Placental Erythroferrone and Erythropoietin mRNA Expression is not Associated with Maternal or Neonatal Iron Status in Adolescents Carrying Singletons and Adult Women Carrying Multiples.

BACKGROUND: The iron regulatory hormones erythroferrone (ERFE), erythropoietin (EPO), and hepcidin, and the cargo receptor nuclear receptor coactivator 4 (NCOA4) are expressed in the placenta. However, determinants of placental expression of these proteins and their associations with maternal or neonatal iron status are unknown. OBJECTIVES: To characterize expression of placental ERFE, EPO, and NCOA4 mRNA in placentae from newborns at increased risk of iron deficiency and to evaluate these in relation to maternal and neonatal iron status and regulatory hormones. METHODS: Placentae were collected from 114 neonates born to adolescents carrying singletons (14-18 y) and 110 neonates born to 54 adults (20-46 y) carrying multiples. Placental EPO, ERFE, and NCOA4 mRNA expression were measured by RT-qPCR and compared with maternal and neonatal iron status indicators (SF, sTfR, total body iron, serum iron) and hormones. RESULTS: Placental ERFE, EPO, and NCOA4 mRNA were detected in all placentae delivered between 25 and 42 wk of gestation. Relationships between placental ERFE and EPO differed by cohort. In the multiples cohort, placental EPO and ERFE were positively correlated (P = 0.004), but only a positive trend (P = 0.08) was evident in the adolescents. Placental EPO and ERFE were not associated with maternal or neonatal iron status markers or hormones in either cohort. Placental NCOA4 was not associated with placental EPO or ERFE in either cohort but was negatively associated with maternal SF (P = 0.03) in the multiples cohort and positively associated with neonatal sTfR (P = 0.009) in the adolescents. CONCLUSIONS: The human placenta expresses ERFE, EPO, and NCOA4 mRNA as early as 25 wk of gestation. Placental expression of ERFE and EPO transcripts was not associated with maternal or neonatal iron status. Greater placental NCOA4 transcript expression was evident in women and newborns with poor iron status (lower SF and higher sTfR, respectively). Further research is needed to characterize the roles of these proteins in the human placenta. TRIAL REGISTRATION NUMBER: These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802).

Placental Iron Content Is Lower than Previously Estimated and Is Associated with Maternal Iron Status in Women at Greater Risk of Gestational Iron Deficiency and Anemia.

BACKGROUND: Based on limited data, it is estimated that the placenta retains 90 mg of iron. Little is known about determinants of placental iron content. Animal data indicate that the placenta prioritizes iron for its own needs, but this hypothesis has not been evaluated in humans. OBJECTIVES: To characterize placental iron content and placental iron concentration (p[Fe]) in pregnant women at risk of iron insufficiency and identify determinants of p[Fe]. METHODS: Placentas were collected from 132 neonates born to teens carrying singletons (≤18 y) and 101 neonates born to 48 women carrying multiples (20-46 y). Maternal and neonatal iron status indicators [hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), serum iron, total body iron (TBI)] and hormones (erythropoietin, hepcidin) were measured. p[Fe] was measured using inductively coupled plasma-mass spectrometry. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe]. RESULTS: Mean placental iron content was 23 mg per placenta (95% CI: 15, 33 mg) in the multiples and 40 mg (95% CI: 31, 51 mg) in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. p[Fe] was higher in anemic (175 µg/g; 95% CI: 120, 254 µg/g) compared with nonanemic (46 µg/g; 95% CI: 26, 82 µg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 µg/g; 95% CI: 40, 102 µg/g) and nonanemic (73 µg/g; 95% CI: 56, 97 µg/g) teens. In women carrying multiples, low maternal iron status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], whereas in teens, improved iron status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe]. CONCLUSIONS: Placental iron content was ∼50% lower than previously estimated. p[Fe] is significantly associated with maternal iron status. In women carrying multiples, poor maternal iron status was associated with higher p[Fe], whereas in teens, improved iron status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable iron partitioning in teens compared with mature women.

Mid-trimester uterine electromyography in patients with a short cervix.

