PON-1活性与MDA、甘油三酯、LDL水平呈负相关(P均<0.05),与HDL水平呈正相关(P<0.05),与BMI及空腹血糖无明显相关性(P>0.05)。对照组、MPE组及SPE组代谢综合征的发生率分别为3.2%,18.4%,33.3%。结论:子痫前期患者有代谢综合征的标志,推断两种疾病相互关联。子痫前期患者血清PON-1活性显著降低,可能为两种疾病相互关联的重要原因之一。     

Gestational diabetes reverses the circadian variation of plasma insulin response to intravenous glucose

Both healthy third-trimester pregnant women and a group of women with gestational diabetes failed to show a difference in glucose clearance rates when given an intravenous glucose bolus at 8 AM compared with 4 PM. The plasma insulin response in the healthy pregnant women was greater at 8 AM. In the diabetic group, the peak insulin response was greater at 4 PM, but it was more prolonged after the 8 AM tests. These alterations in plasma insulin response were especially striking in the subgroup of obese women with gestational diabetes, who demonstrated metabolic differences compared with their nonobese counterparts.     

母胎溶质转运家族2成员2基因型与妊娠期糖尿病的关系

目的 通过对妊娠期糖尿病(gestational diabetes mellitus,GDM)孕妇及其子代溶质转运家族2成员2(solute cartier family 2,member 2,SLC2A2)基因多态性分析,探讨母胎基因型差异与GDM发病的关系. 方法 采用聚合酶链反应-高效变性液相色谱分析方法 ,检测126例孕妇(GDM组51例,正常孕妇对照组75例)及其分娩并随访到的62例新生儿(GDM组子代23例,对照组子代39例)的SLC2A2基因单核苷酸多态性位点rs5396(包括A和G等位基因,AA、AG和GG基因型)的基因频率分布情况. 结果 GDM组孕妇AA基因型频率高于对照组孕妇(86.3%和70.7%,P<0.05).A等位基因频率在对照组母子之间(85.3%和80.8%)、GDM组母子之间(93.1%和87.0%)、对照组子代与GDM组子代之间的分布差异均无统计学意义(P>0.05).GDM组母子均为AA基因型的比例为50.0%,对照组母子为55.0%(P=0.720). 结论 母亲的SLC2A2基因rs5396基因多态性可能与GDM发生相关,但子代的rs5396基因型变异与GDM的发病无相关性.母亲与其子代基因型差异与GDM发病相关的假设尚需进一步研究.     

Maternal serum nitric oxide levels associated with biochemical and clinical parameters in hypertension in pregnancy

OBJECTIVES: To measure maternal serum concentrations of total nitrites, as an index of nitric oxide synthesis, in normal and hypertensive pregnant women, and to examine the correlation between these concentrations and several variables of clinical interest. STUDY DESIGN: A total of 60 women in four different groups were studied: 10 normotensive pregnant women, 17 pregnant women with preeclampsia, 18 pregnant women with gestational hypertension and 15 pregnant women with chronic hypertension. Serum nitrite levels were determined using the Griess reaction after reduction with nitrate reductase. RESULTS: Serum nitrite levels were higher in preeclamptic women (34.11+/-14 micromol/l, P=0.04), lower in chronic hypertensive women (19.56+/-6.46 micromol/l, P=0.04) and similar in women with gestational hypertension (26.97+/-9.44 micromol/l) in comparison to the control group (25.37+/-7.24 micromol/l). Serum nitrite levels in preeclamptic women had significant positive correlations with hematocrit, fasting insulinemia, and apolipoprotein B and negative correlations with platelet count, serum phosphorus and glucose:insulin ratio. In pregnant women with chronic hypertension a negative correlation was found between serum nitrite levels and active partial thromboplastin time. In pregnant women with gestational hypertension, serum nitrite levels had negative correlations with birthweight and 24-h urine calcium, and positive correlations with mean corspuscular hemoglobin, 24-h urine sodium and maternal age. CONCLUSIONS: We suggest that in women with preeclampsia, a higher maternal nitric oxide level may act as a compensatory mechanism against hemoconcentration and platelet aggregation and that nitric oxide production may be related to some metabolic events. In women with gestational hypertension, higher serum nitrite levels may be related to clinical and biochemical findings common in preeclampsia. In chronic hypertension, a lower maternal nitric oxide level is related to the status of coagulation.     

Oxidant release is dramatically increased by elevated glucose concentrations in neutrophils from pregnant women.

OBJECTIVE: To evaluate the mechanism of oxidative stress at glucose levels accompanying diabetic pregnancy. Specifically, we hypothesize that elevated glucose overwhelms hexose monophosphate shunt (HMS) down-regulation observed during pregnancy. METHODS: Peripheral blood cells from normal healthy pregnant women were exposed to heightened glucose levels to provide an in vitro model of the effects of diabetic pregnancy. Changes in NAD(P)H, reactive oxygen species (ROS) and nitric oxide (NO) production were evaluated in single cells. RESULTS: Altered metabolic dynamics, as judged by NAD(P)H autofluorescence of neutrophils from both pregnant and non-pregnant women, were observed during incubation with 14 mM glucose, a pathophysiologic level. In parallel, increased production of ROS and NO was observed. The ROS and NO levels attained in cells from pregnant women were greater than those observed in cells from non-pregnant women. Inhibitors of the HMS and NAD(P)H oxidase blocked these effects. These metabolic and oxidant changes required approximately one minute, suggesting that transient glucose spikes during pregnancy could trigger this response. CONCLUSIONS: Elevated glucose levels enhance HMS activity and oxidant production in cells from pregnant women. This mechanism may be generally applicable in understanding the role of diabetes in materno-fetal health.     

