Sex differences in placenta-derived markers and later autistic traits in children.

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean= 13.5 [SD = 2.0] weeks gestation) and 2nd trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, compared to female pregnancies. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2nd: n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd: n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2nd trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.

Will they fit? Determinants of the adaptability of stock TMJ prostheses where custom TMJ prostheses were utilized.

Currently only two alloplastic temporomandibular joint (TMJ) total joint replacement (TJR) systems are available in the United States. The aim of this study was to define variables that determine whether a Biomet stock prosthesis could have been used to reconstruct a TMJ previously reconstructed with a TMJ Concepts patient-fitted prosthesis. All of the TMJ Concepts prostheses placed between 2010 and 2018 at the University of Texas - Health at San Antonio were analyzed retrospectively. There were 128 cases (241 joints) with intact stereolithographic models analyzed for successful adaptation of the Biomet stock TMJ prosthesis. Anatomical, demographic, etiological, and perioperative data were gathered for each joint to investigate possible causes of failure of stock adaptation. The majority of joints, 74% (178/241), could have had a stock prosthesis adapt. All joints with ≥40mm gap arthroplasty failed stock prosthesis adaptation. Only 50% (32/64) of the joints with at least one previous open TMJ surgery and 60% (58/96) of the joints with concomitant orthognathic surgery could have had a stock TMJ prosthesis. The stock prosthesis could not be adapted for any of the patients requiring TMJ replacement for congenital disorders or those requiring TMJ salvage. Overall, the majority of cases treated with a patient-specific TMJ TJR could have been treated with a stock prosthesis.

Early initiation of direct anticoagulation after stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: The safety of early initiation of anticoagulant therapy in patients with ischaemic stroke related to atrial fibrillation (AF) is unknown. We investigated the safety of early initiation of direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs) or no anticoagulation. METHODS: This observational, retrospective, single-centre study included consecutive patients with recent (<4 weeks) ischaemic stroke and AF. The primary outcome was the rate of major (intracranial and extracranial) bleeding in patients on different treatment schemes, i.e. DOACs, VKAs and not anticoagulated. We also investigated the rate of ischaemic cerebrovascular events and mortality. RESULTS: We included 959 consecutive patients with AF and ischaemic stroke followed up for an average of 16.1 days after the index event. A total of 559 out of 959 patients (58.3%) were anticoagulated with either VKAs (n = 259) or DOACs (n = 300). Anticoagulation was started after a mean of 7 ± 9.4 days in the DOAC group and 11.9 ± 19.7 days in the VKA group. Early initiation of any anticoagulant was not associated with an increased risk of any major bleeding [odds ratio (OR), 0.49; 95% confidence intervals (CI), 0.21-1.16] and in particular of intracranial bleeding (OR, 0.47; 95% CI, 0.17-1.29; P = 0.143) compared with no anticoagulation. In contrast to VKAs (OR, 0.78; 95% CI, 0.28-2.13), treatment with DOACs (OR, 0.32; 95% CI, 0.10-0.96) reduced the rate of major bleeding compared with no anticoagulation. Early recurrences of ischaemic stroke did not differ significantly among the three groups. CONCLUSIONS: Starting DOACs within a mean of 7 days after stroke appeared to be safe. Randomized controlled studies are needed to establish the added efficacy of starting anticoagulation early after stroke.

Fetal sex dependency of maternal vascular adaptation to pregnancy: a prospective population-based cohort study.