BACKGROUND: Preterm birth is the largest single cause of infant death in the United States. A cervical length of <2.5 cm, measured in the mid-trimester, has been shown to identify individuals at increased risk. Uterine electromyography is an emerging technology for noninvasively assessing uterine bioelectrical activity. With its ability to characterize nuanced differences in myometrial signals, uterine electromyography assessments during the mid-trimester may provide insight into the mechanisms of cervical shortening. OBJECTIVE: This study aimed to characterize uterine bioelectrical activity in pregnant individuals with short cervices in the mid-trimester compared with that of pregnant individuals of the same gestational age with normal cervical lengths. STUDY DESIGN: This is a prospective cohort study of subjects with singleton, nonanomalous pregnancies between 16 weeks and 0 days and 22 weeks and 6 days of gestational age. Subjects with normal cervical length (≥3.0 cm) were compared with subjects with short cervical length (<2.5 cm). The short-cervical-length cohort was further stratified by history of preterm birth. Multichannel uterine electromyography recordings were obtained for ∼60 minutes using proprietary, directional electromyography sensors on the abdomen. Uterine electromyography signals were observed and classified in groups as spikes, short bursts, and bursts. Primary outcomes were relative expression of spike, short-burst, and burst uterine electromyography signals. Subgroup analyses assessed each signal percentage by cervical length, history of preterm birth, and gestational age at delivery. Differences in percentage of uterine electromyography signals according to cervical length were analyzed using nonparametric tests of significance. RESULTS: Of the 28 included subjects, 10 had normal and 18 had short cervical length. There were 9 subjects with short cervical length and a history of preterm birth. Spikes were the most commonly recorded signals and were higher in the normal-cervical-length cohort (96.3% [interquartile range, 93.1%-100.0%]) than the short-cervical-length cohort (75.2% [interquartile range, 66.7%-92.0%], P=.001). In contrast, median percentages of short-bursts and bursts were significantly higher in subjects with a short cervical length (17.3% [interquartile range, 13.6%-23.9%] vs 2.5% for normal cervical length [interquartile range, 0%-5.5%], P=.001 and 6.6% [interquartile range, 0%-13.4%] vs 0% for normal cervical length [interquartile range, 0%-2.8%], P=.014, respectively). Within subgroup analyses, cervical length was inversely proportional to percentage of observed short-bursts (P=.013) and bursts (P=.014). Subjects with short cervical length and history of preterm birth had higher burst percentages (12.8% [interquartile range, 9.0%-15.7%]) than those with short cervical length and no history of preterm birth (3.3% [interquartile range, 0%-5.0%], P=.003). CONCLUSION: Short-burst and burst uterine electromyography signals are observed more frequently in mid-trimester patients with short cervical lengths. This relationship provides insight into abnormal myometrial activation in the mid-trimester and offers a plausible biophysiological link to cervical shortening.

Serum Erythroferrone During Pregnancy Is Related to Erythropoietin but Does Not Predict the Risk of Anemia.

BACKGROUND: Maintaining adequate iron status during pregnancy is important for the mother and her developing fetus. Iron homeostasis is influenced by 3 regulatory hormones: erythropoietin (EPO), hepcidin, and erythroferrone (ERFE). To date, normative data on ERFE across pregnancy and its relations to other hormones and iron status indicators are limited. OBJECTIVES: The objective of this study was to characterize maternal ERFE across pregnancy and at delivery and evaluate the utility of hepcidin, ERFE, and EPO in identifying women with increased iron needs. METHODS: ERFE was measured in extant serum samples collected from 2 longitudinal cohorts composed of women carrying multiple fetuses (n = 79) and pregnant adolescents (n = 218) at midgestation (∼26 wk) and delivery (∼39 wk). Receiver operating characteristic curves were generated to characterize the predictive ability of serum ERFE, hepcidin, and EPO and their ratios to identify women at increased risk of iron deficiency and anemia. RESULTS: In these pregnant women, mean ERFE was 0.48 ng/mL at both ∼25 wk of gestation and at delivery. ERFE was positively associated with EPO at midgestation (ß = 0.14, P = 0.002, n = 202) and delivery (ß = 0.12, P < 0.001, n = 225) but was not significantly associated with maternal hepcidin at any time point surveyed. Of all hormones measured at midgestation and delivery, EPO was best able to identify women with anemia (AUC: 0.86 and 0.75, respectively) and depleted iron stores (AUC: 0.77 and 0.84), whereas the hepcidin-to-EPO ratio was best able to identify women with iron deficiency anemia (AUC: 0.85 and 0.84). CONCLUSIONS: Maternal ERFE was significantly associated with EPO but was not able to identify women with gestational iron deficiency. At term, the hepcidin-to-EPO ratio, an index that accounts for both iron status and erythropoietic demand, and EPO were the strongest indicators of maternal iron deficiency and anemia. This trial was registered at clinicaltrials.gov as NCT04517734 (https://clinicaltrials.gov/ct2/show/NCT04517734).

