Do patients with a short cervix, with or without an ultrasound-indicated cerclage, have an increased risk for a small for gestational age newborn?

INTRODUCTION: Mothers with a short cervix have been shown to have increased risk of spontaneous preterm delivery (PTD) and newborn morbidity. Those who require an ultrasound-indicated cerclage experience the highest rates of morbidity. Inflammation has been linked to a short cervix, and it has been linked to pregnancies affected by small for gestational age (SGA) newborns. To date, there are no studies that have investigated an association between a short cervix, with or without an ultrasound-indicated cerclage, and a SGA newborn. METHODS: This was a case-control study examining all pregnancies with a transvaginal cervical length <25 mm found at their second trimester anatomy scan. Cases were subdivided into those who received an ultrasound-indicated cerclage (Group 1, n = 52) and those who did not (Group 2, n = 139). Controls were defined as pregnancies with a transvaginal cervical length >25 mm with no cerclage (Group 3, n = 186) whose due date was within 2 months of the case pregnancy. Each short cervix case was matched with a control from group 3 in a 1:1 ratio. The primary outcome was birthweight <10% (SGA). Unadjusted data was analyzed with simple odds ratios. A logistic regression was used to control for confounding variables and provide an adjusted odds ratios (aOR). RESULTS: The incidence of SGA among cases overall (group 1 + group 2) was 13.6% (26/191). In group 3, the SGA incidence was 4.3% (8/186). The adjusted odds ratio (aOR) for a SGA infant was significant, 2.8 (95% CI 1.2, 6.6). Subgroup analysis showed that Group 1 had an increased risk for an SGA infant [aOR 4.9 (95% CI 1.8, 13.7)], but Group 2 did not show a significant finding [aOR 2.3 (95% CI 0.9, 5.7)]. CONCLUSION: Pregnancies complicated by a short cervical length <25mm, with or without a cerclage, were associated with an increased risk for a SGA newborn. Most of this significance was due to the pregnancies which received an ultrasound-indicated cerclage for a mid-trimester short cervix.

How do pregnant women's perceptions of obstetric forceps change according to their demographic background: a cross sectional study.

BACKGROUND: Women's attitudes towards obstetric forceps likely contribute to declining use and opportunities for residency training, but formal documentation of women's attitudes towards obstetric forceps is currently limited. A clearer understanding should help guide our attempts to preserve its use in modern obstetrics and to improve residency training. Our objective is to document women's attitudes towards obstetric forceps and the influence basic demographic variables have on those attitudes. METHODS: A cross sectional study was performed. We developed a one-time anonymous structured 5-question survey that was given to all women with low-risk pregnancies presenting to our medical center for prenatal care between October 2018-December 2018. The questionnaire asked for the woman's self-reported age, race, education level and insurance type. The five questions were as follows: (1) Do you think forceps should be used to deliver babies, (2) Is forceps safe for the baby, (3) Is forceps safe for the mother, (4) Do you think forceps can help to lower the cesarean section rate, (5) Do you think physicians in training should learn to place forceps on a real patient. We calculated means and proportions for the responses according to the overall group and various subgroups. Statistical analysis included Kruskall-Wallis or Mann-Whitney tests as appropriate. Results were also adjusted by regression using a Generalized Linear Model. Power calculation showed sample size of 384 was required. RESULTS: A total of 499 women returned the questionnaire. Response rate was 56.8% (499/878). The findings suggest that women's perceptions towards forceps are generally negative. Women with white ethnicity, college education or higher and private insurance did have more favorable views than their counterparts, but the majority still had unfavorable views. Age was not shown to have a significant effect on maternal attitude. CONCLUSION: Women's views towards forceps use in the University of Kansas Medical Center are negative and may be contributing to the decline of its use. Improving women's perceptions of forceps would require multiple different strategies rather than a single focused easily-implemented message. If forceps training continues, such training will rely on a minority of women who will accept forceps use in childbirth.

Use of mean platelet volume in the assessment of intrauterine infection in newborns with combined thrombocytopenia and leukopenia at birth.

