Chronic villitis as a distinctive feature of placental injury in maternal SARS-CoV-2 infection.

BACKGROUND: SARS-CoV-2 infection during pregnancy is associated with an increased risk for stillbirth, preeclampsia, and preterm birth. However, this does not seem to be caused by intrauterine fetal infection because vertical transmission is rarely reported. There is a paucity of data regarding the associated placental SARS-CoV-2 histopathology and their relationship with the timing and severity of infection. OBJECTIVE: This study aimed to determine if maternal SARS-CoV-2 infection was associated with specific patterns of placental injury and if these findings differed by gestational age at time of infection or disease severity. STUDY DESIGN: A retrospective cohort study was performed at the University of California San Diego between March 2020 and February 2021. Placentas from pregnancies with a positive SARS-CoV-2 test were matched with 2 sets of controls; 1 set was time-matched by delivery date and sent to pathology for routine clinical indications, and the other was chosen from a cohort of placentas previously collected for research purposes without clinical indications for pathologic examination before the SARS-CoV-2 outbreak. Placental pathologic lesions were defined based on standard criteria and included maternal and fetal vascular malperfusion and acute and chronic inflammatory lesions. A bivariate analysis was performed using the independent Student t test and Pearson chi-square test. A logistic regression was used to control for relevant covariates. Regions of SARS-CoV-2-associated villitis were further investigated using protein-based digital spatial profiling assays on the GeoMx platform, validated by immunohistochemistry, and compared with cases of infectious villitis and villitis of unknown etiology. Differential expression analysis was performed to identify protein expression differences between these groups of villitis. RESULTS: We included 272 SARS-CoV-2 positive cases, 272 time-matched controls, and 272 historic controls. The mean age of SARS-CoV-2 affected subjects was 30.1±5.5 years and the majority were Hispanic (53.7%) and parous (65.7%). SARS-CoV-2 placentas demonstrated a higher frequency of the 4 major patterns of placental injury (all P<.001) than the historic controls. SARS-CoV-2 placentas also showed a higher frequency of chronic villitis and severe chronic villitis (P=.03 for both) than the time-matched controls, which remained significant after controlling for gestational age at delivery (adjusted odds ratio, 1.52; 95% confidence interval, 1.01-2.28; adjusted odds ratio, 2.12; 95% confidence interval, 1.16-3.88, respectively). Digital spatial profiling revealed that programmed death-ligand 1 was increased in villitis-positive regions of the SARS-CoV-2 (logFC, 0.47; adjusted P value =.002) and villitis of unknown etiology (logFC, 0.58; adjusted P value =.003) cases, but it was conversely decreased in villitis-positive regions of the infectious villitis group (log FC, -1.40; adjusted P value <.001). CONCLUSION: Chronic villitis seems to be the most specific histopathologic finding associated with SARS-CoV-2 maternal infection. Chronic villitis involves damage to the vasculosyncytial membrane of the chorionic villi, which are involved in gas and nutrient exchange, suggesting potential mechanisms of placental (and perhaps neonatal) injury, even in the absence of vertical transmission. Surprisingly, changes in protein expression in SARS-CoV-2-associated villitis seem to be more similar to villitis of unknown etiology than to infectious villitis.

Continuous glucose monitoring in pregnancies with type 1 diabetes: small increases in time-in-range improve maternal and perinatal outcomes.

