Hilary Roeder

A look at uterine wound healing through a histopathological study of uterine scars.

Background: Few histopathologic studies of uterine wound healing have been published compared with similar healing in other tissues. Our objective was to examine the histopathology resulting from iatrogenic trauma to the myometrium to acquire a better understanding of possible aberrations in uterine wound healing. Methods: We studied paired injured myometrium and uninvolved myometrium from 7 hysterectomy specimens. All subjects had either abnormal bleeding or chronic pain following an iatrogenic injury to the myometrium. The time between the initial injury and hysterectomy ranged from 2 months to 13 years. Tissue was evaluated with hematoxylin and eosin (H&E) followed by Masson Trichrome staining for collagen, Weigert-Van Gieson elastic staining, and/or Kreyberg staining for fibrin and glycosaminoglycans or MIB-1 (Ki-67) immunhistochemistry for cell proliferation. Results: Histopathologic examination of the 7 paired tissues revealed evidence of altered healing including myofiber disarray, elastosis, tissue edema, and inflammation. Small fibroids, myometrial hyperplasia, a keloid-like region of scar and adenomyosis were also observed. Conclusions: Myofiber disarray and elastosis may be markers of aberrancy in wound healing after iatrogenic uterine trauma. Altered myometrial scarring in these cases may have contributed to the clinical outcome necessitating hysterectomies. Myometrial hyperplasia in the region of the scars might also contribute to the clinical presentation as well. Small fibroids found within scars and evidence of a keloid-like structure may also represent alterations in uterine wound healing.

First trimester gestational diabetes screening - Change in incidence and pharmacotherapy need.

AIMS Adopting recommendations of the International Association of Diabetes in Pregnancy Study Groups (IADPSG) and the California Diabetes and Pregnancy Program, our institution implemented early gestational diabetes (GDM) screening. Our objective was to compare GDM diagnosis rates using the standard two-step approach versus early screening, and secondarily to compare pharmacotherapy needs and perinatal outcomes. METHODS This retrospective study included singleton pregnancies diagnosed between 7/2010 and 6/2012. Two cohorts were compared; those diagnosed via two-step screening versus early screening diagnosis: HbA1c≥5.7% (39 mmol/mol) or fasting plasma glucose (FPG)≥92 mg/dL at ≤24 weeks gestation, or an abnormal 2-h oral glucose tolerance test (GTT) between 24 and 28 weeks. We calculated the rate of diagnosis, analyzed the need for pharmacotherapy, and reviewed neonatal outcomes. RESULTS A total of 2652 patients were screened. GDM was diagnosed in 5.3% with two-step screening and 9.4% with early screening. Of those diagnosed via early screening with HbA1c, FPG, or both HbA1c and FPG, 49.2%, 66.7%, and 78.9% respectively required pharmacotherapy. In contrast, of those diagnosed with a 2-h GTT, 30.6% required pharmacotherapy (p<0.001). When controlling for confounders in a multivariable regression, BMI is most predictive of medication requirements (aOR 1.13, 95% CI 1.08-1.18, p<0.001). There were no differences in mean birth weight (3240±619 g vs. 3179±573 g, p=0.51) and macrosomia rates (7% vs. 2.5%, p=0.12). CONCLUSION Implementing early screening nearly doubled the incidence of GDM. Patients with early screening had a greater need for pharmacotherapy, but BMI was the best predictor of this outcome. There was no significant difference in neonatal outcomes.

CDB-4124 Does Not Cause Apoptosis in Cultured Fibroid Cells:

Objective: Selective progesterone receptor modulators (SPRMs), such as asoprisnil (J867) and ulipristal (CDB-2914), have been shown to reduce fibroid volume in vivo and to induce apoptosis in vitro. CDB-4124 (telapristone), a SPRM with different side groups, also reduced fibroid volume in vivo, and we hypothesized that this SPRM would also cause apoptosis in cultured fibroid cells. Methods: Immortalized, progesterone receptor-positive fibroid cells, known to be capable of apoptosis, were grown to 80% confluence in serum-containing media. Cells were then treated for 48 hours in serum-free media with 0, 10, 100, or 1000 nmol/L CDB-4124. Actinomycin-D and staurosporine were used as positive controls to induce apoptosis. Apoptosis was quantified using a TUNEL-fluorescein kit. Images were captured with a widefield-fluorescence microscope and analyzed using MetaMorph image analysis software. To validate results, Western blots of total cell lysates were probed for cleaved caspase-3 (c-CASP3). Experiments were repeated 3 times using independent cell batches. Results: Analysis of 19 712 nuclei indicated 14.8% ± 10.9% (mean ± SEM), 8.4% ± 4.6%, 8.2% ± 4.7%, and 9.3% ± 6.3% apoptosis in 0, 10, 100, and 1000 nmol/L CDB-4124-treated cells, respectively. There was no evidence of elevated c-CASP3 over vehicle control after treatment with CDB-4124. Conclusion: CDB-4124 did not significantly induce apoptosis in cultured fibroid cells under the conditions described suggesting apoptosis may not be the main pathway responsible for CDB-4124-induced fibroid shrinkage. Variations in SPRM biological effects may be due to differences in fibroid source cells, binding kinetics, or extracellular matrix characteristics, and can be exploited in further investigations of the mechanisms of action of SPRMs in fibroid biology.

First-Trimester Maternal Serum C-reactive Protein as a Predictor of Third-Trimester Impaired Glucose Tolerance

Objective: We evaluated whether first-trimester high-sensitivity C-reactive protein (hsCRP), a suggested marker of pregnancy-associated hyperglycemia, predicts third-trimester impaired glucose tolerance (IGT) in a secondary analysis of a prospective cohort of nondiabetic singletons enrolled at <26 weeks gestation. Study Design: We measured the association between hsCRP collected at <14 weeks among women classified as IGT (gestational diabetes screening results, 135 to <200 mg/dL) and those among normoglycemic women. Multivariable modeling estimated the association between log hsCRP and IGT, adjusted for maternal body mass index (BMI). Results: Among 300 women, 13% (39 of 300) had IGT. The hsCRP was positively associated with glucose (P = .005). Compared with normoglycemic women, women with IGT had higher log hsCRP (0.87 ± 0.66 vs 0.67 ± 0.60, P = .04), but the association was not significant in adjusted models (adjusted odds ratio 1.20, 95% confidence interval 0.65-2.21). The hsCRP did not predict third-trimester IGT in this analysis when BMI is considered. Conclusion: Early identification of women at risk of IGT remains a priority, but the contribution of maternal BMI appears greater than hsCRP.

Continuous Subcutaneous Insulin Infusion versus Multiple Daily Injections of Insulin for the Management of Type 1 Diabetes Mellitus in Pregnancy: Association with Neonatal Chemical Hypoglycemia.

OBJECTIVE We hypothesized that patients with type 1 diabetes mellitus (T1DM) who were managed during their pregnancy with a continuous subcutaneous insulin infusion (CSII) would have a lower incidence of neonatal hypoglycemia (NH) than patients managed with multiple daily injections (MDI) of insulin. STUDY DESIGN This was a retrospective cohort of 95 women with T1DM who delivered singleton, term neonates between 2007 and 2014. The primary outcome was incidence of NH (capillary plasma glucose ≤ 45 mg/dL) in the first 24 hours after birth. RESULTS The incidence of NH was 66.0% (62/95). The NH rate was significantly higher in women managed with CSII versus MDI (62 vs. 38%, p = 0.024). Neonates with NH had a higher birth weight (3,867 ± 658 vs. 3,414 ± 619 g, p = 0.002). When analyzing intrapartum glucose management, mothers of neonates with NH had significantly less time managed on an insulin infusion (median interquartile range 7 [3.5-30.5] vs. 17.5 [2.0-17.5] hours, p = 0.014). In multivariable analysis, only maternal body mass index (BMI) (p = 0.035) and time on an insulin infusion (p = 0.043) were significantly associated with NH. CONCLUSION In our population of patients with T1DM, CSII was more prevalent in the NH group; however, when controlling for other factors, intrapartum glucose management and early maternal BMI were the only variables associated with NH.

Changes in Postpartum Insulin Requirements for Patients with Well-Controlled Type 1 Diabetes.