Objective: Intrauterine stress can be reflected on hematological disturbance at birth. Thrombocytopenia and leukopenia may be a result of exposure to maternal hypertensive disorders but may also indicate fetal inflammatory response to intrauterine infection, prompting empiric antibiotics use during the initial assessment after birth. Emerging data suggest long-term adverse health outcomes associated with antibiotics exposure early in life. In this report, we sought to assess the use of mean platelet volume (MPV) at birth in predicting fetal inflammatory response in newborns with combined thrombocytopenia and leukopenia.Materials and methods: This is a retrospective study from a single academic medical center. Data were collected prospectively on all newborns with thrombocytopenia and leukopenia within the first 24 h of life. The primary outcome was a composite of fetal tachycardia, premature preterm rupture of membrane with preterm labor, and histological evidence of chorioamnionitis/funisitis/villitis on placental pathology reports evaluated using a multiple logistical regression analysis.Results: The prevalence of combined thrombocytopenia and leukopenia was 5.8% (99 out of 1693 newborns) during the study period. The prevalence was highly associated with gestational age (R2 = 0.873). Twenty-four (32.4%) had abnormal MPV values at birth, defined as MPV > 9 or < 7 fL. Newborns with abnormal MPV had lower platelet counts and were more likely to have I:T ratio ≥0.2. In a univariate analysis, abnormal MPV (OR: 6.205, 95% CI: 1.923-20.022, p = .002), I:T ratio ≥0.2 (OR: 8.462, 95% CI: 1.396-51.281, p = .02), and platelet counts (OR: 98.4, 95% CI: 96.9%-99.9%, p = .035) were each significantly associated with a positive composite outcome. In a multivariate analysis, only abnormal MPV remained significantly associated with an increased likelihood of having a positive composite outcome, with an OR of 3.922 (95% CI: 1.094-14.06, p = .036).Conclusions: MPV may be a more reliable marker than I:T ratio ≥0.2 for fetal inflammatory response in newborns with combined thrombocytopenia and leukopenia during the initial assessment of intrauterine infection. Future prospective studies are required to confirm findings from this report.

Exposure to placental insufficiency alters postnatal growth trajectory in extremely low birth weight infants.

Growth in the immediate postnatal period for extremely low birth weight (ELBW, birth weight < 1000 g) infants is an important topic in neonatal medicine. The goal is to ensure adequate postnatal growth and to minimize complications resulting from suboptimal growth. Past efforts have focused on postnatal nutrition as well as on minimizing comorbidities. It has not been systematically assessed whether antenatal factors play a role in postnatal growth. In this report, we conducted a retrospective study on 91 maternal-neonatal pairs. We prospectively collected maternal and neonatal demographic data, neonatal nutrition in the first 7 days of life and after enteral nutrition is fully established, comorbidity data, as well as weight data from birth to 50 weeks corrected gestational age. We developed a linear mixed-effects model to examine the role of placental insufficiency, as defined by fetal Doppler studies, in postnatal weight z-score trajectory over time in the ELBW population. We relied on Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) for model selection. Interestingly, the selected model included a quadratic term of time and a placental insufficiency-by-time interaction term. In a covariate analysis, AIC and BIC both favored a model that included calories intake in the first 7 days of life and the total duration of antibiotics as fixed-effects, but not their interaction terms with time. Overall, we demonstrated for the first time that placental insufficiency, an antenatal factor, is a major determinant of postnatal weight trajectory in the ELBW population. Prospective studies are warranted to confirm our findings.

The Utility of Lower Glycemic Targets for Treating Gestational Diabetes: A Retrospective Study.