BACKGROUND: Continuous glucose monitors provide detailed information regarding glycemic control in pregnant patients with type 1 diabetes. Little data have been published examining the association between continuous glucose monitor parameters and perinatal outcomes among gravidas with type 1 diabetes using continuous glucose monitors. OBJECTIVE: This study aimed to examine the association between perinatal outcomes and time-in-range as assessed by continuous glucose monitors used in pregnant individuals with type 1 diabetes. We hypothesized that higher time-in-range would be associated with lower risk of adverse perinatal outcomes. STUDY DESIGN: This multicenter retrospective cohort study included all gravidas with type 1 diabetes using continuous glucose monitors who delivered from 2020 to 2022 at 5 University of California sites. Only those with continuous glucose monitor target range set to 70 to 140 mg/dL (±10 mg/dL) were included. Time-in-range (%) was recorded at 12, 16, 20, 24, 28, and 32 weeks. The primary maternal and neonatal outcomes were preeclampsia and large for gestational age, defined as birthweight ≥95th percentile. Kruskal-Wallis tests were used to compare median time-in-range between those with and without the primary outcomes. Log-binomial regression was used to obtain risk ratios, with adjustment for microvascular disease and years with type 1 diabetes. RESULTS: A total of 91 patients were included. Most used an insulin pump (81%) and did not have diabetic microvascular disease (72%). Median time since diagnosis of type 1 diabetes was 16 years, and median periconception hemoglobin A1c was 6.7%. Compared with those with preeclampsia, normotensive gravidas had significantly higher time-in-range at nearly every time point. A similar pattern was observed for those with normal-birthweight infants compared with large-for-gestational-age infants. On adjusted analyses, every 5-unit increase in time-in-range at 12 weeks was associated with 45% and 46% reductions in the risks of preeclampsia and large for gestational age, respectively (preeclampsia: adjusted risk ratio, 0.55; 95% confidence interval, 0.30-0.99; large for gestational age: adjusted risk ratio, 0.54; 95% confidence interval, 0.29-0.99). CONCLUSION: Higher time-in-range is associated with lower risk of preeclampsia and large for gestational age. This association is observed early in gestation, when each 5-unit increase in time-in-range is associated with ∼50% reduction in the risk of these complications. These findings can be used to counsel patients regarding the risk of pregnancy complications at specific time-in-range values, and to encourage patients that even small improvements in time-in-range can have significant impact on pregnancy outcomes. Larger studies are needed to further explore these findings and to identify optimal time-in-range to reduce perinatal complication rates.

Cerebrospinal fluid as vaginal discharge: ventriculoperitoneal shunt migration following Cesarean section.

Congenital hydrocephalus was once a permanently disabling and even fatal disease. With the advent of ventriculoperitoneal shunts, affected women are now surviving to their reproductive years and beyond. Pregnancy outcomes in this population are generally positive. However due to possible shunt complications, including infection, migration, and organ perforation, perinatal care for pregnant individuals with a ventriculoperitoneal shunt is complex and requires input from both obstetric and neurosurgical providers. We present the case of a 28-year-old G1P1 with a history of congenital hydrocephalus and ventriculoperitoneal shunt who presented to the emergency department at two months postpartum with clear fluid leaking from her vagina. The shunt's distal end had migrated and perforated the uterus causing cerebrospinal fluid to leak into the uterine cavity. Surgical repair was required of both the uterine hysterotomy and ventriculoperitoneal shunt, and the patient's symptoms ultimately resolved. Patients with a history of shunt placement who later undergo abdominal surgery, including cesarean section, are at risk for shunt complications. Shunt-dependent patients presenting in the post-partum period with new neurological or abdominopelvic complaints should undergo evaluation by a multidisciplinary team.

Cytomegalovirus in Pregnancy.

Cytomegalovirus is a pervasive DNA herpesvirus that, while clinically insignificant to an immunocompetent adult host, can cause significant morbidity to a congenitally infected fetus. Although detection is often possible with several common ultrasonographic markers and good diagnostic accuracy using polymerase chain reaction testing of amniotic fluid, there are no proven prenatal prevention or antenatal treatment options. Therefore, universal screening is not currently recommended in pregnancy. Strategies that have been studied in the past include immunoglobulins, antivirals, and the development of a vaccine. In this review, we will further discuss the themes above, along with future direction for prevention and treatment.

Hematometrocolpos following Low Transverse Cesarean Delivery Complicated by Uterine Dehiscence.

BACKGROUND: Hematometrocolpos is a rare complication following procedures performed on the female genital tract. While usually seen in adolescents with congenital anomalies including imperforate hymen and vaginal stenosis, it has also been described following obstetric vaginal lacerations. The incidence following cesarean delivery is unknown. CASE: This is a 43-year-old multigravida who underwent a low transverse cesarean delivery complicated by uterine dehiscence, as well as cervical and vaginal lacerations. The repair resulted in lower genital tract obstruction. She presented seven months afterwards with severe abdominopelvic pain and secondary amenorrhea, which resolved after vaginal dilation and excision of the vaginal scar. CONCLUSION: Systematic inspection of the upper vagina should be undertaken following complicated cesarean delivery with vaginal extension. Hematometrocolpos after cesarean delivery should be managed similar to a transverse vaginal septum.