OBJECTIVE: To investigate fetal sex dependency of maternal vascular adaptation to pregnancy as assessed by uteroplacental vascular resistance and maternal blood pressure. DESIGN: Prospective population-based cohort study. SETTING: Rotterdam, the Netherlands. POPULATION: In total, 8224 liveborn singleton pregnancies were included. METHODS: Maternal vascular adaptation was assessed in all trimesters of pregnancy. Pregnancies were stratified into being either complicated by the placental syndrome (i.e. pre-eclampsia, fetal growth restriction or preterm birth, n = 1229) or uncomplicated (n = 6995). MAIN OUTCOME MEASURES: First trimester: blood pressures. Second trimester: blood pressures, pulsatility index of the uterine artery (PI-UtA). Third trimester: blood pressures, PI-UtA, presence of notching in the uterine artery. RESULTS: In women carrying a male fetus PI-UtA was higher than in women with a female fetus in the total group (second trimester P < 0.001, third trimester P = 0.005). Effect estimates differed between women with or without the placental syndrome. In the total group, women with a male fetus more often showed notching in the Doppler resistance pattern (odds ratio 1.42, 95% confidence interval 1.17-1.72). Different blood pressure patterns were observed between pregnant women with a male fetus and pregnant women with a female fetus and between complicated pregnancies and uncomplicated pregnancies. CONCLUSION: Fetal sex is significantly associated with maternal vascular adaptation to pregnancy with differential effects in uncomplicated pregnancies and in pregnancies complicated by the placental syndrome. TWEETABLE ABSTRACT: Fetal sex is significantly associated with maternal vascular adaptation to pregnancy.

Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action.

Chemokines and chemokine receptors are key modulators in inflammatory diseases and malignancies. Here, we describe the identification and pharmacologic characterization of nanobodies selectively blocking CXCR2, the most promiscuous of all chemokine receptors. Two classes of selective monovalent nanobodies were identified, and detailed epitope mapping showed that these bind to distinct, nonoverlapping epitopes on the CXCR2 receptor. The N-terminal-binding or class 1 monovalent nanobodies possessed potencies in the single-digit nanomolar range but lacked complete efficacy at high agonist concentrations. In contrast, the extracellular loop-binding or class 2 monovalent nanobodies were of lower potency but were more efficacious and competitively inhibited the CXCR2-mediated functional response in both recombinant and neutrophil in vitro assays. In addition to blocking CXCR2 signaling mediated by CXCL1 (growth-related oncogene α) and CXCL8 (interleukin-8), both classes of nanobodies displayed inverse agonist behavior. Bivalent and biparatopic nanobodies were generated, respectively combining nanobodies from the same or different classes via glycine/serine linkers. Interestingly, receptor mutation and competition studies demonstrated that the biparatopic nanobodies were able to avidly bind epitopes within one or across two CXCR2 receptor molecules. Most importantly, the biparatopic nanobodies were superior over their monovalent and bivalent counterparts in terms of potency and efficacy.

Fetal sex specific differences in human placentation: a prospective cohort study.

INTRODUCTION: Our objective was to assess fetal sex specific differences in first trimester placental biomarkers of both physiological and pathological pregnancies and their interaction with environmental influences. This study is embedded in the Generation R Study, a prospective cohort study. METHODS: Only live singleton births were included. Linear regression was performed to assess the effect of sex on first trimester placental biomarkers. Interaction analyses were performed to assess interaction of fetal sex with environmental influences. First trimester soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF), plasminogen activator inhibitor (PAI-2) and homocysteine levels were assessed. RESULTS: Significant fetal sex specific differences in placental biomarkers were observed. S-Flt1, PAI-2 and PLGF log transformated concentrations were 0.08 ng/mL (95% CI 0.05; 0.11), 0.07 ng/mL (95% CI 0.06; 0.09) and 0.04 pg/mL (95% CI 0.01; 0.06) higher in case of female as compared to male placentas. In pregnancies complicated by pre-eclampsia (PE), preterm birth (PTB) or a newborn being small for gestational age (SGA) no fetal sex specific differences were observed. Interaction analyses suggest that concentrations of s-Flt1, PLGF and PAI-2 decrease in male placentas in the case of hyperhomocysteinemia but remain equal in female placentas. DISCUSSION: Fetal sex affects early placentation processes with discrepancies regarding pregnancies complicated by PE, PTB or a newborn being SGA. This suggests that other mechanisms causing these complications may dominate the fetal sex effect. The differences concerning homocysteine suggest that fetal sex dependent placental gene-environment interactions exist. CONCLUSION: Fetal sex specific differences in placental biomarkers exist.

