Neonatal outcomes and rationale for timing of birth in perinatal diabetes: a retrospective cohort study.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends delivery in the 39th week of pregnancy for patients with pregestational and medication-controlled gestational diabetes with consideration for earlier delivery among those with poor glucose control. OBJECTIVE: We sought to evaluate the impact of birth before 39 weeks' gestation exclusively for diabetes-related indications on neonatal outcomes and clinician rationale for these recommendations. STUDY DESIGN: This was a retrospective cohort study of all singleton, nonanomalous pregnancies complicated by diabetes. Patients were identified through an obstetrical database containing information of 90,185 births from 2011 to 2021. Patients who delivered in a given week of gestation exclusively for diabetes-related indications were compared with ongoing pregnancies. Recommended births for other obstetrical indications were excluded from the diabetes-related indications cohorts. The primary outcome was neonatal intensive care unit admission. Secondary outcomes included neonatal intensive care unit length of stay, stillbirth, neonatal death, hypoglycemia, respiratory distress syndrome, and shoulder dystocia. For all births before 39 weeks' gestation, the electronic medical records were reviewed to confirm the rationale for the intervention for a diabetes-indicated condition. RESULTS: From the 90,185 recorded births that occurred in 2011 to 2021, 4750 patients with diabetes were identified. Of those, 30.5% (n=1449) had a recommended birth for a diabetes-related indications with 2.2% of those (n=32) occurring at 36 weeks' gestation, 7.9% (n=114) at 37 weeks' gestation, 9.7% (n=141) at 38 weeks' gestation, and 63.0% (n=913) at 39 weeks' gestation. Births that occurred at 36 and 37 weeks' gestation exclusively for diabetes-related indications had higher rates of neonatal intensive care unit admission than the respective ongoing pregnancies (62.5% vs 8.7%; P<.001 and 25.4% vs 7.2%; P<.001). There was no difference in neonatal intensive care unit admission for births at 38 or 39 weeks' gestation when compared with ongoing pregnancy. For neonates born at 36 and 37 weeks' gestation in comparison with ongoing pregnancies, the median neonatal intensive care unit length of stay was 11.0 vs 2.8 days, (P<.001) and 4.4 vs 2.6 days (P=.026), respectively. There were significantly increased rates of neonatal hypoglycemia and respiratory distress syndrome among births that occurred at 36, 37, and 38 weeks' gestation when compared with ongoing pregnancies. There were no differences in the rate of stillbirth in this cohort. Primary factors cited for early birth were poor glycemic control (71.4%), recommendation by a maternal-fetal medicine specialist (38.7%), and suspected fetal macrosomia (27.9%). Overall, 46.7%, 32.8%, and 20.6% of patients had 1, 2, or ≥3 indications, respectively, listed as rationale for early birth. Overall, few objective measures were used to recommend birth before 39 weeks' gestation owing to diabetes. CONCLUSION: In pregnancies complicated by diabetes, early birth exclusively for diabetes-related indications was associated with increased neonatal intensive care unit admission and length of stay and with neonatal morbidity. Little objective data are documented by clinicians to support their recommendations for early birth associated with diabetes. Additional clinical guidelines are needed to define suboptimal glucose control necessitating birth before 39 weeks' gestation.

The Effect of Financial Incentives on Adherence to Glucose Self-Monitoring during Pregnancy among Patients with Insulin-Requiring Diabetes: A Randomized Clinical Trial.