Umbilical Cord Erythroferrone Is Inversely Associated with Hepcidin, but Does Not Capture the Most Variability in Iron Status of Neonates Born to Teens Carrying Singletons and Women Carrying Multiples.

BACKGROUND: The developing fetus requires adequate iron and produces its own hormones to regulate this process. Erythroferrone (ERFE) is a recently identified iron regulatory hormone, and normative data on ERFE concentrations and relations between iron status and other iron regulatory hormones at birth are needed. OBJECTIVES: The objective of this study was to characterize cord ERFE concentrations at birth and assess interrelations between ERFE, iron regulatory hormones, and iron status biomarkers in 2 cohorts of newborns at higher risk of neonatal anemia. METHODS: Umbilical cord ERFE concentrations were measured in extant serum samples collected from neonates born to women carrying multiples (age: 21-43 y; n = 127) or teens (age: 14-19 y; n = 164). Relations between cord blood ERFE and other markers of iron status or erythropoiesis in cord blood were assessed by linear regression and mediation analysis. RESULTS: Cord ERFE was detectable in all newborns delivered between 30 and 42 weeks of gestation, and mean concentration at birth was 0.73 ng/mL (95% CI: 0.63, 0.85 ng/mL). Cord ERFE was on average 0.25 ng/mL lower in newborns of black as opposed to white ancestry (P = 0.04). Cord ERFE was significantly associated with transferrin receptor (ß: 1.17, P < 0.001), ferritin (ß: -0.27, P < 0.01), and hemoglobin (Hb) (ß: 0.04, P < 0.05). However, cord hepcidin and the hepcidin:erythropoietin (EPO) ratio captured the most variance in newborn iron and hematologic status (>25% of variance explained). CONCLUSIONS: Neonates born to teens and women carrying multiples were able to produce ERFE in response to neonatal cord iron status and erythropoietic demand. ERFE, however, did not capture significant variance in newborn iron or Hb concentrations. In these newborns, cord hepcidin and the hepcidin:EPO ratio explained the most variance in iron status indicators at birth.

Umbilical Cord Serum Ferritin Concentration is Inversely Associated with Umbilical Cord Hemoglobin in Neonates Born to Adolescents Carrying Singletons and Women Carrying Multiples.

BACKGROUND: It has been proposed that the fetus prioritizes iron for hemoglobin production over delivery to tissues. However, few studies have evaluated the interrelations between hemoglobin and multiple iron status biomarkers in umbilical cord blood. A full understanding is needed of how these parameters influence each other within cord blood to fully interpret iron and hematologic status at birth. OBJECTIVES: We evaluated the determinants of neonatal hemoglobin and assessed the interrelations between hemoglobin, serum iron status indicators, and serum iron regulatory hormones in healthy neonates. METHODS: This was an observational study that assessed umbilical cord hemoglobin (Hb), serum ferritin (SF), erythropoietin (EPO), soluble transferrin receptor (sTfR), serum iron, hepcidin, vitamin B-12, folate, IL-6, and CRP measured in 234 neonates born to adolescents or to women carrying multiples. Correlations between these indicators were evaluated and mediation models consistent with the observed significant determinants of cord Hb concentrations were developed. RESULTS: A highly significant inverse association was found between cord SF and Hb concentrations that was not attributable to neonatal or maternal inflammation (as measured by IL-6 and CRP). The inverse association was present in the combined cohort, as well as in the adolescent and multiples cohorts independently. Mediation analyses found that EPO and hepcidin had significant indirect effects on cord Hb, associations that are explicable by mediation through SF and sTfR. CONCLUSION: In contrast to observations made in older infants, a highly significant inverse association between Hb and SF, as well positive associations between Hb and both sTfR and EPO, were observed in umbilical cord blood from neonates born to adolescents or women carrying multiples. These findings, combined with review of the published literature, indicate a need for analysis of the relations between multiple parameters to assess iron and hematologic status at birth. These clinical trials were registered at clinicaltrials.gov as NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802) and NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902).