Changes in cardiac index and blood pressure on positioning children prone for scoliosis surgery.

In this prospective observational study we investigated the changes in cardiac index and mean arterial pressure in children when positioned prone for scoliosis correction surgery. Thirty children (ASA 1-2, aged 13-18 years) undergoing primary, idiopathic scoliosis repair were recruited. The cardiac index and mean arterial blood pressure (median (IQR [range])) were 2.7 (2.3-3.1 [1.4-3.7]) l.min(-1).m(-2) and 73 (66-80 [54-91]) mmHg, respectively, at baseline; 2.9 (2.5-3.2 [1.7-4.4]) l.min(-1).m(-2) and 73 (63-81 [51-96]) mmHg following a 5-ml.kg(-1) fluid bolus; and 2.5 (2.2-2.7 [1.4-4.8]) l.min(-1).m(-2) and 69 (62-73 [46-85]) mmHg immediately after turning prone. Turning prone resulted in a median reduction in cardiac index of 0.5 l.min(-1).m(-2) (95% CI 0.3-0.7 l.min(-1).m(-2), p=0.001), or 18.5%, with a large degree of inter-subject variability (+10.3% to -40.9%). The changes in mean arterial blood pressure were not significant. Strategies to predict, prevent and treat decreases in cardiac index need to be developed.

Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors.

RATIONALE: Two pharmacological stressors commonly used in the study of stress-induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the α(2)-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine-seeking behaviour have not been fully characterized. OBJECTIVE: The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking. METHODS: Male Long-Evans rats were trained to self-administer cocaine (0.23 mg/kg/infusion) for 8-10 days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5 µg; i.c.v.) and yohimbine-induced (1.25 mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1 mg/kg; i.p.) and/or SCH31966 (0.2 mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5 mg/kg; i.p.). RESULTS: Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking. CONCLUSIONS: These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine.

Prevention of neonatal herpes.

Neonatal herpes can occur when the neonate is exposed to herpes simplex virus in the maternal genital tract during labour. Attack rates are highest when the mother has a newly acquired infection and, therefore, does not have antibodies to protect the neonate. Even with early therapy, there is significant morbidity and mortality associated with neonatal herpes, suggesting that preventing neonatal herpes simplex virus exposure or early recognition of exposure is important. The incidence of neonatal herpes has not declined despite national guidelines for prevention. This suggests that the prevention guidelines need to be re-addressed.

SB265610 is an allosteric, inverse agonist at the human CXCR2 receptor.

BACKGROUND AND PURPOSE: In several previous studies, the C-X-C chemokine receptor (CXCR)2 antagonist 1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea (SB265610) has been described as binding competitively with the endogenous agonist. This is in contrast to many other chemokine receptor antagonists, where the mechanism of antagonism has been described as allosteric. EXPERIMENTAL APPROACH: To determine whether it displays a unique mechanism among the chemokine receptor antagonists, the mode of action of SB265610 was investigated at the CXCR2 receptor using radioligand and [(35)S]-GTPgammaS binding approaches in addition to chemotaxis of human neutrophils. KEY RESULTS: In equilibrium saturation binding studies, SB265610 depressed the maximal binding of [(125)I]-interleukin-8 ([(125)I]-IL-8) without affecting the K(d). In contrast, IL-8 was unable to prevent binding of [(3)H]-SB265610. Kinetic binding experiments demonstrated that this was not an artefact of irreversible or slowly reversible binding. In functional experiments, SB265610 caused a rightward shift of the concentration-response curves to IL-8 and growth-related oncogene alpha, but also a reduction in maximal response elicited by each agonist. Fitting these data to an operational allosteric ternary complex model suggested that, once bound, SB265610 completely blocks receptor activation. SB265610 also inhibited basal [(35)S]-GTPgammaS binding in this preparation. CONCLUSIONS AND IMPLICATIONS: Taken together, these data suggest that SB265610 behaves as an allosteric inverse agonist at the CXCR2 receptor, binding at a region distinct from the agonist binding site to prevent receptor activation, possibly by interfering with G protein coupling.