OBJECTIVE: Glucose self-monitoring is critical for the management of diabetes in pregnancy, and increased adherence to testing is associated with improved obstetrical outcomes. Incentives have been shown to improve adherence to diabetes self-management. We hypothesized that use of financial incentives in pregnancies complicated by diabetes would improve adherence to glucose self-monitoring. STUDY DESIGN: We conducted a single center, randomized clinical trial from May 2016 to July 2019. In total, 130 pregnant patients, <29 weeks with insulin requiring diabetes, were recruited. Participants were randomized in a 1:1:1 ratio to one of three payment groups: control, positive incentive, and loss aversion. The control group received $25 upon enrollment. The positive incentive group received 10 cents/test, and the loss aversion group received $100 for >95% adherence and "lost" payment for decreasing adherence. The primary outcome was percent adherence to recommended glucose self-monitoring where adherence was reliably quantified using a cellular-enabled glucometer. Adherence, calculated as the number of tests per day divided by the number of recommended tests per day×100%, was averaged from time of enrollment until admission for delivery. RESULTS: We enrolled 130 participants and the 117 participants included in the final analysis had similar baseline characteristics across the three groups. Average adherence rates in the loss aversion, control and positive incentive groups were 69% (SE=5.12), 57% (SE = 4.60), and 58% (SE=3.75), respectively (p=0.099). The loss aversion group received an average of $50 compared with $38 (positive incentive) and $25 (control). CONCLUSION: In this randomized clinical trial, loss aversion incentives tended toward higher adherence to glucose self-monitoring among patients whose pregnancies were complicated by diabetes, though did not reach statistical significance. Further studies are needed to determine whether use of incentives improve maternal and neonatal outcomes. KEY POINTS: · Self-glucose monitoring is a critical part of diabetes management in pregnancy.. · Loss aversion financial incentives may increase adherence to glucose self-monitoring in pregnancy.. · The impact of testing incentives on maternal and neonatal outcomes requires further investigation..

Redesigned Care Delivery for Insulin-Requiring Diabetes in Pregnancy Improves Perinatal Glycemic Control While Reducing Neonatal Intensive Care Admissions, Length of Stay, and Costs.

Objective: We sought to improve perinatal glycemic control and downstream neonatal outcomes through redesigned ambulatory management for women with insulin-requiring diabetes in pregnancy. Methods: To address gaps in perinatal glycemic management of women with insulin-requiring diabetes in pregnancy, redesigned care delivery (RCD) utilized integrated practice unit and minimally disruptive medicine concepts with incorporation of cellular-enabled glucose monitoring. Primary outcomes of RCD (N = 129) included hemoglobin A1c ([HbA1c], within RCD cohort), and gestational age (GA) at delivery, neonatal intensive care (NICU) admission, and NICU length of stay (LOS) compared with a preredesign care cohort (Pre-RCD; N = 122). Secondary outcomes included facility, payer reimbursement, and program costs. Generalized linear models assessed continuous variables while logistic regression methods assessed categorical outcomes. Results: Utilizing RCD, 92% of women with an initial HbA1c <6.5% maintained glycemic control until delivery, and 67.2% with an initial HbA1c ≥6.5% achieved delivery levels <6.5%. NICU admissions and GA-adjusted LOS decreased significantly [Pre-RCD vs. RCD: NICU admissions, 41.0% vs. 27.3%, p < 0.024; NICU LOS (95% confidence interval [CI]), 21.9 (17.1-26.6) vs. 14.6 (9.1-20.1), p = 0.045]. Every 10 days of redesigned management decreased mean NICU LOS by 1 day. Mean payer neonatal reimbursements decreased over $18,000 per delivery (p = 0.08) compared with implementation costs of $1,942 per delivery. Conclusion: Redesigned perinatal diabetes care with remote glucose monitoring demonstrated improved outcomes and value through downstream neonatal outcomes and lower payer costs. Therefore, subsequent dissemination and sustainability of similar programs' improved outcomes will likely require payer support.

Cellular-Enabled Glucometers and Maternal Glucose Control: A Quality Improvement Initiative.

