Nizar Khatib

Maternal lipopolysaccharide-induced inflammation during pregnancy programs impaired offspring innate immune responses

OBJECTIVE Because the fetal innate immune system is responsive, while still maturing during the preterm period, we hypothesized that the early activation of fetal inflammatory pathways may have an impact on the ultimate expression of immune competency. STUDY DESIGN Pregnant Sprague Dawley rats (n = 7; Harlan Sprague Dawley Inc, Jerusalem, Israel) at 18 days gestation received intraperitoneal injections of saline solution or lipopolysaccharides (500 microg/kg). Pups were delivered spontaneously. At postnatal day 24, pups received intraperitoneal lipopolysaccharide (100 microg/kg), and plasma cytokine levels were measured before and 4 hours after lipopolysaccharide administration. RESULTS In response to lipopolysaccharides, pups of the lipopolysaccharide-injected dams had significantly (P < .05) reduced interleukin-6 (median [25th,75th percentile], 229 [84,6086] vs 4745 [2765,6643] pg/mL), interleukin-1beta (median [25th,75th percentile], 820 [125,1196] vs 1682 [1515,2127] pg/mL), tumor necrosis factor-alpha (median [25th,75th percentile], 4.8 [1.2,91] vs 163 [46,205] pg/mL), and interleukin-10 responses, when compared with saline solution-injected dams. CONCLUSION Maternal lipopolysaccharide exposure suppresses offspring innate immune response to inflammatory stimuli. These results suggest that maternal inflammatory exposures during pregnancy may impair newborn infant innate responses and increase susceptibility to infection.

N-acetyl-cysteine (NAC) attenuates LPS-induced maternal and amniotic fluid oxidative stress and inflammatory responses in the preterm gestation

OBJECTIVE Maternal infection is associated with oxidative stress and inflammation. We sought to determine whether N-acetyl-cysteine can decrease maternal oxidative stress and the inflammatory response in preterm gestation. STUDY DESIGN Pregnant rats 16 days, were treated with (1) lipopolysaccharide, (2) N-acetyl-cysteine 120 minutes after lipopolysaccharide, or (3) saline solution (intraperitoneal). Six hours after lipopolysaccharide administration, serum lipid peroxide formation (LPO), tumor necrosis factor-α, interleukin-6, and interleukin-1β levels in maternal serum and amniotic fluid were determined. RESULTS Lipopolysaccharide significantly increased maternal serum lipid peroxide formation (24-118.5 nmol/mL; P < .05), and maternal serum and amniotic fluid tumor necrosis factor-α, interleukin-6, and interleukin-1β. N-acetyl-cysteine treatment after lipopolysaccharide significantly attenuated lipid peroxide formation (47.5 nmol/mL) and proinflammatory cytokines response in maternal serum and amniotic fluid. CONCLUSION Maternal and amniotic fluid oxidative stress and inflammatory stimulation are attenuated by N-acetyl-cysteine even when administered after lipopolysaccharide. These results suggest that N-acetyl-cysteine may protect the fetus from adverse sequelae associated with inflammatory stimulation.

Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging

OBJECTIVE Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl-cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging. STUDY DESIGN Pregnant Sprague Dawley dams (n = 5-8) at embryonic day 18 received intraperitoneal injection of LPS or saline at time 0. Animals were randomized to receive 2 intravenous injections of NAC or saline (time -30 and 120 minutes). Pups were delivered spontaneously and allowed to mature until postnatal day 25. Female offspring were examined by magnetic resonance brain imaging and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess white matter injury and diffusion tensor imaging for apparent diffusion coefficient (ADC) to assess white and gray matter injury. RESULTS Offspring of LPS-treated dams exhibited significantly increased T2 levels and increased ADC levels in white and gray matter (eg, hypothalamus, motor cortex, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of NAC-treated LPS dams demonstrated similar T2 and ADC levels as control in both white and gray matter. CONCLUSION Maternal NAC treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. These studies suggest that maternal NAC therapy may be effective in human deliveries associated with maternal/fetal inflammation.

A comparison between ultrasonography and hysteroscopy in the diagnosis of uterine pathology

OBJECTIVE To evaluate the diagnostic accuracy of transvaginal sonography (TVS) compared to hysteroscopy in diagnosing uterine abnormalities. In addition, to determine whether the number of diagnostic hysteroscopies can be reduced and replaced by TVS examinations. STUDY DESIGN In this retrospective study, we summarized data from 128 patients who underwent TVS examination and hysteroscopy in our ultrasound unit during the last two years. Specimens were obtained and sent for histopathological examination. Sensitivity, specificity, positive and negative predictive values for diagnosing uterine pathology were calculated for each method. RESULTS Hysteroscopy had a significantly higher sensitivity in diagnosing intra-uterine fibroids while TVS had a significantly higher sensitivity in diagnosing retained products of conception. Although hysteroscopy had better predictive values for diagnosing uterine polyps the difference was not statistically significant. The combination of both TVS and hysteroscopy did not seem to improve the sensitivity and specificity. There were three additional important findings: two cases of uterine hyperplasia and one case of endometrial carcinoma in patients with abnormal uterine bleeding were all diagnosed by hysteroscopy after being suspected on the TVS examination. CONCLUSION TVS is an excellent tool in evaluating retained products of conception. In other cases of uterine pathology, diagnostic hysteroscopy is needed to improve diagnostic accuracy.

