Maternal obesity, gestational weight gain, and offspring adiposity: the exploring perinatal outcomes among children study.

OBJECTIVE: To determine whether adequate vs excessive gestational weight gain (GWG) attenuated the association between maternal obesity and offspring outcomes. STUDY DESIGN: Data from 313 mother-child pairs participating in the Exploring Perinatal Outcomes among Children study were used to test this hypothesis. Maternal prepregnancy body mass index (BMI) and weight measures throughout pregnancy were abstracted from electronic medical records. GWG was categorized according to the 2009 Institute of Medicine criteria as adequate or excessive. Offspring outcomes were obtained at a research visit (average age 10.4 years) and included BMI, waist circumference (WC), subcutaneous adipose tissue (SAT) and visceral adipose tissue, high-density lipoprotein cholesterol, and triglyceride levels. RESULTS: More overweight/obese mothers exceeded the Institute of Medicine GWG recommendations (68%) compared with normal-weight women (50%) (P < .01). Maternal prepregnancy BMI was associated with worse childhood outcomes, particularly among offspring of mothers with excessive GWG (increased BMI [20.34 vs 17.80 kg/m(2)], WC [69.23 vs 62.83 cm], SAT [149.30 vs 90.47 cm(2)], visceral adipose tissue [24.11 vs 17.55 cm(2)], and homeostatic model assessment [52.52 vs 36.69], all P < .001). The effect of maternal prepregnancy BMI on several childhood outcomes was attenuated for offspring of mothers with adequate vs excessive GWG (P < .05 for the interaction between maternal BMI and GWG status on childhood BMI, WC, SAT, and high-density lipoprotein cholesterol). CONCLUSION: Our findings lend support for pregnancy interventions aiming at controlling GWG to prevent childhood obesity.

The long-term impact of intrauterine growth restriction in a diverse U.S. cohort of children: the EPOCH study.

OBJECTIVE: To explore the long-term impact of intrauterine growth restriction (IUGR) among a diverse, contemporary cohort of U.S. children. DESIGN AND METHODS: A retrospective cohort of 42 children exposed to IUGR and 464 unexposed who were members of Kaiser Permanente of Colorado. Height and weight measurements since birth and measures of abdominal adiposity and insulin-resistance were measured at an average age of 10.6 (±1.3) years. RESULTS: Infants born IUGR experienced "catch-up growth" in the first 12 months of life at a rate of 3.58 kg/m² compared to 2.36 kg/m² in unexposed infants (P = 0.01). However, after 1 year of age, no differences in BMI growth velocity were observed. Nevertheless children exposed to IUGR had higher waist circumference (67.0 vs. 65.3 cm, P = 0.03), higher insulin (15.2 vs. 11.0 µU/ml, P = 0.0002), higher HOMA-IR (2.8 vs. 2.3, P = 0.03), and lower adiponectin levels (9.0 vs. 12.0 µg/ml, P = 0.003) in adolescence, independent of other childhood and maternal factors. CONCLUSIONS: Our data from a contemporary US cohort suggests that children exposed to IUGR have increased abdominal fat and increased insulin resistance biomarkers despite no differences in BMI growth patterns beyond 12 months of age. These data provide further support for the fetal programming hypothesis.

Long-term impact of neonatal breastfeeding on childhood adiposity and fat distribution among children exposed to diabetes in utero.

OBJECTIVE: To evaluate whether breastfeeding attenuates increased childhood adiposity associated with exposure to diabetes in utero. RESEARCH DESIGN AND METHODS: Retrospective cohort study of 89 children exposed to diabetes in utero and 379 unexposed youth with measured BMI, waist circumference, skinfolds, visceral (VAT) and subcutaneous (SAT) abdominal fat. A measure of breast milk-months was derived from maternal self-report and used to categorize breastfeeding status as low (<6) and adequate (≥ 6 breast milk-months). Multiple linear regression was used to model the relationship between exposure to diabetes in utero and offspring adiposity outcomes among youth stratified according to breastfeeding status. RESULTS: Adequate (vs. low) breastfeeding status was associated with significantly lower BMI, waist circumference, SAT, and VAT at ages 6-13 years. Among youth in the low breastfeeding category, exposure to diabetes in utero was associated with a 1.7 kg/m(2) higher BMI (P = 0.03), 5.8 cm higher waist circumference (P = 0.008), 6.1 cm(2) higher VAT (P = 0.06), 44.6 cm(2) higher SAT (P = 0.03), and 0.11 higher ratio of subscapular-to-triceps skinfold ratio (P = 0.008). Among those with adequate breastfeeding in infancy, the effect of prenatal exposure to diabetes on childhood adiposity outcomes was not significant. CONCLUSIONS: Adequate breastfeeding protects against childhood adiposity and reduces the increased adiposity levels associated with exposure to diabetes in utero. These data provide support for mothers with diabetes during pregnancy to breastfeed their infants in order to reduce the risk of childhood obesity.