Preterm Prelabor Rupture of Membranes: Outcomes with Expectant Management until 34 versus 35 Weeks.

OBJECTIVE: To evaluate outcomes with expectant management of preterm prelabor rupture of membranes (PROM) until 35 weeks versus immediate delivery at ≥34 weeks. STUDY DESIGN: This was a multicenter retrospective cohort study of singletons with preterm PROM at >20 weeks from 2011 through 2017. Groups were defined as expectant management until 35 weeks versus immediate delivery at ≥34 weeks. Primary outcome was composite neonatal morbidity: need for respiratory support, culture positive neonatal sepsis, or antibiotic administration for >72 hours. Univariate and general estimating equation models were used with p < 0.05 considered significant. RESULTS: A total of 280 mother-infant dyads were included. There was no difference in composite neonatal outcome in pregnancies managed with expectant management compared with immediate delivery (43.4 vs. 37.5%; p = 0.32). Those with expectant management had shorter length of neonatal intensive care unit (NICU) admission but higher rates of neonatal antibiotics for > 72 hours, endometritis, and histological chorioamnionitis. There were no cases of fetal demise, neonatal death, or maternal sepsis, and only three cases of neonatal sepsis. CONCLUSION: There is no difference in composite neonatal morbidity in pregnancies with preterm PROM managed with expectant management until 35 weeks as compared with immediate delivery at 34 weeks. Expectant management is associated with a decreased length of NICU admission but increased short-term infectious morbidity.

Umbilical Cord Hepcidin Concentrations Are Positively Associated with the Variance in Iron Status among Multiple Birth Neonates.

Background: Hepcidin is a systemic regulator of iron homeostasis. Little is known about the relative role of maternal compared with cord hepcidin on neonatal iron homeostasis. Objective: This study was undertaken to evaluate inter- and intrauterine variance in neonatal iron status, vitamin B-12, folate, and inflammatory markers in a cohort of twins (n = 50), triplets (n = 14), and quadruplets (n = 1) born to 65 women. Methods: Umbilical cord blood was obtained from 144 neonates born at 34.8 ± 2.7 wk of gestation with a mean birth weight of 2236 ± 551 g (means ± SDs). Cord hemoglobin and cord serum measures of ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, erythropoietin (EPO), iron, vitamin B-12, folate, interleukin 6, and C-reactive protein were evaluated. Results: Intraclass correlation coefficient (ICC) analyses were used to examine inter- and intrauterine variance in neonatal iron indicators. A greater variability in cord hepcidin (ICC = 0.39) was found between siblings. Cord hepcidin had the greatest association with cord iron indicators because cord hepcidin alone captured 63.8%, 48.4%, 44.4%, and 31.3% of the intrauterine variance in cord hemoglobin, SF, sTfR, and EPO, respectively, whereas maternal hepcidin had no effect on cord iron indicators. Significantly greater differences in cord SF (P = 0.03), sTfR (P = 0.03), hepcidin (P = 0.0003), and EPO (P = 0.03) were found between di- and trichorionic siblings than between monochorionic siblings. In contrast, cord folate (ICC = 0.79) and vitamin B-12 (ICC = 0.74) exhibited a greater variability between unrelated neonates. Conclusions: In summary, fetally derived hepcidin might have more control on intrauterine variance in iron indicators than maternal hepcidin and appears to be capable of regulating fetal iron status independently of maternal hepcidin. The use of a multiple-birth model provides a unique way to identify factors that may contribute to placental nutrient transport and iron stores at birth.