Objective To compare postpartum with preconception insulin doses in well-controlled (HbA1c ≤ 7.4%) type 1 diabetes mellitus (T1DM) and to characterize differences in postpartum insulin dosing based on infant feeding. Study Design The primary outcome in this retrospective cohort was the change in total daily insulin (TDI) from preconception to postpartum. Insulin administration (continuous subcutaneous insulin infusion [CSII] vs. multiple daily injections [MDI]), HbA1c, body mass index (BMI), and infant feeding were abstracted. Results We identified 44 women with T1DM and HbA1c ≤ 7.4%. Preconception mean BMI was 24.6 ± 3.6 kg/m(2) and median (interquartile range [IQR]) HbA1c was 6.4 (6.0-6.9)%. Of these, 73% used CSII and 27% used MDI. Additionally, 80% of patients reported exclusive breastfeeding, 7% were exclusively formula feeding, and 13% used both breast milk and formula. Median (IQR) preconception TDI was 0.64 (0.49-0.69) U/kg/day, and postpartum: 0.39 (0.30-0.50) U/kg/day. Postpartum TDI was 34% lower than preconception TDI (p = 0.02). There was no difference in the postpartum TDI in patients who were breast versus formula feeding or when comparing CSII with MDI. Conclusion There was a significant decrease in the TDI required postpartum when compared with preconception. Dosages do not seem to be impacted by administration route or breastfeeding. These findings warrant consideration when dosing postpartum insulin in patients with T1DM.

Abnormal uterine artery Doppler velocimetry predicts adverse outcomes in patients with abnormal analytes

OBJECTIVES Our aim was to determine if uterine artery (UtA) Doppler studies would risk-stratify women with abnormal serum analytes on prenatal genetic screening into those at baseline and increased risk for preeclampsia and small-for-gestational age (SGA). STUDY DESIGN This retrospective cohort study examined outcomes of patients with ⩾one abnormal analyte (PAPP-A<0.3, hCG>3.0, AFP>2.5, inhibin>2.0, or unconjugated estriol<0.3MoM). At approximately 24weeks, we assessed UtA pulsatility index (PI). MAIN OUTCOME MEASURES Preeclampsia, preterm preeclampsia, SGA (birthweight (BW) <10%) and intrauterine growth restriction (IUGR) (BW<3%). RESULTS We identified 132 patients with ⩾one abnormal analyte, UtA Doppler screening, and delivery outcomes. Twenty-four (18%) had an elevated UtA PI (PI>1.6); preeclampsia occurred in 16 (12%) and 26 (20%) delivered a SGA neonate. Abnormal UtA Doppler PI increased the likelihood of a composite outcome of preeclampsia or SGA from 27% to 71% (LR 6.48 (2.93, 14.30)); a negative UtA Doppler PI reduced the likelihood to 18% (LR 0.57 (0.42, 0.78)). Abnormal UtA Doppler PI increased the likelihood of a more severe composite outcome of preterm preeclampsia or IUGR from 11% to 39% (LR 5.49 (3.03, 9.97)); a negative UtA Doppler study reduced the likelihood to 4% (LR 0.35 (0.16, 0.80)). CONCLUSIONS In patients with abnormal serum analytes, abnormal UtA Doppler PI is significantly associated with preeclampsia or SGA and improves the prediction of these adverse outcomes by 9-15-fold. Providers can incorporate UtA Doppler PI into an abbreviated surveillance regimen; they can be reassured that a normal study markedly decreases the risk of a severe early adverse outcome.

Anti-coagulation complications in pregnancies with severe pulmonary arterial hypertension

Abstract Background: Epoprostenol, a potent vasodilator, is the treatment of choice for severe pulmonary arterial hypertension (PAH) in pregnancy. However, its inhibition of platelet aggregation increases the risk of coagulation complications with conjunctive use of anti-coagulants for thromboprophylaxis. Cases: Case 1 demonstrates a pregnancy complicated by thrombocytopenia. Case 2 describes a pregnancy with newly diagnosed PAH at 35 weeks who delivered by repeat cesarean delivery complicated by a wound hematoma. Case 3 describes a patient who delivered at 32 weeks. She required extracorporeal membrane oxygenation and a heart–lung transplant. Her care was further complicated by severe thrombocytopenia with postpartum hemorrhage refractory to usual conservative measures. Conclusions: This case series describes three patients with severe PAH in pregnancy and the range of different complications that arose from anticoagulation in the setting of epoprostenol.