A descriptive evaluation of unfractionated heparin use during pregnancy.

BACKGROUND: The mainstay of oral anticoagulant therapy, warfarin sodium, crosses the placenta during pregnancy and may cause fetal complications. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) do not cross the placenta and have demonstrated utility in the prevention and treatment of thrombosis during pregnancy. OBJECTIVES: The purpose of this study was to review treatment strategy, indication, and maternal and fetal outcomes in anticoagulated pregnancies at Kaiser Permanente Colorado. PATIENTS/METHODS: We identified 103 pregnancies in 93 mothers prescribed an anticoagulant during a pregnancy occurring between January 1, 1998 and March 31, 2005. RESULTS: The majority of patients were treated with UFH (89.3%). Indications for anticoagulation included venous thromboembolism (VTE) prophylaxis (53.4%), history of pregnancy loss (29.1%), acute VTE (16.5%), and history of cerebral vascular accident (CVA) (1.0%). There were no maternal deaths. Fetal demise occurred in 8 pregnancies (7.8%) at a median 14 weeks gestation (range 7-22 weeks). No fetal demise occurred in pregnancies treated for acute VTE or history of CVA. There were two occurrences of pulmonary embolism (1.9%) and two hemorrhagic events requiring transfusion (1.9%). CONCLUSIONS: Maternal and fetal adverse events were infrequent in our population of anticoagulated pregnancies. UFH remains a viable option among more expensive LMWH products.

Intrauterine balloon tamponade in the management of postpartum hemorrhage.

This article reviews our experience with the use of intrauterine tamponade with balloon catheters in the management of severe postpartum hemorrhage. This is a case series report of 23 patients with postpartum hemorrhage unresponsive to medical therapy managed with intrauterine balloon tamponade. We identified these patients by International Classification of Diseases (ICD-9) codes and by reviewing labor and delivery logs. Balloon tamponade was attempted in 23 patients. When properly placed, catheters controlled postpartum hemorrhage in 18 of 20 cases (90%). In two cases, hysterectomy was required despite successful placement of the catheter. For hemorrhage due to uterine atony, our success rate was 100% (11/11 cases). In three cases, technical difficulties led to placement failure. For bleeding due to retained placenta, our success rate was 80% (4/5; failure with placenta percreta). Vaginal bleeding was stopped with the catheter in two of three cases of amniotic fluid embolus and in one case after dilation and curettage for postpartum septic shock. Thus balloon tamponade is an effective adjunct in the treatment of severe postpartum hemorrhage, especially when due to uterine atony when medical therapy fails.

Perinatal loss among twins.

OBJECTIVE: We evaluated prenatal factors related to perinatal loss in twins, using medical records and death certificates, to determine the main perinatal event that contributed to babies' deaths. DESIGN: This was a retrospective cohort study of 550 monochorionic diamniotic or diamniotic dichorionic twins who were delivered at Kaiser Permanente Colorado between 1994 and 2001. MAIN OUTCOME: The main outcome of the study was perinatal loss (stillbirth or neonatal death). OUTCOMES MEASURES: Select maternal risk factors (maternal age, race, marital status, assisted conception, past history of preterm birth, cigarette smoking, and placentation) were included in the univariable and multivariable logistic regression analysis. Data on these risk factors came from review of records from our multiple-birth perinatal database. A comprehensive review of clinical events recorded in the medical records and on the death certificate was conducted to assess the main event that contributed to the loss. RESULTS: In the cohort of 1100 babies, there were 12 stillbirths and 34 neonatal deaths, with an overall frequency of perinatal loss of 4.2%. We found a strong association between a monochorionic diamniotic placentation and perinatal loss (adjusted odds ratio, 3.9; 95% confidence interval, 2, 7.7). At delivery, placental pathology and spontaneous preterm birth accounted for 36% and 41%, respectively, of the clinical events contributing to the demises. Compared with the medical record, review of death certificate information did not contribute significantly to the understanding of the sequence of perinatal events leading to the demise. CONCLUSIONS: We conclude that loss in twins is most strongly associated with monochorionic diamniotic placentation. Although this condition is not preventable, early identification (by ultrasound) and referral to subspecialists may decrease the chances of perinatal loss. Prevention of spontaneous preterm birth in all women remains an important initiative in obstetric care to reduce perinatal mortality and neonatal morbidity. We believe that improvements in the reporting on death certificates will allow future research on large data sets and may provide further insight into perinatal loss in twins. We emphasize the importance of a comprehensive clinical review of each case of perinatal loss to fully understand the sequence of clinical events leading to this adverse pregnancy outcome.

Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program.

OBJECTIVE: The prevalence of gestational diabetes mellitus (GDM) varies in direct proportion with the prevalence of type 2 diabetes in a given population or ethnic group. Given that the number of people with diabetes worldwide is expected to increase at record levels through 2030, we examined temporal trends in GDM among diverse ethnic groups. RESEARCH DESIGN AND METHODS: Kaiser Permanente of Colorado (KPCO) has used a standard protocol to universally screen for GDM since 1994. This report is based on 36,403 KPCO singleton pregnancies occurring between 1994 and 2002 and examines trends in GDM prevalence among women with diverse ethnic backgrounds. RESULTS: The prevalence of GDM among KPCO members doubled from 1994 to 2002 (2.1-4.1%, P < 0.001), with significant increases in all racial/ethnic groups. In logistic regression, year of diagnosis (odds ratio [OR] and 95% CI per 1 year = 1.12 [1.09-1.14]), mother's age (OR per 5 years = 1.7 [1.6-1.8]) and ethnicity other than non-Hispanic white (OR = 2.1 [1.9-2.4]) were all significantly associated with GDM. Birth year remained significant (OR = 1.06, P = 0.006), even after adjusting for prior GDM history. CONCLUSIONS: This study shows that the prevalence of GDM is increasing in a universally screened multiethnic population. The increasing GDM prevalence suggests that the vicious cycle of diabetes in pregnancy initially described among Pima Indians may also be occurring among other U.S. ethnic groups.

Perinatal factors and development of islet autoimmunity in early childhood: the diabetes autoimmunity study in the young.

The objective of this study was to test whether maternal age at delivery, child's birth order, cesarean section, complicated delivery, maternal smoking during pregnancy, or neonatal jaundice predict islet autoimmunity in children at genetically increased risk of type 1 diabetes in a birth cohort with blood draws at ages 9, 15, and 24 months and yearly thereafter. Newborns with diabetes-associated human leukocyte antigen genotypes (n = 938) and offspring or siblings of persons with type 1 diabetes (n = 428) from the Denver, Colorado, metropolitan area were examined from January 1994 to February 2003. Information on perinatal factors was collected by using questionnaires soon after the birth. Islet autoimmunity was defined as positivity for > or = 1 autoantibody to glutamic acid decarboxylase65, insulin, or protein tyrosine phosphatase-2/ICA512 at > or = 2 consecutive visits (n = 52; mean follow-up, 3.9 years). Complicated delivery (breech, forceps, vacuum extraction) predicted a higher risk of islet autoimmunity (hazard ratio = 2.10, 95% confidence interval: 1.09, 4.05). Increasing maternal age was related to risk of islet autoimmunity among first-degree relatives of persons with type 1 diabetes (hazard ratios = 3.96 and 8.88 for maternal ages 25-34 and > or = 35 years, respectively, compared with < 25 years; p for trend = 0.008. Other factors evaluated were not related to risk of islet autoimmunity. In conclusion, influences in utero or during delivery may affect the fetal immune system.

Experimental intrauterine infection with Prevotella bivia in New Zealand White rabbits.