Gestational Age and Maternal Serum 25-hydroxyvitamin D Concentration Interact to Affect the 24,25-dihydroxyvitamin D Concentration in Pregnant Adolescents.

Background: Interpretation of serum vitamin D biomarkers across pregnancy is complex due to limited understanding of pregnancy adaptations in vitamin D metabolism. During pregnancy, both gestational age and serum 25-hydroxyvitamin D [25(OH)D] concentrations may influence the concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D], 24,25-dihydroxyvitamin D [24,25(OH)2D], and parathyroid hormone (PTH). Objective: We aimed to identify predictors of change in serum 25(OH)D across gestation in pregnant adolescents and to assess the contribution made by cholecalciferol (vitamin D3) supplementation. We sought to determine whether gestational age and 25(OH)D concentration interacted to affect serum 1,25(OH)2D, 24,25(OH)2D, or PTH. Methods: Pregnant adolescents (n = 78, 59% African American, mean ± SD age: 17 ± 1 y) living in Rochester, NY (latitude 43°N) were supplemented with 200 IU or 2000 IU vitamin D3/d and allowed to continue their daily prenatal supplement that contained 400 IU vitamin D3. Serum was collected at study entry (18 ± 5 wk of gestation), halfway through study participation, and at delivery (40 ± 2 wk). Serum concentrations of the biochemical markers were modeled with linear mixed-effects regression models. Results: Vitamin D3 supplement intake and season of delivery determined change in 25(OH)D across pregnancy. Fall-winter delivery was associated with a decline in 25(OH)D unless vitamin D3 supplement intake was >872 IU/d. The interaction of gestational age and 25(OH)D affected 24,25(OH)2D concentrations. For a given 25(OH)D concentration, model-predicted serum 24,25(OH)2D increased across gestation except when 25(OH)D was <13 ng/mL. Below this threshold, 24,25(OH)2D was predicted to decline over time. Mean serum 1,25(OH)2D was elevated (>100 pg/mL) throughout the study. Conclusion: Our results suggest that when maternal serum 25(OH)D was low, its catabolism into 24,25(OH)2D decreased or remained stable as pregnancy progressed in order to maintain persistently elevated serum 1,25(OH)2D. Furthermore, in adolescents living at latitude 43°N, standard prenatal supplementation did not prevent a seasonal decline in 25(OH)D during pregnancy. This study was registered at clinicaltrials.gov as NCT01815047.

SMFM Consult Series #46: Evaluation and management of polyhydramnios.

Polyhydramnios, or hydramnios, is an abnormal increase in the volume of amniotic fluid. Identification of polyhydramnios should prompt a search for an underlying etiology. Although most cases of mild polyhydramnios are idiopathic, the 2 most common pathologic causes are maternal diabetes mellitus and fetal anomalies, some of which are associated with genetic syndromes. Other causes of polyhydramnios include congenital infection and alloimmunization. The purpose of this document is to provide guidance on the evaluation and management of polyhydramnios. The following are Society for Maternal-Fetal Medicine recommendations: (1) we suggest that polyhydramnios in singleton pregnancies be defined as either a deepest vertical pocket of ≥8 cm or an amniotic fluid index of ≥24 cm (GRADE 2C); (2) we recommend that amnioreduction be considered only for the indication of severe maternal discomfort, dyspnea, or both in the setting of severe polyhydramnios (GRADE 1C); (3) we recommend that indomethacin should not be used for the sole purpose of decreasing amniotic fluid in the setting of polyhydramnios (GRADE 1B); (4) we suggest that antenatal fetal surveillance is not required for the sole indication of mild idiopathic polyhydramnios (GRADE 2C); (5) we recommend that labor should be allowed to occur spontaneously at term for women with mild idiopathic polyhydramnios; that induction, if planned, should not occur at <39 weeks of gestation in the absence of other indications; and that mode of delivery should be determined based on usual obstetric indications (GRADE 1C); and (6) we recommend that women with severe polyhydramnios deliver at a tertiary center due to the significant possibility that fetal anomalies may be present (GRADE 1C).