BACKGROUND: Management of diabetes in pregnancy is burdensome due to self-glucose monitoring, recording, and reporting demands. Cellular-enabled glucometers provide real-time transmission of glucose values independent of internet access and cell phone data plans. We describe a quality improvement (QI) intervention that introduced cellular-enabled glucometers for use during pregnancies complicated by diabetes. METHODS: Our aim was to improve maternal glucose control in a cohort of insulin-requiring pregnant women enrolled in a telemedicine diabetes program. During initial establishment of a QI program, women were offered cellular-enabled glucometers but could elect to keep their standard meter. The primary outcome evaluated was glycosylated hemoglobin A1c (HbA1c) at delivery. RESULTS: Baseline characteristics including initial HbA1c were similar between women using a standard glucometer (n = 45) and those using a cellular-enabled glucometer (n = 72). Women who used a cellular-enabled glucometer had a lower HbA1c at delivery compared to those using a standard glucometer (5.8% vs 6.3%, P = .03). This improvement was particularly notable for women with poor glucose control (defined as HbA1c >6.5%) at initial obstetric visit. Women with poor glucose control who used a cellular-enabled glucose monitor had significantly lower HbA1c at delivery (6.0% vs 6.8%, P = .03) and greater change from initial visit compared to those using a standard glucometer (-2.6% vs -1.4%, P = .02). No statistically significant differences were detected in tracked neonatal outcomes. CONCLUSION: For pregnancies complicated by insulin-requiring diabetes, use of cellular-enabled glucometers as part of a perinatal diabetes program improves glucose control at delivery with timely transmission of accurate values throughout gestation.

Adherence to self-glucose monitoring recommendations and perinatal outcomes in pregnancies complicated by diabetes mellitus.

BACKGROUND: Self-glucose monitoring is critical for the management of diabetes mellitus in pregnancy; yet, validated reports of adherence to testing recommendations and associated perinatal outcomes are limited. OBJECTIVE: Using cloud-based, self-glucose monitoring technology, we sought to answer the following questions: (1) Are there differences in the rates of testing adherence based on type of diabetes mellitus in pregnancy? (2) Is adherence to glucose monitoring recommendations associated with perinatal outcomes in pregnancies that are complicated by diabetes mellitus? We hypothesized that adherence to glucose testing recommendations varies by type of diabetes mellitus and that increased adherence to testing recommendations would be associated with improved perinatal outcomes. STUDY DESIGN: This single-center, prospective cohort study included women with type 2 diabetes mellitus and gestational diabetes mellitus who were enrolled in a perinatal diabetes program at <29 weeks gestation between December 2015 and June 2018. All women received a cellular-enabled glucometer that uploaded glucose values to a cloud-based, Health Insurance Portability and Accountability Act-compliant platform in real time that ensured transmission of accurate glucose values. The primary outcome was adherence to self-glucose monitoring recommendations. Four glucose checks were advised daily, and percentage of adherence was calculated. Secondary outcomes were preeclampsia, cesarean delivery, large-for-gestational-age neonates, and neonatal hypoglycemia. The study was powered to detect a 10% difference in the primary outcome of adherence to advised self-glucose monitoring by diabetes mellitus type. Adjusted risk ratios and 95% confidence intervals were generated with the use of logistic regression. RESULTS: This study included 103 eligible women. Baseline characteristics differed between groups, with women with type 2 diabetes mellitus having higher initial HgbA1c and body mass index when compared with women with gestational diabetes mellitus. No differences were noted in age or parity. Adherence was calculated over 20±6 weeks for women with type 2 diabetes mellitus compared with 9±4 weeks for women with gestational diabetes mellitus. Overall adherence to glucose monitoring was significantly less for women with type 2 diabetes mellitus compared with those with gestational diabetes mellitus. Mean testing adherence rates were 51%, 66%, and 70% for type 2 diabetes mellitus, and gestational diabetes mellitus, class A1 and A2, respectively (P=.016). We found that, for every 10% increase in adherence to testing recommendations, the odds of cesarean delivery, neonatal hypoglycemia, and large-for-gestational-age fetuses decreases by 15-20%. There was no association between adherence and rates of preeclampsia. CONCLUSION: This study shows that overall adherence to testing recommendations differs by diabetes mellitus type and is associated with neonatal outcomes. Improved outcomes with higher adherence may reflect more timely medication adjustments in response to real-time glucose values. Programs aimed at improving adherence could prove beneficial.

Pregnant women have increased incidence of IgE autoantibodies reactive with the skin and placental antigen BP180 (type XVII collagen).