Third-trimester erythrocytapheresis in pregnant patients with sickle cell disease.

OBJECTIVE: To evaluate the effects of prophylactic transfusion by means of erythrocytapheresis at the beginning of the third trimester of pregnancy in women with sickle cell disease (SCD). METHODS: A cohort of 14 pregnant women with SCD who received prophylactic erythrocytapheresis transfusions at the beginning of the third trimester was retrospectively compared with a cohort of 17 pregnant women who received simple prophylactic transfusions for no indication other than SCD severity. RESULTS: Prophylactic erythrocytapheresis transfusions were associated with a lower risk of intrauterine growth restriction (OR, 0.11; 95% confidence interval, 0.01-1.00) and oligohydramnios (OR, 0.65; 95% confidence interval, 0.45-0.92) in pregnant women with SCD. CONCLUSION: These results suggest that erythrocytapheresis transfusions are beneficial in women with SCD who are in the third trimester of pregnancy. Given the decrease in transfusion risks, this therapy deserves further evaluation in future trials.     

How to diagnose and manage Cushing’s disease during pregnancy,when hypercortisolism is mild?

Diagnosis of mild Cushing’s disease (CD) can be difficult in pregnant women, because its clinical and biochemical features can be erroneously interpreted as consequence of the gestation. Corticotropin releasing hormone (CRH) and desmopressin (DDAVP) tests are currently used to confirm CD, but data concerning adrenocorticotropic hormone (ACTH) response during pregnancy are lacking. A woman with mild cushingoid features was evaluated during the first trimester of gestation. Serum cortisol was normal at morning, but increased at midnight and incompletely suppressed by 1-mg dexamethasone overnight administration. Also 24-h urinary free cortisol levels were mildly elevated. She delivered vaginally a healthy newborn at the 39th week of an uneventful pregnancy. After delivery, an ACTH-secreting microadenoma was surgically removed. During the first trimester of gestation and after delivery, human CRH (h-CRH) and DDAVP-stimulated ACTH peaks were higher than those measured in 22 healthy premenopausal women. While the ACTH/h-CRH peak was intermediate between those measured in the healthy women and in 9 CD female patients, ACTH/DDAVP peak was in the range of CD patients and dramatically higher than those of healthy women. However, ACTH increase after h-CRH was significantly higher after delivery than during gestation (p?<?0.003), while ACTH responses to DDAVP were similar. In pregnant women with mild cushingoid features, h-CRH and DDAVP tests are useful to confirm the diagnosis of CD. Mild hypercortisolism can be well tolerated, but cardiovascular and metabolic parameters should be monitored carefully.     

Alterations of maternal metabolism in normal and diabetic pregnancies: differences in insulin-dependent, non-insulin-dependent, and gestational diabetes

In normal and diabetic pregnancies, the placenta functions as a complex endocrine gland that modulates all classes of maternal nutrients to the fetus. The metabolic alterations of normal pregnancy are diabetogenic and associated with modest resistance to endogenous insulin. Pregnant women with carbohydrate intolerance represent three metabolically heterogeneous groups: type I (insulin-dependent), type II (non-insulin-dependent), and gestational diabetes. Patients with type I diabetes are at risk for ketosis and require replacement therapy because of a deficient production of insulin. They have decreased 24-hour, around-the-clock levels of C-peptide and glucagon, and lower nocturnal cortisol values and higher 24-hour prolactin levels than those of women with type II diabetes. Type II pregnant diabetic patients are not prone to ketosis and are more resistant to endogenous and exogenous insulin. They have higher fasting and meal-stimulated levels of C-peptide, accentuated fasting hypertriglyceridemia, and significantly lower high-density lipoprotein cholesterol levels than those of normal or type I women. In gestational diabetes, the metabolic stress of pregnancy evokes reversible hyperglycemia which may be associated with either a surfeit or a deficiency of insulin. These metabolic differences among diabetic pregnant women could have implications for placental structure and function that might influence fetal growth.     

Plasma From Women with Preeclampsia Has a Low Lipid and Ketone Body Content—A Nuclear Magnetic Resonance Study

Objective: Using ¹H-nuclear magnetic resonance spectroscopy and chemometrics, we sought to establish the metabolic profile for preeclampsia and to identify biomarkers that would permit a distinction between women with a normal pregnancy and those suffering from preeclampsia. Methods: Plasma samples from 11 normotensive pregnant women and 11 women with preeclampsia were analyzed. Principal component analysis was applied to differentiate between the two groups of patients. Results: Lipid concentrations were found to be significantly lower in the plasma of patients suffering from preeclampsia than those in normotensive pregnant women (p = 0.031). There is also evidence to suggest that ketone body constituents may contribute to the discrimination. Conclusion: ¹H-nuclear magnetic resonance-based metabolic profiling can detect patients with preeclampsia.     

Management of third-trimester diabetic pregnancies with the use of continuous subcutaneous insulin infusion therapy: A pilot study

Six women with juvenile-onset diabetes were managed as outpatients during the third trimester of pregnancy with continuous subcutaneous insulin infusion therapy. Twenty-four-hour metabolic profiles for plasma glucose, β-hydroxybutyrate, and triglycerides were monitored prior to, 1 week, 5 weeks, and 10 weeks after initiation of continuous subcutaneous insulin infusion therapy and compared with the metabolic profiles of 10 normal (nondiabetic) pregnant women. Near-normal metabolic profiles were achieved in these patients after 5 weeks of therapy in this pilot study. Patient motivation, compliance, and understanding of their illness were crucial in achieving the therapeutic goals of normoglycemia.