Predictors of anemia and iron status at birth in neonates born to women carrying multiple fetuses.

BACKGROUND: Iron (Fe) status of neonates born to women carrying multiple fetuses might be compromised as a consequence of the high prevalence of maternal Fe deficiency and anemia coupled with an increased risk of preterm birth. This study aimed to characterize and identify determinants of anemia in this neonatal population. METHODS: Umbilical cord blood obtained from 183 neonates was utilized to assess hemoglobin (Hb), ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum Fe, erythropoietin, folate, vitamin B-12, C-reactive protein, and interleukin-6. Associations with maternal Fe status were explored. RESULTS: Cord Hb or SF did not change significantly as a function of gestational age at birth (25-38 wks). Neonates born to women who were obese prior to pregnancy or smoked cigarettes during pregnancy had a 4-5-fold greater odds of anemia at birth. Cord sTfR was the strongest indicator of cord Hb (P < 0.0001), and it was significantly associated with maternal sTfR at mid-gestation (P = 0.01) and delivery (P = 0.002). Cord Fe indicators were significantly associated with cord hepcidin, but not maternal hepcidin. CONCLUSION: Screening for Fe status in neonates born to women carrying multiple fetuses is warranted, especially for those born to smokers or to women who are obese at entry into pregnancy.

Umbilical Cord Coiling in High-risk Pregnancies: Associations With Determinants of Adverse Birth Outcomes and Iron Status.

Abnormal umbilical cord coiling has been associated with adverse neonatal outcomes, but the etiology of these findings remains poorly characterized. This study was undertaken to examine associations between cord coiling and maternal iron (Fe) status and to identify potential determinants of hypo- and hypercoiling in 2 higher risk obstetric groups: pregnant adolescents (≤18 years, n = 92) and adult women carrying twins (n = 49), triplets (n = 11), or quadruplets (n = 1). Umbilical cords were classified as hypo-, normo-, or hypercoiled using digital photographs to assess gross appearance. Hypocoiling and hypercoiling were observed in 44% (n = 86/195) and 13% (n = 26/195) of the combined study population. The prevalence of hypocoiling among women carrying multiples was over 3-fold higher than the prevalence in singleton pregnancies based on the published data. Within the entire study population, hypocoiling was associated with a lower gestational age at birth when compared to normocoiling and hypercoiling (36.3 ± 3.6 weeks [n = 86] vs 37.8 ± 2.7 [n = 83], P < .01, and 38.2 ± 2.6 [n = 26], P < .01, respectively), whereas hypercoiling was associated with significantly lower serum ferritin when compared to normocoiling ( P < .01) and hypocoiling ( P < .001). In the multiples cohort only, hypercoiling was significantly associated with multiparity ( P < .01) and lower birth weight ( P < .05). Further studies are needed to identify the determinants and consequences of cord coiling.

Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans.

The placenta richly expresses nonheme and heme Fe transport proteins. To address the impact of maternal and neonatal Fe status and hepcidin on the regulation of these proteins, mRNA expression and protein abundance of nonheme and heme Fe transport proteins were evaluated in placental tissue from 154 adolescents. Regression analyses found maternal Fe status was significantly associated with multiple placental nonheme and heme transporters, whereas neonatal Fe status was related to only 3 heme transporters. Across statistical analyses, maternal Fe status was consistently associated with the placental nonheme Fe importer transferrin receptor 1 (TfR1). Protein abundance of TfR1 was related to midgestation maternal serum ferritin (SF) (ß = -0.32; P = 0.005) and serum TfR (ß = 0.25; P = 0.024). Protein abundance of the heme importer, proton-coupled folate transporter, was related to neonatal SF (ß = 0.30; P = 0.016) and serum TfR (ß = -0.46; P < 0.0001). Neonatal SF was also related to mRNA expression of the heme exporter feline leukemia virus subgroup C receptor 1 (ß = -0.30; P = 0.004). In summary, maternal Fe insufficiency during pregnancy predicts increased expression of the placental nonheme Fe transporter TfR1. Associations between placental heme Fe transporters and neonatal Fe status require further study.-Best, C. M., Pressman, E. K., Cao, C., Cooper, E., Guillet, R., Yost, O. L., Galati, J., Kent, T. R., O'Brien, K. O. Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans.