BP180 (type XVII collagen) is a transmembrane protein expressed in a variety of cell types. It is also the target of autoantibodies in cutaneous autoimmune disease including bullous pemphigoid and pemphigoid gestationis, a disease unique to pregnancy. The purpose of this study was to determine the prevalence and specificity of cutaneous autoantibodies in a cohort of pregnant women. De-identified sera were collected from pregnant women (n=299) and from non-pregnant controls (n=134). Sera were analyzed by ELISA for the presence of IgG and IgE autoantibodies directed against several cutaneous autoantigens. IgE antibodies against the NC16A domain of BP180 were detected in 7.7% of pregnant women, compared to 2.2% of healthy controls (p=0.01). No increase in total or cutaneous autoantigen specific IgG was seen. Total serum IgE was within the normal range. Full-length BP180 was detected by western immunoblot in epidermal, keratinocyte, placental and cytotrophoblast (CTB) cell lysates. Furthermore, flow cytometry and indirect immunofluorescence confirmed the expression of BP180 on the surface of cultured CTBs. Finally, it was demonstrated that IgE antibodies in the pregnancy sera labeled not only cultured CTBs, but also the placental amnion and cutaneous basement membrane zone using indirect immunofluorescence. We conclude that some pregnant women develop antibodies specific for BP180, and that these autoantibodies are capable of binding both CTB and the placental amnion, potentially affecting placental function.

Screening for Staphylococcus aureus carriage in pregnancy: usefulness of novel sampling and culture strategies.

OBJECTIVE: The purpose of this study was to determine the most sensitive strategy for the detection of Staphylococcus aureus among pregnant women and newborn infants. STUDY DESIGN: We obtained cultures for S aureus from 5 body sites of women at 35-37 weeks' gestation. We obtained cultures from their newborn infants before hospital discharge. RESULTS: Of 209 women who were screened, 29% of the women had at least 1 culture that was positive for S aureus; 5% of infants were S aureus carriers. The sensitivities of each site for S aureus detection were 52% nares, 50% throat, 13% rectum, 8% vagina, and 10% skin. The most sensitive combination of 2 sites was nares and throat (88%). Perinatal transmission of S aureus occurred in 4 women. Maternal methicillin-resistant S aureus carriage rate was 1%. Two infants carried the USA300 methicillin-resistant S aureus. CONCLUSION: Screening single body sites is insensitive for the detection of S aureus carriage in pregnancy. Sampling nares and throat is essential to the identification of S aureus carriers.

A recently evolved novel trophoblast-enriched secreted form of fms-like tyrosine kinase-1 variant is up-regulated in hypoxia and preeclampsia.

CONTEXT: Recent published studies indicate a possible role for sFlt1 in the development of preeclampsia. OBJECTIVE: The objective of the study was to investigate the expression and regulation of sFlt1-e15a, a recently described novel C-terminal variant isoform of sFlt1. DESIGN: The studies included a computational comparative analysis of the genomic locus of sFlt1 across vertebrate species; an assessment of sFlt1 variants in human and rhesus cells and tissues; an analysis of sFlt1 variants transiently expressed in HeLa and COS-7 cells; an evaluation of the effect of hypoxia on sFlt1 expression in trophoblasts; and a comparison of placental sFlt1 expression between pregnancies complicated by preeclampsia and control pregnancies. RESULT AND CONCLUSIONS: sFlt1-e15a emerged as an alternate transcript of Flt1 late in evolution with the insertion of an AluSq sequence into the primate genome after the emergence of the simian infraorder about 40 million years ago. sFlt1-e15a is particularly abundant in human placenta and trophoblasts and is also highly expressed in nonhuman primate placenta. The expressed protein has a C-terminal polyserine tail and, like reference sequence sFlt1 (sFlt1-i13), is glycosylated and secreted. Consistent with a role in placental pathophysiology, hypoxia stimulates sFlt1-e15a expression in isolated cytotrophoblasts and a trophoblast cell line, and differentiation into syncytiotrophoblasts further enhances the effect of hypoxia. Placental levels of sFlt1-e15a and sFlt1-i13 transcripts are significantly elevated in patients with preeclampsia compared with normal pregnancies. We speculate that sFlt1-e15a may contribute to the pathophysiology of preeclampsia.

