Giuseppe Chiossi

Spontaneous preterm birth is a leading cause of perinatal morbidity and mortality; however, accurate identification of women who will deliver prematurely after the onset of uterine contractions is still challenging, because less than 10% actually give birth within 7 days of presentation. Risk stratification in women with preterm contractions would allow targeting of interventions such as corticosteroids, magnesium sulfate, and maternal transfer to a perinatal center to those who will indeed deliver preterm. Moreover, unnecessary treatments associated with potential complications could be avoided in symptomatic women who are unlikely to deliver preterm. Fetal fibronectin testing and cervical length measurement are the most used methods to assess the risk of preterm birth among symptomatic women. Interventional studies in singleton gestations suggest that assessment of cervical length, unlike fetal fibronectin testing, improves diagnostic accuracy and leads to better perinatal outcomes.

Objective: As anemia in pregnancy is associated with adverse perinatal outcomes, we sought to define the mean and the fifth percentile of Hb and Ht using a contemporary multiethnic large cohort of low-risk pregnancies, and assess potential racial differences. Methods: We conducted a retrospective cohort study on women who delivered between 1 January 2008 and 31 December 2013 in Reggio Emilia County, Italy. Linear mixed effects models were used to describe changes in mean Hb and Ht, while quantile regression with matrix-design bootstrap defined changes in the fifth percentile of Hb and Ht, controlling for race, maternal age, smoking, and pregnancy number. Results: We analyzed 23,657 hemograms from 7318 pregnancies and 6870 women. Multivariate analysis showed that when compared to Caucasians’, African women’s mean Hb and Ht were respectively 0.24 (95%CI 0.3–0.17) g/dl and 0.7 (95%CI 0.8–0.5) % lower, while Asian mothers’ were 0.11 (95%CI 0.19–0.03) g/dl and 0.3 (95%CI 0.5–0.1) % inferior. Similarly, both African and Asian women had lower fifth Ht percentiles (−1, 95%CI −1.3 to −0.6, and −0.4, 95%CI −0.7 to −0.04) than Caucasians, while African mothers also had lower fifth Hb percentile (0.3, 95%CI 0.5–0.1). The fifth percentile for Hb and Ht were, respectively, 11.3 (95%CI 11–11.5) g/dl and 32.8 (95%CI 32.3–33.4) % in the first trimester, 10.4 (95%CI 10.1–10.6) g/dl and 30.2 (95%CI 29.6–30.8) % in the second trimester, 10.1 (95%CI 9.8–10.3) g/dl and 30.6 (95%CI 30–31.1) % in the third trimester. Conclusions: We provided contemporary references to define anemia in pregnancy, and we confirmed that even in pregnancy, African and Asian women have lower Hb and Ht than Caucasian. Racial and population-specific references may have significant clinical and public health implication for more accurate disease diagnosis and appropriate treatment.