Elemental content of the placenta: A comparison between two high-risk obstetrical populations, adult women carrying multiples and adolescents carrying singletons.

BACKGROUND: The placenta is responsible for the exchange of nutrients and for preventing harmful compounds from entering the fetal circulation. With increasing industrialization, exposures to commercial and toxic metals become a concern for both pregnant women and those planning a pregnancy. The understanding of transport mechanisms and pharmacokinetics for most inorganic elements is incomplete and limited to normal term deliveries. OBJECTIVES: To obtain novel data on 46 inorganic elements in placentae from two high-risk obstetric populations, women carrying multiples and adolescents carrying singletons, evaluating differences, if present, and identifying predictors of placental content. METHODS: Placental tissue was collected from adolescents carrying singletons and adults carrying multiples. Elemental content was analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). Multivariate regression and factor analyses were used. RESULTS: With the exception of Au and Pt, almost all placentae contained quantifiable concentrations of each element analyzed. All placentae contained the essential elements Ca, Fe, Mg, Se and Zn, which clustered together onto the same factor. Most elements were higher in placentae from women carrying multiples. Differences in placental content disappeared after adjusting for maternal age. Rare earth elements (REEs) clustered together and remained higher in the multiples even after adjusting for maternal age. CONCLUSION: Human placentae contain a wide range of elements, including REEs. Ranges differed considerably between cohorts. Elements with similar chemical properties, like REEs or nutritionally essential elements, clustered together. Maternal age, and therefore longer environmental exposure, was significantly associated with elevated element concentrations in the placenta. Placental concentrations of several metals that are known to be nutritionally essential (e.g., Fe, Ca, Mg, and Zn) did not differ significantly between cohorts, suggesting tight regulation, whereas concentrations of environmental contaminants differed significantly between groups, even after adjusting for maternal age.

Prevalence of anemia and associations between neonatal iron status, hepcidin, and maternal iron status among neonates born to pregnant adolescents.

BACKGROUND: Little is known about anemia and iron status in US newborns because screening for anemia is typically not undertaken until 1 y of age. This study was undertaken to characterize and identify determinants of iron status in newborns born to pregnant adolescents. METHODS: Pregnant adolescents (≤ 18 y, n = 193) were followed from ≥ 12 wk gestation until delivery. Hemoglobin, ferritin, soluble transferrin receptor, serum iron, hepcidin, erythropoietin (EPO), IL-6, and C-reactive protein were assessed in maternal and cord blood. RESULTS: At birth, 21% of the neonates were anemic (Hb < 13.0 g/dl) and 25% had low iron stores (ferritin < 76 µg/l). Cord serum ferritin concentrations were not significantly associated with gestational age (GA) at birth across the range of 37-42 wk. Neonates born to mothers with ferritin < 12 µg/l had significantly lower ferritin (P = 0.003) compared to their counterparts. Hepcidin and IL-6 were significantly (P < 0.05) higher in neonates born to mothers with longer durations of active labor. CONCLUSION: Given the importance of the iron stores at birth on maintenance of iron homeostasis over early infancy, additional screening of iron status at birth is warranted among those born to this high risk obstetric population.

The Effects of Trauma History and Prenatal Affective Symptoms on Obstetric Outcomes.

Prenatal maternal mood may inform the adverse obstetric outcomes seen in disadvantaged populations. The contribution of having a trauma history is not well studied. We examined the impact of trauma exposure and mood symptoms on obstetric outcomes in 358 women. Women with antecedent trauma were more likely to have a history of depression, odds ratio = 2.83, 95% confidence interval [1.81, 4.42], were younger at their first pregnancy, 18.86 years versus 20.10 years, and had a higher number of previous pregnancies, 2.01 versus 1.54, compared to those with no trauma exposure. Women with prenatal anxiety had significantly smaller babies than nonanxious women, 3,313.17 g, (SD = 441.58) versus 3,429.27 g, (SD = 437.82) Trauma history magnified the effects of maternal prenatal mood on birthweight; the moderating effect was limited to those who first experienced a trauma under 18 years of age. Childhood trauma exposure increased vulnerability for low birthweight delivery associated with prenatal mood disturbance. Screening pregnant women for trauma history and current mood symptoms is indicated.