OBJECTIVE: The purpose of this study was to develop a model of chronic intrauterine and fetal infection with Prevotella bivia, an anaerobe of the lower genital tract that is associated often with bacterial vaginosis. STUDY DESIGN: Thirty timed pregnant New Zealand White rabbits on gestational day 21 were inoculated with P bivia or saline solution in a planned ratio of 4:1 (24 P bivia: 6 saline solution). Rabbits were inoculated 6 cm transcervically with 10(5) to 10(8) colony-forming units/uterine horn of P bivia or with saline solution. Necropsy was scheduled on days 4, 6, or 7 after inoculation. Cultures were collected from blood, uterus, amniotic fluid and fetal brain, lung, and heart. Tissues from placenta, uterus, fetal brain, and lung were evaluated with the histologic inflammation score, with a range of 0 to 13. Amniotic fluid was assayed for tumor necrosis factor-alpha by bioassay. Animals with contamination by other organisms were excluded. Categoric data were evaluated with the use of the Fisher exact test, and continuous data were evaluated with the use of the Wilcoxon rank sum. RESULTS: After the exclusion of 8 animals because of contamination with other organisms, 22 animals were evaluated. Of 3 rabbits with an inoculum of 10(8) P bivia colony-forming units/horn, 2 animals (67%) had fever within 24 hours. These results were not compatible with chronic, subclinical infection. Therefore, 14 does had inocula of 10(5-6) P bivia colony-forming units/horn, with necropsy planned at day 4 (n=5 animals), day 6 (n=3 animals), and day 7 (n=6 animals), and 5 animals were inoculated with saline solution. Animals that had been inoculated with P bivia were significantly more likely to have a positive culture than were those animals that were inoculated with saline solution (64% vs 0%; P<.04). Preterm delivery without fever occurred in 21% of does (3/14 does) that were inoculated with P bivia overall and in 33% of the does (3/9 does) that were followed for 6 to 7 days. No saline-solution inoculated animal had preterm birth. There was an increase in amniotic fluid tumor necrosis factor-alpha levels over time in the P bivia group (P=.12). Histologic inflammation scores were not significantly different between P bivia and saline solution groups. CONCLUSION: Inoculation with P bivia at 10(5-6) colony-forming units/horn leads to chronic intrauterine and fetal infection that are accompanied by preterm birth in up to 33% of cases. This model may serve to explore the mechanism of preterm birth that is induced by chronic infection with genital tract anaerobes.

The contribution of assisted conception, chorionicity and other risk factors to very low birthweight in a twin cohort.

OBJECTIVES: To investigate the contribution of assisted conception (assisted reproductive technology and ovulation induction), chorionicity and selected maternal risk factors for very low birthweight. DESIGN: Retrospective twin cohort study. SETTING: Staff model Colorado Health Maintenance Organization. SAMPLE: Five hundred and sixty-two twin gestations [assisted = 193 (34%); unassisted = 369 (66%)]. METHODS: Data were collected from a perinatal database and medical record review. Data were analysed using univariate and multivariable logistic regression analysis. MAIN OUTCOME MEASURE: Very low birthweight. RESULTS: Women with assisted twin gestation were more likely to be older, nulliparous, non-smokers, married, have a prior history of a miscarriage and a dichorionic placentation. There was no difference in the distribution of low and very low birthweight, discordant growth or preterm delivery between assisted and unassisted twin gestations. Significant risk factors for very low birthweight were: a prior preterm birth (odds ratio, OR, 3.8, 95% confidence interval, CI, 2, 7), monochorionicity (OR 3, 95% CI 2, 4.7), nulliparity (OR 2, 95% CI 1.3, 3), cigarette smoking (OR 1.8, 95% CI 1, 3) and prior miscarriage (OR 1.6, 95% CI 1, 2). Monochorionicity was significantly associated with adverse perinatal outcomes. CONCLUSION: Assisted conception did not play a significant role in the occurrence of very low birthweight in this cohort. A history of preterm birth and a monochorionic twin gestation were the leading risk factors for very low birthweight. Associated risk factors for very low birthweight were nulliparity, cigarette smoking and a prior miscarriage.

Chronic intrauterine and fetal infection with Gardnerella vaginalis.