Objective: To compare the effectiveness of customized vs population‐based growth charts for the prediction of adverse pregnancy outcomes.Methods: MEDLINE, ClinicalTrials.gov and The Cochrane Library were searched up to 31 May 2016 to identify interventional and observational studies comparing adverse outcomes among large‐ (LGA) and small‐ (SGA) for‐gestational‐age neonates, when classified according to customized vs population‐based growth charts. Perinatal mortality and admission to the neonatal intensive care unit (NICU) of both SGA and LGA neonates, intrauterine fetal demise (IUFD) and neonatal mortality of SGA neonates, and neonatal shoulder dystocia and hypoglycemia as well as maternal third‐ and fourth‐degree perineal lacerations in LGA pregnancies were evaluated.Results: The electronic search identified 237 records that were examined based on title and abstract, of which 27 full‐text articles were examined for eligibility. After excluding seven articles, 20 observational studies were included in a Bayesian meta‐analysis. Neonates classified as SGA according to customized growth charts had higher risks of IUFD (odds ratio (OR), 7.8 (95% CI, 4.2–12.3)), neonatal death (OR, 3.5 (95% CI, 1.1–8.0)), perinatal death (OR, 5.8 (95% CI, 3.8–7.8)) and NICU admission (OR, 3.6 (95% CI, 2.0–5.5)) than did non‐SGA cases. Neonates classified as SGA according to population‐based growth charts also had increased risk for adverse outcomes, albeit the point estimates of the pooled ORs were smaller: IUFD (OR, 3.3 (95% CI, 1.9–5.0)), neonatal death (OR, 2.9 (95% CI, 1.2–4.5)), perinatal death (OR, 4.0 (95% CI, 2.8–5.1)) and NICU admission (OR, 2.4 (95% CI, 1.7–3.2)). For LGA vs non‐LGA, there were no differences in pooled ORs for perinatal death, NICU admission, hypoglycemia and maternal third‐ and fourth‐degree perineal lacerations when classified according to either the customized or the population‐based approach. In contrast, both approaches indicated that LGA neonates are at increased risk for shoulder dystocia than are non‐LGA ones (OR, 7.4 (95% CI, 4.9–9.8) using customized charts; OR, 8.0 (95% CI, 5.3–10.1) using population‐based charts).Conclusions: Both customized and population‐based growth charts can identify SGA neonates at risk for adverse outcomes. Although the point estimates of the pooled ORs may differ for some outcomes, the overlapping CIs and lack of direct comparisons prevent conclusions from being drawn on the superiority of one method. Future clinical trials should compare directly the two approaches in the management of fetuses of abnormal size. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Key points: Nitric oxide is essential in the vascular adaptation to pregnancy, as knockout mice lacking nitric oxide synthase (NOS3) have abnormal utero‐placental perfusion, hypertension and growth restriction. We previously showed withex vivostudies on transgenic animals lacking NOS3 that adverse intrauterine environment alters fetal programming of vascular reactivity in adult offspring. The current research shows that altered vascular reactivity correlates with higher blood pressurein vivo. Our data suggest that higher blood pressure depends on both genetic background (NOS3 deficiency) and uterine environment, becomes more evident with age (> 7 postnatal weeks), activity and stress, is gender specific (preponderant among males), and can be affected by the sleep–awake cycle. In uteroor early postnatal life (< 7 weeks), before onset of hypertension, may represent a potential window for intervention to prevent future cardiovascular disorders. Nitric oxide is involved in the vascular adaptation to pregnancy. Using transgenic animals, we previously showed that adverse intrauterine environment alters vascular reactivity in adult offspring. The aim of our study was to determine if altered vascular programming is associated with abnormal blood pressure (BP) profilesin vivo. Mice lacking a functional endothelial nitric oxide synthase (KO, NOS3^−/−) and wild‐type mice (WT, NOS3^+/+) were crossbred to generate homozygous NOS3^−/−(KO), maternally derived heterozygous NOS3^+/−(KOM: mother with adverse intrauterine environment from NOS3 deficiency), paternally derived heterozygous NOS3^+/−(KOP: mother with normalin uteromilieu) and NOS3^+/+(WT) litters. BP was measuredin vivoat 7, 14 and 21 weeks of age. After univariate analysis, multivariate population‐averaged linear regression models were used to identify factors affecting BP. When compared to WT offspring, systolic (SBP), diastolic (DBP) and mean (MAP) BP progressively increased from KOP, to KOM, and peaked among KO (P< 0.001), although significance was not reached for KOP. Higher BP was also associated with male gender, older age (> 7 postnatal weeks), higher locomotor activity, daytime recordings, and recent blood pressure transducer insertion (P< 0.001). Post hoc analysis showed that KOM had higher SBP than KOP (P< 0.05). Our study indicates that adverse intrauterine environment contributes, along with multiple other factors, to account for hypertension; moreover,in uteroor early postnatal life may represent a possible therapeutic window for prevention of cardiovascular disease later in life.

Objective To investigate the effects of different pharmacological induction agents on myometrial contractility. Study Design Myometrial biopsies were obtained from 13 term nonlaboring women undergoing scheduled cesarean delivery. Tissue strips were suspended in organ chambers for isometric tension recording. The effects of cumulative doses (10⁻¹⁰ mol/L to 10⁻⁵ mol/L) of prostaglandin E1 (PGE1), E2 (PGE2), and oxytocin on spontaneous uterine contractility were determined. Areas under the contraction curve were compared using one-way analysis of variance on ranks with Dunn post hoc test. Results Oxytocin-induced myometrial contractility was superior to PGE1, PGE2, and time controls (CTR) at all the concentrations tested. When only prostaglandins were compared with CTR, PGE1 10⁻⁵ mol/L increased myometrial contractility, and PGE2 had no effects. Conclusion Oxytocin and prostaglandins have different effects on myometrial contractility accounting for different mechanisms of action and side effects. The increased uterine contractility observed with PGE1 as compared with PGE2 can contribute to explain the higher success of vaginal delivery.