OBJECTIVE: In vivo study of glucose homeostasis in pregnancy suggests normal glucose levels are lower than current glycemic targets used in gestational diabetes. After the HAPO study results, our institution began using glycemic targets of fasting 85 mg/dL and 2-hour postprandial of 110 mg/dL. We reviewed our results. METHODS: A retrospective cohort of GDM patients that delivered at KUMC from January 2007 to May 2017 was reviewed. All patients were diagnosed with the 2-step Carpenter-Coustan thresholds. High targets were compared with low targets. The primary outcome investigated was birthweight > 90% (large for gestational age, LGA). RESULTS: 604 patients were studied, and 34% were treated with low glycemic targets. Our unadjusted results showed that the low-target group had a lower incidence of LGA infants (24.0 vs. 31.8%), higher incidence of neonatal hypoglycemia (20.7 vs. 11.6%), and inductions (39.4 vs. 20.5%). After adjustment for demographic variables, only a higher risk of inductions remained (aOR 2.54 (1.44, 4.49)). CONCLUSION: Lower glycemic targets did not produce large reductions in fetal overgrowth, but they were associated with a higher rate of inductions. As there were no observed differences in maternal or neonatal outcomes otherwise, aiming for lower glycemic targets in GDM is likely not cost-effective.

Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium.

OBJECTIVE: Calmodulin (CaM) plays a key role in the orchestration of Ca2+ signaling events, and its regulation is considered an important component of cellular homeostasis. The control of uterine smooth muscle function is largely dependent on the regulation of Ca2+ and CaM signaling. The objective of this study was to investigate the expression, function, and regulation of CaM regulatory proteins in myometrium during pregnancy. STUDY DESIGN: Myometrium was obtained from nonpregnant women and 4 groups of pregnant women at the time their primary cesarean delivery: (i) preterm not in labor, (ii) preterm in labor with clinical and/or histological diagnosis of chorioamnionitis, (3) term not in labor; and (4) term in labor. The effect of perinatal inflammation on pcp4/pep-19 expression was evaluated in a mouse model of Ureaplasma parvum-induced chorioamnionitis. Human myometrial cells stably expressing wild-type and mutant forms of PCP4/PEP-19 were used in the evaluation of agonist-induced intracellular Ca2+ mobilization. RESULTS: Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. In the mouse uterus, pcp4/pep-19 expression was lower in late compared to mid-gestation and decreased in mice injected intra-amniotic with Ureaplasma parvum. In myometrial smooth muscle cells, tumor necrosis factor alpha and progesterone decreased and PCP4/PEP-19 promoter activity increased. Finally, the overexpression of PCP4/PEP-19 reduced agonist-induced intracellular Ca2+ levels in myometrial cells. CONCLUSION: The decreased expression of PCP4/PEP-19 in myometrium contributes to a loss of quiescence in response to infection-induced inflammation at preterm pregnancy.

A retrospective study comparing outcomes in a midwestern US population after introduction of IADPSG guidelines for gestational diabetes.

OBJECTIVE: More evidence is required to endorse the 1-step approach for gestational diabetes mellitus (GDM) for clinical practice. Since 2010, our department has pragmatically allowed faculty to self-select the guidelines they use to screen and diagnose GDM. We sought to compare the maternal and neonatal outcomes from these two simultaneous cohorts. STUDY DESIGN: We performed a retrospective cohort study of all singleton pregnancies delivered between October 2011 and -November 2013 at our hospital. Patients were excluded if they had preexisting diabetes, were not screened or screened inappropriately, or their fetus had congenital anomalies. Patients were grouped by their screening strategy, and maternal and neonatal outcomes were analyzed. RESULTS: The 1-step group had a higher incidence of GDM (21.6% versus 5.0%). Initial results suggested higher rates of neonatal hypoglycemia, phototherapy for hyperbilirubinemia, and a lower rate of gestational HTN. After adjustment, these differences disappeared, but a lower rate of large for gestational age (LGA) infants was discovered (adjusted odds ratios (aOR) 0.78). CONCLUSION: The picture remains unclear as to whether the 1-step approach is associated with significantly improved outcomes compared with the 2-step approach. We did find a lower risk for a LGA infant in our 1-step cohort, but it is unlikely that the 1-step approach would be cost-effective due to the absence of other improved outcomes.

Regulation of human placental drug transporters in HCV infection and their influence on direct acting antiviral medications.