OBJECTIVE: We sought to develop a model of chronic intrauterine and fetal infection with Gardnerella vaginalis. STUDY DESIGN: The uterine horns of pregnant New Zealand White rabbits were inoculated on day 21 of gestation with either 10(7) colony-forming units (cfu) of G vaginalis or saline solution. At necropsy, cultures were taken from blood, uterus, amniotic fluid, and fetal tissues. Amniotic fluid was assayed for tumor necrosis factor (TNF)-alpha by bioassay. Maternal and fetal tissue samples were evaluated using the histologic index score. A P value <.05 was considered significant. RESULTS: Compared with saline solution-inoculated animals, the G vaginalis group had significantly more positive cultures from uterus, amniotic fluid, and fetal brain and lung (P =.02 to <.01). For the G vaginalis group, mean TNF-alpha levels and fetal brain scores increased significantly over time (P <.001 for both). CONCLUSION: Chronic intrauterine and fetal infection with G vaginalis is accompanied by progressive increases in amniotic fluid TNF-alpha concentrations and fetal brain histologic index scores.

Preeclampsia in multiple gestation: the role of assisted reproductive technologies.

OBJECTIVE: To estimate the relationship of assisted reproductive technologies and ovulation-inducing drugs with preeclampsia in multiple gestations. METHODS: This historical cohort study was conducted on 528 multiple gestations from a Colorado health maintenance organization. Using univariate and logistic regression analysis, we determined if women who conceived a multiple gestation as a result of assisted conception were at a greater risk of preeclampsia than those who conceived spontaneously. RESULTS: Between January 1994 and November 2000, there were 330 unassisted and 198 assisted multiple gestations. Sixty-nine multiple gestations followed assisted reproductive technologies (in vitro fertilization and gamete intrafallopian transfer). Human menopausal gonadotropins and clomiphene citrate were associated with 38 and 91 of the multiple gestations, respectively. Compared with unassisted multiple gestations, the relative risk of mild or severe preeclampsia among mothers who received assisted reproductive technologies was 2.7 (95% confidence interval [CI] 1.7, 4.7) and 4.8 (CI 1.9, 11.6), respectively. Adjusted for maternal age and parity, women who received assisted reproductive technologies were two times more likely to develop preeclampsia (odds ratio 2.1, CI 1.1, 4.1) compared with those who conceived spontaneously. The adjusted odds ratios of nulliparity and maternal age for preeclampsia were 2.1 (CI 1.3, 3.4) and 1.1 (CI 1, 1.1), respectively. Although the incidence of preeclampsia was greater in mothers who received clomiphene citrate and human menopausal gonadotropins, this association did not reach statistical significance at the P <.05 level. CONCLUSION: Women who conceive multiple gestations through assisted reproductive technologies have a 2.1-fold higher risk of preeclampsia than those who conceive spontaneously.

Chronic intrauterine infection and inflammation in the preterm rabbit, despite antibiotic therapy.

OBJECTIVE: In a pregnant rabbit model using intracervical inoculation of Escherichia coli with delayed antibiotic therapy, we investigated the rate of positive cultures and histologic inflammation of maternal and fetal compartments and the concentration of tumor necrosis factor-alpha in the amniotic fluid for up to 5 days. STUDY DESIGN: New Zealand White rabbits at 70% gestation were inoculated intracervically with 10(3) - 10(4) colony-forming units of E coli per uterine horn. At varying intervals after inoculation (0.5 - 4.0 hours), antibiotic therapy was initiated with ampicillin-sulbactam. Primary outcomes were positive cultures and histologic inflammation score. Tumor necrosis factor-alpha levels in the amniotic fluid were determined by bioassay. RESULTS: A total of 60 animals were inoculated with E coli. At the endpoint, uterine cultures were positive more commonly than in the fetus or amniotic fluid (41.8% vs 27.5% vs 17.3%, respectively), which was consistent with an ascending pathway of infection. Inflammation scores were similar in uterus and placenta but lower in fetal lung and absent in fetal brain (2.8 vs 3.1 vs 0.84 vs 0.0, respectively). Comparing the durations of delay in antibiotic administration, we found a significant increase in positive uterine cultures and a significant increase in histologic inflammation score with increasing delay. The proportion of dead pups within a litter was significantly associated with the log of the tumor necrosis factor-alpha concentration in amniotic fluid and the degree of histologic inflammation in the uterus, but not with amniotic fluid or other culture positivity. CONCLUSION: The administration of therapeutic doses of antibiotic does not consistently eradicate bacteria from the rabbit uterus nor, more importantly, from the fetus and the amniotic fluid. Obtaining a negative amniotic fluid culture does not exclude either infection in the decidua or the fetus or histologic inflammation with tumor necrosis factor-alpha elaboration.