Development and certification of the new SRM 695 trace elements in multi-nutrient fertilizer.

During the past seven years, several states within the US have enacted regulations that limit the amounts of selected non-nutritive elements in fertilizers. Internationally, several countries, including Japan, China, and Australia, and the European Union also limit the amount of selected elements in fertilizers. The elements of interest include As, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Se, and Zn. Fertilizer manufacturers and state regulatory authorities, faced with meeting and verifying these limits, need to develop analytical methods for determination of the elements of concern and to validate results obtained using these methods. Until now, there were no certified reference materials available with certified mass fraction values for all elements of interest in a blended, multi-nutrient fertilizer matrix. A new standard reference material (SRM) 695 trace elements in multi-nutrient fertilizer, has been developed to help meet these needs. SRM 695 has recently been issued with certified mass fraction values for seventeen elements, reference values for an additional five elements, and information values for two elements. The certificate of analysis includes an addendum listing percentage recovery for eight of these elements, determined using an acid-extraction inductively-coupled plasma optical-emission spectrometry (ICP-OES) method recently developed and tested by members of the Association of American Plant Food Control Officials.

Declining insulin requirement in the late first trimester of diabetic pregnancy.

OBJECTIVE: To investigate whether pregnancies complicated by type 1 diabetes are associated with a decrease in first-trimester insulin requirement. RESEARCH DESIGN AND METHODS: We examined the weekly insulin requirement (as units per kilogram per day) during the first trimester of pregnancy in diabetic women in the Diabetes in Early Pregnancy Study (DIEP) with accurate gestational dating, regular glucose monitoring, daily insulin-dose recording, and monthly glycohemoglobin measurements. RESULTS: In pregnancies that resulted in live-born full-term singleton infants, a significant 18% increase in mean weekly dosage was observed between weeks 3 and 7 (P = 0.000), followed by a significant 9% decline from week 7 through week 15 (P = 0.000). Further testing localized a significant change in insulin dose in the interval beginning weeks 7-8 and ending weeks 11-12 (P = 0.014). Within this interval, the maximum decrease was between weeks 9 and 10 (mean), 10 and 11 (median), and 8 and 9 (most frequent maximal decrease). To determine whether prior poor glucose control exaggerated these trends, we categorized the women based on their glycohemoglobin values: <2 SDs above the mean of a normal population (subgroup 1), 2-4 SDs (subgroup 2), and >4 SDs (subgroup 3) at baseline. Late first-trimester declines in dosage were statistically significant in subgroup 2 (P = 0.002) and subgroups 2 and 3 together (P = 0.003). Similarly, women with BMI >27.0 had a greater initial insulin rise and then fall compared with leaner women. CONCLUSIONS: Observations in the DIEP cohort disclose a mid-first-trimester decline in insulin requirement in type 1 diabetic pregnant women. Possible explanations include overinsulinization of previously poorly controlled diabetes, a transient decline in progesterone secretion during the late first-trimester luteo-placental shift in progesterone secretion, or other hormonal shifts. Clinicians should anticipate a clinically meaningful reduction in insulin requirement in the 5-week interval between weeks 7 and 12 of gestation.

Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus.