Risk Factors for Co-Twin Fetal Demise following Radiofrequency Ablation in Multifetal Monochorionic Gestations.

BACKGROUND: Umbilical cord occlusion via radiofrequency ablation (RFA) is utilized to maximize outcomes of the co-twin in complicated multifetal monochorionic (MC) gestations. However, post-procedure co-twin fetal demise is of concern. OBJECTIVE: The aim of this study was to determine risk factors for co-twin fetal demise following RFA. METHODS: This is a retrospective study of MC multiples that underwent RFA. Indications for RFA included twin reversed arterial perfusion (TRAP) sequence, selective fetal growth restriction (sFGR) type II, discordant lethal anomalies, and twin-twin transfusion syndrome (TTTS) with proximate placental cord insertion sites. The primary outcome was co-twin fetal demise. Bivariate analyses and multiple logistic regression modeling of identified risk factors were conducted. RESULTS: Of 36 patients studied, surgical indications were: TRAP (n = 15, 41.7%), sFGR (n = 10, 27.8%), discordant anomalies (n = 9, 25.0%), and TTTS (n = 2, 5.6%). Nine patients (25.0%) experienced a co-twin fetal demise. In multiple logistic regression analysis, fetal growth restriction (FGR) of one co-twin was associated with increased risk of co-twin fetal demise (OR = 10.85, 95% CI 1.03-114.48, p = 0.0474) and a preoperative diagnosis of TRAP was protective against fetal demise (OR = 0.06, 95% CI 0.00-0.84, p = 0.0368). CONCLUSION: Co-twin FGR was associated with an increased risk of post-RFA demise. When compared to other indications, patients with TRAP sequence were less likely to have a co-twin demise.

Survival Outcomes by Fetal Weight Discordance after Laser Surgery for Twin-Twin Transfusion Syndrome Complicated by Donor Fetal Growth Restriction.

INTRODUCTION: Management options for treatment of twin-twin transfusion syndrome (TTTS) with severe donor intrauterine growth restriction (IUGR) include fetoscopic laser surgery and umbilical cord occlusion (UCO). We studied perinatal survival outcomes in this select group after laser surgery, stratifying patients by preoperative estimated fetal weight (EFW) discordance. METHODS: In this retrospective study of monochorionic diamniotic twin gestations with TTTS and selective donor IUGR who underwent laser surgery (2006-2017), preoperative EFW discordance was calculated ([(larger twin - smaller twin)/(larger twin)] × 100) and cases were divided into discordance strata. Severe EFW discordance was defined as >35%. The primary outcome was 30-day donor twin neonatal survival. RESULTS: The 371 cases were distributed by discordance strata: ≤20% (74 [19.9%]), 21-25% (49 [13.2%]), 26-30% (68 [18.3%]), 31-35% (53 [14.3%]), 36-40% (51 [13.7%]), 41-45% (38 [10.2%]), >45% (38 [10.2%]). Donor 30-day survival declined as the discordance strata increased: 86.5, 85.7, 83.8, 75.5, 64.7, 63.2, and 65.8% (p = 0.0046); 30-day survival was inversely associated with severe discordance (>35%) (64.6 vs. 83.2%, p < 0.0001). DISCUSSION: In TTTS cases complicated by donor IUGR with severe growth discordance, laser surgery was associated with donor survivorship greater than 60% suggesting that, in this setting, laser surgery remains a reasonable alternative treatment to UCO.

Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice.

How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in DAT knock-down mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase-positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3-4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined.

Immediate postpartum glycemic control and risk of surgical site infection.