INTRODUCTION: The objectives of this study were to determine how HCV infection affects placental drug transporters, and to determine the role of drug transporters on the cellular accumulation of direct-acting antiviral drugs in human trophoblasts. METHODS: Eighty-four ABC and SLC transporter genes were first screened in normal and HCV infected pregnant women using PCR profiler array. The changes in expression were confirmed by qPCR and Western blot. The impact of selected drug transporters on the cellular accumulation of radiolabeled antiviral drugs sofosbuvir, entecavir, and tenofovir was measured in primary human trophoblasts (PHT) and BeWo b30 cells in the presence or absence of transporter-specific inhibitors. PHT were then treated with CL097, ssRNA40, and imquimod to determine the impact of Toll-like receptor (TLR) 7/8 activation on drug transporter expression. RESULTS: The expression of the ABC efflux transporters ABCB1/P-gp and ABCG2/BCRP was increased in placenta of women with HCV, while the nucleoside transporters SLC29A1/ENT1 and SLC29A2/ENT2 remained unchanged. The accumulation of sofosbuvir and tenofovir was unaffected by inhibition of these transporters in trophoblast cells. Entecavir accumulation was decreased by the inhibition of ENT2. P-gp and BCRP inhibition enhanced entecavir accumulation in BeWo b30, but not PHT. Overall, there was little effect of TLR7/8 activation on these drug transporters, and the accumulation of entecavir in PHT. DISCUSSION: The data suggest that expression of placental drug transporters and selection of antiviral drug may impact fetal drug exposure in pregnancies complicated by HCV infections.

What is the accuracy of an early third trimester sonogram for identifying LGA infants born to GDM patients diagnosed with the one-step approach?

PURPOSE: The one-step approach for screening of GDM will increase the incidence 2- to 3-fold. These larger cohorts may need to target high-morbidity subsets to be cost-effective. We asked whether ultrasound could stratify the GDM patients with the highest risk for a large for gestational age (LGA) infant. MATERIALS AND METHODS: A retrospective analysis was performed on 413 GDM patients diagnosed using the one-step approach. Ultrasound data from 28 weeks 0 day to 34 weeks 6 days was studied. The abdominal circumference (AC) and EFW at thresholds between 70 and 95% were examined for their prognostic utility. The primary outcome was an LGA infant. RESULTS: Both the AC and EFW at all gestational ages were predictive of a LGA infant. The AC and EFW at 28-32 weeks 6 days using a threshold of ≥70% showed the following test characteristics: sensitivity (73 versus 66%), specificity (61 versus 77%), positive predictive value (PPV) (30 versus 40%), and negative predictive value (NPV) (91 versus 91%). The specificity of the EFW was significantly higher than the AC (p < .001). CONCLUSION: Among GDM patients diagnosed using the one-step approach, an elevated AC and EFW in the early third trimester are predictive of a LGA infant. This is a possible cost-effective way to stratify the one-step GDM pregnancies at highest risk for neonatal morbidity.

Effect of prostaglandin E2 on multidrug resistance transporters in human placental cells.

Prostaglandin (PG) E2, a major product of cyclooxygenase (COX)-2, acts as an immunomodulator at the maternal-fetal interface during pregnancy. It exerts biologic function through interaction with E-prostanoid (EP) receptors localized to the placenta. The activation of the COX-2/PGE2/EP signal pathway can alter the expression of the ATP-binding cassette (ABC) transporters, multidrug resistance protein 1 [P-glycoprotein (Pgp); gene: ABCB1], and breast cancer resistance protein (BCRP; gene: ABCG2), which function to extrude drugs and xenobiotics from cells. In the placenta, PGE2-mediated changes in ABC transporter expression could impact fetal drug exposure. Furthermore, understanding the signaling cascades involved could lead to strategies for the control of Pgp and BCRP expression levels. We sought to determine the impact of PGE2 signaling mechanisms on Pgp and BCRP in human placental cells. The treatment of placental cells with PGE2 up-regulated BCRP expression and resulted in decreased cellular accumulation of the fluorescent substrate Hoechst 33342. Inhibiting the EP1 and EP3 receptors with specific antagonists attenuated the increase in BCRP. EP receptor signaling results in activation of transcription factors, which can affect BCRP expression. Although PGE2 decreased nuclear factor κ-light chain-enhancer of activated B activation and increased activator protein 1, chemical inhibition of these inflammatory transcription factors did not blunt BCRP up-regulation by PGE2. Though PGE2 decreased Pgp mRNA, Pgp expression and function were not significantly altered. Overall, these findings suggest a possible role for PGE2 in the up-regulation of placental BCRP expression via EP1 and EP3 receptor signaling cascades.