Objective To estimate the effects of prostaglandin E1 (PGE1) and E2 (PGE2) on myometrial contractility and structure in vitro. Study Design Myometrial strips from 18 women were incubated with PGE1 (10⁻⁵ mol/L), PGE2 (10⁻⁵ mol/L), or solvent (CTR) for up to 360 minutes in organ chambers for isometric tension recording. The area under the contraction curve, total collagen content, and percentage of the area covered by connective tissue were calculated at various time periods. Results PGE1 significantly increased in vitro myometrial contractility up to 90 minutes when compared with PGE2 and CTR (p < 0.01) and up to 180 minutes as compared with PGE2 (p < 0.05). After 360 minutes, CTR and PGE1 samples had lower total collagen content and area covered by connective tissue than PGE2 (p < 0.01). Conclusion The effects of prostaglandins on the uterus cannot be solely explained by contractility. Treatment with PGE1 significantly increased myometrial contractions and decreased both total collagen content and the area covered by connective tissue. Such findings may explain the higher rates of vaginal delivery, tachysystole, and uterine rupture associated with PGE1 use.

OBJECTIVE: To explore the factors possibly associated with the intrapartum management of nonreassuring fetal status and the factors affecting the decision to expedite delivery for fetal distress among different obstetric health care providers. METHODS: In a cross-sectional study, a standardized hypothetical clinical scenario of management of fetal distress was presented by a study investigator to labor and delivery personnel, including faculty obstetricians, residents, and registered nurses (N=52). An intervention index was calculated for each faculty by dividing the number of cesarean and operative deliveries for nonreassuring fetal status by the actual number of laboring patients supervised by each faculty in 2008. RESULTS: Selection of the timing of delivery and characterization of nonreassuring fetal heart rate patterns was not different among the different providers (P=.3). However, compared with residents, registered nurses notified the attending obstetricians at an earlier stage and in response to different fetal heart rate tracing scenarios suggestive of fetal distress (P<.001). Personal or professional experience, type of clinical practice, and psychological traits did not affect the management of the standardized clinical scenario or the intervention index (P=.3–.9). CONCLUSION: Different providers practicing in the same environment may develop a similar approach in the setting of nonreassuring fetal status that overcomes individual differences and follows the current guidelines on electronic fetal monitoring. LEVEL OF EVIDENCE: II

The objective of this study was to investigate vascular function at different ages in a transgenic murine model of fetal vascular programming using a model of uteroplacental insufficiency induced by lack of endothelial nitric oxide synthase. Homozygous NOS3 knockout (KO) and wild-type (WT) mice were cross bred to produce WT, KO, and heterozygous that developed in WT (KOP) or KO (KOM) mothers. Male/female offspring from the four groups were killed at 7, 14, and 21 wk of age ( n = 5–10/group), and carotid arteries were used for in vitro vascular studies. Responses to phenylephrine (PE), with/without N^G-nitro-l-arginine methyl ester (l-NAME), angiotensin (ANG), acetylcholine (ACh), sodium nitroprusside, and isoproterenol (ISO) were studied. At 7 wk, only KO offspring showed higher contractile response to PE, whereas, at 14 and 21 wk, both KO and KOM had a higher response. Incubation with l-NAME abolished these differences. ANG contraction was higher in male KO in all age groups and in 21-wk-old females. Relaxation to ACh and ISO was absent in KO, and significantly decreased in KOM offspring in all age groups compared with KOP and WT, independent of gender. Sodium nitroprusside was not different between groups. The effect of the altered intrauterine environment on the development of abnormal vascular function was limited at 7 wk of age and most evident at 14 wk; further deterioration was limited to ANG-mediated vascular contractility in KO offspring. Our findings provide some hope that at least the first seven postnatal weeks may be an appropriate therapeutic window to prevent cardiovascular disease later in life.