OBJECTIVE: Nearly one-third of all births in the United States in 2013 were by cesarean delivery, with 6% complicated by diabetes. The purpose of this study was to correlate immediate postoperative hyperglycemia with wound morbidity in diabetic women who underwent cesarean delivery. METHODS: This retrospective case-control study was performed at UC Irvine Health and Miller Women's & Children's Hospital Long Beach between 2009 and 2015. Subjects included women with at least Class B diabetes mellitus who underwent cesarean birth. Fasting and postprandial blood glucose levels (BGL) were recorded daily during postoperative days one through four. Outcomes included abscess formation, cellulitis, wound separation, fascial dehiscence, hospital readmission, secondary wound closure, antibiotic treatment, and a composite of the above. RESULTS: Outcomes were evaluated for 176 subjects. Twenty-nine experienced wound complications. Women readmitted for wound complications and those with composite morbidity experienced significantly higher mean fasting BGL, however, BGL during the immediate postoperative setting were not predictive of wound morbidity. CONCLUSION: In our cohort of diabetic women who underwent cesarean delivery, immediate postoperative hyperglycemia was not associated with wound morbidity.

Use of hemoglobin A1c as an early predictor of gestational diabetes mellitus.

OBJECTIVE: The purpose of this study was to assess an early hemoglobin A1c (HgbA1c) value from 5.7-6.4% as an early predictor of progression to gestational diabetes (GDM). STUDY DESIGN: A retrospective cohort study was performed on all women who delivered at a single institution over 2 years who had an early screening HgbA1c test performed at ≤20 weeks of gestation. Women with known preexisting diabetes mellitus or HgbA1c values ≥6.5% were excluded. The primary outcome was GDM development. Secondary outcomes included delivery route, maternal weight gain, birthweight, and neonatal morbidities. Women with an HgbA1c value of 5.7-6.4% were compared with those with an HgbA1c level of <5.7%. RESULTS: Nearly one-third of those patients in the HgbA1c 5.7-6.4% group (27.3%) experience the development of GDM compared with only 8.7% in the HgbA1c <5.7% group (odds ratio, 3.9; 95% confidence level, 2.0-7.7). This 3-fold increase remained significant (adjusted odds ratio, 2.4) after adjustment for age, prepregnancy body mass index, gestational age at HgbA1c collection, gestational age at screening, ethnicity, and method of screening. There were no significant differences in the need for medical treatment, weight gain, delivery route, birthweight, macrosomia, or neonatal morbidities. CONCLUSION: More than 10% of patients in our cohort had an early screening HgbA1c value of 5.7-6.4%. Women in this group have a significantly higher risk of progression to GDM compared with women with normal HgbA1c values and should be considered for closer GDM surveillance and possible intervention.

Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein.

Parkinson's disease (PD) is characterized by widespread alpha-synuclein pathology and neuronal loss, primarily of the nigrostriatal dopaminergic neurons. Inflammation has been implicated in PD, and alpha-synuclein can initiate microglial activation; however, the kinetics and distribution of inflammatory responses to alpha-synuclein overexpression in vivo are not well understood. We have examined the regional and temporal pattern of microglial activation and pro-inflammatory cytokine production in mice over-expressing wild-type human alpha-synuclein driven by the Thy1-promoter (Thy1-aSyn mice). An increased number of activated microglia, and increased levels of TNF-α mRNA and protein were first detected in the striatum (1 month of age) and later in the substantia nigra (5-6 months), but not the cerebral cortex or cerebellum; in contrast, IL-1ß and TGF-ß remained unchanged in the striatum and substantia nigra at all ages examined. Microglial activation persisted up to 14 months of age in these regions and only minimal increases were observed in other regions at this later age. Increased concentrations of serum TNF-α were observed at 5-6 months, but not at 1 month of age. The expression of toll-like receptors (TLRs) 1, TLR 4 and TLR 8, which are possible mediators of microglial activation, was increased at 5-6 months in the substantia nigra but not in the cerebral cortex, and TLR 2 was increased in the substantia nigra at 14 months of age. With the exception of a slight increase in the striatum of 14 month old Thy1-aSyn mice, MHCII staining was not detected in the regions and ages examined. Similarly, peripheral CD4 and CD8-postive T cells were increased in the blood but only at 22 months of age, suggesting later involvement of the adaptive immune response. These data indicate that, despite the presence of high levels of alpha-synuclein in other brain regions, alpha-synuclein overexpression caused a selective early inflammatory response in regions containing the axon terminals and cell bodies of the nigrostriatal pathway. Our results suggest that specific factors, possibly involving a regionally and temporally selective increase in TLRs, mediate alpha-synuclein-induced inflammatory responses in the SN, and may play a role in the selective vulnerability of nigrostriatal dopaminergic neurons in PD.