Does the use of fetal fibronectin in an algorithm for preterm labor reduce triage evaluation times?

OBJECTIVE: To determine the effectiveness of a novel algorithm based on fetal fibronectin (FFN) for management of preterm labor (PTL). METHODS: A randomized trial was performed on patients who presented with symptoms of PTL at 24-34 weeks. Patients were randomized to algorithms with cervical exams only versus cervical exams plus FFN. In this algorithm, physicians had to discharge patients with a negative FFN result. The primary outcome was the evaluation time for triage. The secondary outcomes were admission to the hospital for PTL, preterm birth <34 weeks and preterm birth <37 weeks. RESULTS: A total of 76 patients were enrolled and randomized (control n = 32, FFN n = 44). There were no differences in triage time, hospital admissions or preterm deliveries (PTDs) between the two groups. CONCLUSION: An algorithm based on FFN for management of PTL does not reduce evaluation times for triage, hospital admissions or PTDs.

Cervilenz assessment of cervical length compared to fetal fibronectin in the prediction of preterm delivery in women with threatened preterm labor.

OBJECTIVE: To determine whether cervical length (CL) measured by the Cervilenz™ measuring device is an effective screening tool for the prediction of preterm delivery (PTD) compared to fetal fibronectin (fFN). METHODS: We evaluated fFN and CL among women who enrolled into a randomized control trial (RCT) comparing management algorithms for threatened preterm labor between 24 and 34 weeks' gestation. In all subjects, fFN was collected, with CL determined in blinded fashion. The sensitivity, specificity, and positive and negative predictive values (NPV) for fFN or Cervilenz in prediction of PTD within 7 days or prior to 37 weeks were determined. RESULTS: Fifty-two subjects were evaluated. CL <30 mm correlated with PTD <7 days (r = 0.31, p = 0.04) and fFN positivity (r = 0.43, p = 0.006). CL <30 mm and fFN had excellent NPV for PTD <7 days (97.1 vs. 97.3%), and the area under the receiver operator characteristic curves were similar for prediction of PTD <7 days (76.6 vs. 75.2%, p = 0.71) or <37 weeks (56.7 vs. 55.2%, p = 0.71). CONCLUSIONS: Measurement of CL with Cervilenz appears to be equivalent to fFN in screening symptomatic women for PTD within 7 days or prior to 37 weeks. Given cost and turnaround time with fFN testing, Cervilenz represents a promising new tool for real time, clinically useful results in the management of women with threatened preterm labor.

Blinded comparison of cervical portio length measurements by digital examination vs Cervilenz.

OBJECTIVE: Cervical length (CL) examinations may identify patients in preterm labor or those who may benefit from prophylactic therapy. We sought to compare the accuracy of clinician digital CL examinations with objective measurements using the Cervilenz device in women presenting with symptoms of preterm labor. STUDY DESIGN: Forty-two patients with singleton gestation from 24 to 34 weeks' gestation and cervical dilation less than 3 cm underwent speculum examination and Cervilenz measurement. A second examiner, blinded to results, digitally measured CL. Pearson's correlation coefficient, Student t tests and McNemar's tests were used to compare digital and Cervilenz measures. RESULTS: Digital CL was significantly less than Cervilenz (2.88 vs 3.40 cm; P < .001), and in 36% of subjects, this difference exceeded 1 cm. The discrepancy in CL estimates persisted whether women were multiparous or had soft cervices or a history of preterm delivery. CONCLUSION: Digital assessment underestimates CL, whereas the Cervilenz device permits a visualized and objective CL measure in patients with preterm labor.