OBJECTIVE: Glycemic control, perinatal outcome, and health care costs were evaluated among women with type 1 diabetes mellitus who began insulin pump therapy during pregnancy (group 1, n = 24), were treated with multiple insulin injections (group 2, n = 24), or were already using an insulin pump before pregnancy (group 3, n = 12). Patient satisfaction and continuation of pump therapy post partum were assessed. STUDY DESIGN: A retrospective review of maternal and neonatal medical records was performed, and a questionnaire was sent to patients after delivery. Patients in groups 1 and 2 were matched for age, age at onset and duration of diabetes mellitus, White class, and date of delivery. RESULTS: No differences in glycosylated hemoglobin A levels were observed among groups 1, 2 or 3 in the first, second, or third trimester. Patients in group 1 started pump therapy at a mean of 16.8 weeks' gestation, and 17 (70.8%) began therapy as outpatients. No deterioration in glycemic control was noted during the 2- to 4-week period after the start of pump treatment. Among the women in group 1 eight had at least one episode of severe hypoglycemia before starting pump therapy, but only one had such an episode after this treatment was begun. Two episodes of ketoacidosis occurred in group 1, and no episodes occurred in groups 2 and 3. No significant differences in perinatal outcomes or health care costs were observed among groups 1, 2, and 3. After delivery 94. 7% of the women in group 1 continued to use the pump because it provided better glycemic control and a more flexible lifestyle. Postpartum glycosylated hemoglobin A values were 7.2% in group 1 and 9.1% in group 2, a significant difference. CONCLUSIONS: Insulin pump therapy was initiated during pregnancy without a deterioration of glycemic control and was associated with maternal and perinatal outcomes and health care costs comparable to those among women who were already using the pump before pregnancy or who received multiple-dose insulin therapy. Women who began pump therapy in pregnancy were highly likely to continue pump use after delivery and preferred the flexible lifestyle that this treatment allowed.

HSV-2 specific serology should be offered routinely to antenatal patients.

The most devastating consequence of genital herpes is neonatal herpes. It is clear that the majority of newborns acquire their infection by contact with infected genital secretions during delivery from an asymptomatic mother who acquired a first episode of genital herpes near the time of labour. Since the majority of cases of first episode genital herpes during pregnancy are unrecognised, the prevention of neonatal transmission will depend upon the identification of the HSV serologically discordant couple and the institution of appropriate interventions by mid pregnancy. Therefore, the précis of this discussion paper is that universal HSV serological testing should be performed at the first prenatal visit. As a corollary, type specific HSV serology will need to be commercially available and relatively inexpensive. In any country, pregnant women and their partners represent a broad, cross section of sexually active adults. The vast majority present themselves to the health care system for care during their pregnancies which is a period of time in which the focus of care is primarily preventive and during which women are generally motivated and compliant. This is truly the 'golden opportunity' to identify patients already infected as well as those at risk for acquiring genital herpes. Information regarding genital herpes and methods of preventing transmission to susceptible partners and newborn infants can easily be added to educational programmes which have already become an institution within prenatal care.

p38 MAPK signalling cascades in inflammatory disease.

Inflammatory mediators released during acute and chronic diseases activate multiple intracellular signalling cascades including the mitogen-activated protein kinase (MAPK) signal transduction pathway, which plays a significant role in the recruitment of leukocytes to sites of inflammation. Stimulation of leukocytes by pro-inflammatory cytokines is known to result in the activation of the MAPK isoform p38. However, the functional consequences of p38 MAPK activation during leukocyte recruitment, including adhesion, migration and effector functions such as oxidative burst and degranulation, are only just beginning to be elucidated. Specific p38 inhibitors aimed at reducing the production of inflammatory mediators are now being developed, and might in the future provide more effective treatment for inflammatory diseases.

Apical proteins stimulate complement synthesis by cultured human proximal tubular epithelial cells.