Cytomegalovirus and the role of interferon in the expression of tumor necrosis factor-related apoptosis-inducing ligand in the placenta.

OBJECTIVE: Cytomegalovirus infection causes adverse outcomes during pregnancy. Our objective was to determine the role of cytomegalovirus in modulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand expression in the placenta. STUDY DESIGN: TNF-related apoptosis-inducing ligand messenger RNA and protein were quantified in cytomegalovirus-infected placental fibroblasts by polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Blocking antibodies against interferon and type I interferon receptor were applied to culture medium to characterize the role of type I interferon in cytomegalovirus-induced TNF-related apoptosis-inducing ligand upregulation. RESULTS: Expression of TNF-related apoptosis-inducing ligand messenger RNA and protein was increased in cytomegalovirus-infected placental fibroblasts, compared with uninfected controls. The cytomegalovirus-induced TNF-related apoptosis-inducing ligand messenger RNA upregulation was demonstrated across gestation, occurred in the absence of viral gene expression, and required cellular protein synthesis. TNF-related apoptosis-inducing ligand messenger RNA upregulation was markedly attenuated by inactivation of either type I interferon or its receptor. CONCLUSION: One mechanism by which cytomegalovirus infection causes unfavorable pregnancy outcomes may involve placental upregulation of TNF-related apoptosis-inducing ligand via an interferon-mediated pathway.

The yeast connection: is Candida linked to breastfeeding associated pain?

OBJECTIVE: The objective of the study was to determine whether the isolation of Candida from breastfeeding women is associated with self-reported pain. STUDY DESIGN: A prospective cohort study was conducted from May 2004 to July 2006. Ninety-eight breastfeeding women were enrolled: 20 women reported breastfeeding associated pain, and 78 women were asymptomatic. Cultures were obtained from breast milk, areolae, and infants' oropharynx. RESULTS: Six of the 20 symptomatic women had breast milk cultures positive for yeast, compared with 6 of 78 controls (30% vs 7.7%, P = .015). Among the 12 women from whom yeast was isolated, 11 grew Candida albicans. Incidence of Staphylococcus aureus isolation did not differ significantly between groups (5 of 20 vs 15 of 78, P > .05). CONCLUSION: C. albicans is found more often in breastfeeding mothers who report pain as compared with asymptomatic breastfeeding mothers. Further studies, including treatment trials, are needed to determine whether Candida plays an etiologic role in breastfeeding associated pain.

Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta.

The gene FLT1 produces at least two transcripts from a common transcription start site: full-length Flt1 contains 30 exons encoding a membrane-bound VEGF receptor; soluble Flt1 (sFlt1) shares the first 13 exons but utilizes poly(A) signal sequences within intron 13 to create a transcript that lacks downstream exons. To address the mechanisms that regulate human sFlt1, we mapped the 3' end of sFlt1 mRNA and defined the full extent of its 3' untranslated region (UTR). We identified a 3.2 Kb sFlt1 transcript that is cleaved within an alternatively spliced exon downstream of exon 14 and is predicted to encode a C-terminal variant of sFlt1 with an unusual polyserine tail. sFlt1 mRNA cleavage sites within intron 13 were identified in human placenta and in vascular endothelium by ribonuclease protection assay (RPA). A proximal and two distal mRNA cleavage sites were identified by RPA downstream of consensus polyadenylation signals that create variant transcripts with a 3' UTR ranging from 30 bases to approximately 4 Kb. Northern blot analysis and 3' rapid amplification of cDNA ends (RACE) in placenta confirmed the existence of distal intronic sFlt1 cleavage sites that give rise to a sFlt1 transcript of approximately 7 Kb. The identity of the distal signal sequences were then confirmed by mutagenesis of putative signal elements in a polyadenylation reporter assay. We demonstrate the heterogeneity of human sFlt1 that arises from alternate splicing and from alternative polyadenylation directed by strong intronic poly(A) signal sequences leading to C-terminal variants and to an sFlt1 transcript with a large 3' UTR containing several AU rich elements and poly(U) regions that may regulate mRNA stability.

Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway.

The human cytomegalovirus (HCMV) major immediate-early (MIE) enhancer contains five functional cyclic AMP (cAMP) response elements (CRE). Because the CRE in their native context do not contribute appreciably to MIE enhancer/promoter activity in lytically infected human fibroblasts and NTera2 (NT2)-derived neurons, we postulated that they might have a role in MIE enhancer/promoter reactivation in quiescently infected cells. Here, we show that stimulation of the cAMP signaling pathway by treatment with forskolin (FSK), an adenylyl cyclase activator, greatly alleviates MIE enhancer/promoter silencing in quiescently infected NT2 neuronal precursors. The effect is immediate, independent of de novo protein synthesis, associated with the phosphorylation of ATF-1 serine 63 and CREB serine 133, dependent on protein kinase A (PKA) and the enhancer's CRE, and linked to viral-lytic-cycle advancement. Coupling of FSK treatment with the inhibition of either histone deacetylases or protein synthesis synergistically activates MIE gene expression in a manner suggesting that MIE enhancer/promoter silencing is optimally relieved by an interplay of multiple regulatory mechanisms. In contrast, MIE enhancer/promoter silence is not overcome by stimulation of the gamma interferon (IFN-gamma) signaling pathway, despite the enhancer having two IFN-gamma-activated-site-like elements. We conclude that stimulation of the cAMP/PKA signaling pathway drives CRE-dependent MIE enhancer/promoter activation in quiescently infected cells, thus exposing a potential mode of regulation in HCMV reactivation.

Diagnosis of fetal infections.

PURPOSE OF REVIEW: The purpose of this review is to present recent developments in the prenatal diagnosis of the most clinically relevant congenital infections. RECENT FINDINGS: Immunoglobin G avidity testing can help to differentiate between recent or prior infection. A combination of tests, including serology, avidity and polymerase chain reaction, may be necessary to improve accuracy of diagnosis. The interval between exposure to an infectious agent and prenatal testing can be critical to the interpretation of the test result. SUMMARY: This review reinforces the need for accurate testing to guide appropriate counseling and individual fetal risk assessment. The findings of viral-specific antibodies or sonographic abnormalities do not accurately predict the severity or outcome of fetal infection. Further research is necessary to determine the pathogenesis of transplacental viral transmission and thereby allow us to target prevention strategies.

Prenatal testing for infectious disease.

Prenatal testing for infectious diseases is performed frequently and for a variety of indications. The purpose of this article is to review the maternal and fetal infections that pose diagnostic concerns. Recent advances in diagnostic testing (such as avidity testing) is included. Testing issues focus on the diagnosis of maternal and fetal infection.

Molecular epidemiology of macrolide resistance in neonatal bloodstream isolates of group B streptococci.

Pulsed-field gel electrophoresis (PFGE) was performed on 122 neonatal bloodstream isolates of group B streptococci (GBS) to further examine the relationship between macrolide resistance and serotype V GBS (GBS-V). Over one-third (35%) of macrolide-resistant GBS belonged to a single PFGE subtype of GBS-V, which was also the most common GBS-V subtype noted in previous Centers for Disease Control and Prevention surveillance studies. Erm methylase (ermA and ermB) was the most common resistance mechanism detected, present in 12 of 20 macrolide-resistant GBS.

Antenatal hydronephrosis: evaluation and outcome.

We present a comprehensive and current review of the etiology, evaluation, treatment, and outcome of antenatal hydronephrosis. When a diagnosis of antenatal hydronephrosis is made, many questions regarding pregnancy, prenatal care, intervention, and what may be expected after birth are raised. Debate and controversy exist on the diagnosis and subsequent evaluation and management of the child with antenatal hydronephrosis. A review of the literature and our own experience with antenatal hydronephrosis are presented in order to guide the physician who is caring for mother and child.