Prenatal diagnosis and outcome of isolated interrupted inferior vena cava

OBJECTIVE Report our experience in prenatal diagnosis of 11 cases of interrupted inferior vena cava, summarize the clinical significance and implications of this variant. STUDY DESIGN Retrospective analysis of 11 fetuses diagnosed with interrupted inferior vena cava, of 55,457 pregnant women who underwent extensive fetal anomaly scan during 20 years. RESULTS Eight of the 11 fetuses with interrupted inferior vena cava had a completely normal outcome. One had also normal outcome but abnormal function of the spleen. One had multiple abnormalities, and 1 case was lost to follow up. CONCLUSION The incidence of IIVC is 1:5000. In the vast majority (90%) of the cases, it is an isolated variant not associated with isomerism or fetal anomalies. In all the cases of isolated interrupted inferior vena cava, the outcome is favorable. In 10% of isolated interrupted inferior vena cava, abnormal function of the spleen may be detected after delivery, necessitating antipneumococcal vaccination.

Fetal bowel calcifications: A sign of anal atresia with rectourethral fistula

Fetal bowel calcifications were observed at 24 weeks of gestation in a male fetus, suggesting an anorectal malformation (ARM) with rectourethral fistula. At birth, the newborn presented with complex ARM including anal atresia, rectourethral fistula, and esophageal atresia. The prenatal sonographic visualization of calcifications within distended bowel should raise the suspicion of ARM including anal atresia and rectourethral fistula, the presence of such calcification depending on the timing of onset of fistula formation.

Magnesium sulfate (MG) prevents maternal inflammation induced offspring cerebral injury evident on MRI but not via IL-1β

OBJECTIVE As maternal treatment with magnesium sulfate (MG) may protect the fetal brain, we sought to assess the inflammation associated neuroprotective potential of MG and its association to interleukin 1β (IL-1β). METHODS Pregnant Sprague-Dawley rats at 18-day gestation received i.p. lipopolysaccharide (LPS) or saline. Dams were randomized to treatment with s.c. saline (control), or MG prior to or following the i.p. injection, resulting in three groups. At the end of the treatment, fetal brain IL-1β was quantified for 18 pregnant rats (six of each group). Another 18 pregnant rats delivered spontaneously and pups were allowed to mature. At postnatal day 25, female offspring were examined by magnetic resonance imaging (MRI) and analyzed using voxel based analysis. Apparent diffusion coefficient (ADC) and T2 relaxation protocols were performed to assess white and gray matter injury. RESULTS Offspring of LPS-treated dams exhibited (1) significantly increased T2 levels, and (2) increased ADC levels in white and gray matter, consistent with diffuse cerebral injury. Offspring of MG-treated LPS dams demonstrated similar T2 and ADC levels as control dams. Fetal brain IL-1β was significantly increased following maternal LPS compared to control (0.125±0.01 vs 0.100±0.01u, p<0.05). No significant decrease in IL-1β level was observed in response to maternal MG. CONCLUSIONS Maternal LPS-induced neonatal brain injury can be prevented by maternal MG. Maternal MG therapy may be effective in human deliveries associated with maternal/fetal inflammation. The absence of a decrease in fetus brain levels of IL-1β following MG treatment implies that the mechanism of MG is not through inhibition of IL-1β production. SIGNIFICANCE STATEMENT Intrauterine fetal exposure to maternal inflammation and pro-inflammatory cytokines is associated with adverse offspring neurological outcomes. Although its precise mechanism is not elucidated, magnesium sulfate (MG) is commonly used as neuroprotection for white matter brain injuries in preterm fetuses. A proposed mechanism involves the ability of MG to reduce pro-inflammatory cytokine levels. In the current study, we used a rat model of LPS-induced maternal inflammation to investigate the short-term effect of MG on fetal brain IL-1β levels, and its long-term neuroprotective effect on the offspring brain by using MRI. We demonstrated that maternal administration of MG can prevent long-term neonatal brain injury but, since no decrease was observed in fetal brain IL-1β levels, the neuro-protective mechanism of MG is not mediated by inhibition of IL-1β production.

The recurrence of sonographic “soft markers”: ominous sign or “just” genetics?

‘Soft markers’ (SMs) are nonspecific findings that might convey a higher risk for Down syndrome. We sought to determine the recurrence rate of the most common SM in subsequent pregnancies.

Early prenatal diagnosis of intraabdominal esophageal duplication cyst

Esophageal duplication cysts are uncommon, are usually diagnosed in infancy or childhood1 and are located in the posterior mediastinum in close contact with the esophageal wall2. Only intrathoracic and cervical esophageal duplication cysts have been detected prenatally1–5; in-utero diagnosis of abdominal cysts has not previously been reported. Here, we describe the prenatal sonographic features and pregnancy outcome of two cases of intraabdominal esophageal duplication cysts. In the first case, a 29-year-old primigravida with unremarkable medical history was referred at 15 weeks’ gestation following visualization of the ‘double bubble’ sign on transvaginal ultrasound. A fetal anatomic survey revealed appropriate biometry and the presence of a cystic mass located posterior and superior to the stomach and connected to the esophagus (Figure 1a,b)

Early prenatal diagnosis of intra-abdominal esophageal duplication cysts.

Esophageal duplication cysts are uncommon, are usually diagnosed in infancy or childhood1 and are located in the posterior mediastinum in close contact with the esophageal wall2. Only intrathoracic and cervical esophageal duplication cysts have been detected prenatally1–5; in-utero diagnosis of abdominal cysts has not previously been reported. Here, we describe the prenatal sonographic features and pregnancy outcome of two cases of intraabdominal esophageal duplication cysts. In the first case, a 29-year-old primigravida with unremarkable medical history was referred at 15 weeks’ gestation following visualization of the ‘double bubble’ sign on transvaginal ultrasound. A fetal anatomic survey revealed appropriate biometry and the presence of a cystic mass located posterior and superior to the stomach and connected to the esophagus (Figure 1a,b)