There is increasing evidence to suggest that the renal tubular epithelium is important in the pathogenesis of progressive renal failure resulting from persistent proteinuria. The role of complement in the progression of chronic renal failure is not well defined. The purpose of this study was to characterize the production of complement by human proximal tubular epithelial cells exposed to serum proteins at the apical surface. Complement C3 gene expression was analyzed by reverse transcription and PCR. C3 protein biosynthesis was confirmed by metabolic labeling followed by immunoprecipitation and quantified by enzyme-linked immunosorbent assay. In the quiescent state, proximal tubular epithelial cells grown on permeable membrane supports secreted C3 predominantly into the apical medium. The addition of 5 mg/ml serum proteins led to an 8.9-fold increase in basolateral C3 secretion and a 2.1-fold increase in apical C3 secretion, altering the ratio of basolateral: apical C3 secretion from 0.44 +/- 0.16 to 1.87 +/- 0.52. C3 mRNA expression was also upregulated in a time- and dose-dependent manner. Serum fractionation demonstrated that the stimulant responsible for these effects was in the molecular weight range 30 to 100 kD. The observed phenomenon was not reproduced when purified human albumin alone was used as the stimulant. These findings could provide a possible mechanism for the link between proteinuria and interstitial fibrosis. This may have potential implications for strategies directed against complement in retarding the progression of chronic renal failure.

Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before onset of hypertension.

OBJECTIVE: To determine if assessment of maternal hemodynamics could predict women at risk for the development of preeclampsia, if treatment directed at hemodynamic abnormalities before the onset of hypertension could prevent preeclampsia, and if mothers could be treated in a way that protects fetal growth. METHODS: A double-blinded, randomized controlled trial was conducted. Subjects were considered to be at risk for preeclampsia if their cardiac output was greater than 7.4 L/min before 24 weeks' gestation. Nulliparous and diabetic subjects at risk were treated with 100 mg of atenolol or placebo. Cardiac output was measured by Doppler technique. Inulin and para-aminohippurate clearances were performed. RESULTS: Treatment with atenolol reduced the incidence of preeclampsia from 5 of 28 (18%) to 1 of 28 (3.8%), (P = .04). Nulliparous women determined to be at risk for preeclampsia were similar to diabetic women at risk. Each was significantly heavier and had inulin and para-aminohippurate clearances greater than the control group. Treatment with atenolol was associated with infants weighing 440 g less than infants in the nulliparous placebo group, (P = .02). No effect on birth weight was seen in the diabetic patients. Mothers of the smallest infants who were treated with atenolol could be identified by unexpectedly large reductions in cardiac output. CONCLUSION: Measurement of cardiac output in the second trimester identified women at risk for preeclampsia. Treatment with atenolol decreased the incidence of preeclampsia. Nulliparous and diabetic women at risk for preeclampsia were similar with regard to maternal hemodynamics, maternal weight, and renal function. Treatment with atenolol was associated with reduced infant birth weight.

Why don't women with diabetes plan their pregnancies?

OBJECTIVE: To determine why women with diabetes generally do not plan their pregnancies, consequently entering their pregnancies with poor blood glucose control and greatly increasing the risk of birth defects in their infants. RESEARCH DESIGN AND METHODS: A population-based sample of 85 women with diabetes diagnosed before the index pregnancy were recruited within 6 months postpartum from 15 hospitals in the state of Washington. Women with planned and unplanned pregnancies were compared using qualitative and quantitative analysis of personal interviews, self-administered questionnaires, and medical record review. RESULTS: Although most women (79%) knew they should optimize their blood glucose levels before conception, fewer than half (41%) of their pregnancies were planned. Women with planned pregnancies had significantly higher income and more education; were more likely to have private health insurance, to see an endocrinologist before pregnancy, to be happily married, and to be Caucasian; and were less likely to use tobacco. Most unplanned pregnancies were not contraceptive failures, but may have been consciously or subconsciously intended. Women with planned pregnancies generally described an ongoing and positive relationship with their health care providers. Women who felt that their doctors discouraged pregnancy were more likely to have an unplanned pregnancy than were women who had been reassured they could have a healthy baby. CONCLUSIONS: Many women with diabetes still perceive negative messages about pregnancies and become pregnant without optimal planning. We believe there are many opportunities for increasing the proportion of women with diabetes who plan their pregnancies, particularly in the areas of prepregnancy information, support that women are given, and the quality of the relationships they experience within the health care system. It is crucial that couples be reassured that with pre-conception glucose control, almost all women with diabetes can have healthy babies.