The course and outcome of pregnancy in women with nondystrophic myotonias.

INTRODUCTION: Nondystrophic myotonias (NDM) are muscle channelopathies characterized by clinical and electrical myotonia. Little is known about pregnancy in NDM. The aim of this work was to assess pregnancy outcomes in women with NDM. METHODS: In this investigation, we utilized a cross-sectional approach and obtained questionnaire data and medical record review information. Pregnancy outcomes were compared with U.S. national data. RESULTS: Twenty-five women completed the study. There were 63 pregnancies with 53 live births, 8 miscarriages, 4 terminations, and 1 stillbirth. The infertility rate was 28% (above the U.S. average). Fetal distress was reported in 11.7% (U.S. average 3.6%) of the patients. NDM symptoms worsened in 62% of pregnancies. In those who worsened, symptoms usually resolved completely (66%) or partially (32%) after delivery in 2 days to 12 months, the majority (76%) within 3 months. CONCLUSIONS: Most pregnancy outcomes were favorable. NDM worsened in nearly two-thirds of pregnancies, but usually improved shortly after delivery. Incidences of infertility and fetal distress were higher than overall U.S. rates.

Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status.

LDL receptor-related protein 1 (LRP1) is a transmembrane receptor highly expressed in human placenta. It was recently found to be the receptor for heme and its plasma-binding protein hemopexin (Hx) and is integral to systemic heme clearance. Little is known about systemic concentrations of Hx during pregnancy and whether maternal Hx and placental LRP1 contributes to fetal iron (Fe) homeostasis during pregnancy. We hypothesized that placental LRP1 would be upregulated in maternal/neonatal Fe insufficiency and would be related to maternal circulating Hx. Placental LRP1 expression was assessed in 57 pregnant adolescents (14-18 years) in relationship with maternal and cord blood Fe status indicators (hemoglobin (Hb), serum ferritin, transferrin receptor), the Fe regulatory hormone hepcidin and serum Hx. Hx at mid-gestation correlated positively with Hb at mid-gestation (r=0.35, P=0.02) and Hx at delivery correlated positively with cord hepcidin (r=0.37, P=0.005). Placental LRP1 protein expression was significantly higher in women who exhibited greater decreases in serum Hx from mid-gestation to term (r=0.28, P=0.04). Significant associations were also found between placental LRP1 protein with cord hepcidin (r=-0.29, P=0.03) and placental heme exporter feline leukemia virus C receptor 1 (r=0.34, P=0.03). Our data are consistent with a role for placental heme Fe utilization in supporting fetal Fe demands.

Maternal inflammation at delivery affects assessment of maternal iron status.

Pregnant adolescents (aged ≤ 18 y, n = 253) were followed from ≥ 12 wk of gestation to delivery to assess longitudinal changes in anemia and iron status and to explore associations between iron status indicators, hepcidin, and inflammatory markers. Hemoglobin, soluble transferrin receptor (sTfR), ferritin, serum iron, erythropoietin (EPO), hepcidin, C-reactive protein, interleukin-6 (IL-6), folate, and vitamin B-12 were measured, and total body iron (TBI) (milligrams per kilogram) was calculated using sTfR and ferritin values. Anemia prevalence increased from trimesters 1 and 2 (3-5%, <28 wk) to trimester 3 (25%, 33.2 ± 3.7 wk, P < 0.0001). The prevalence of iron deficiency (sTfR > 8.5 mg/L) doubled from pregnancy to delivery (7% to 14%, P = 0.04). Ferritin and hepcidin concentrations at delivery may have been elevated as a consequence of inflammation because IL-6 concentrations at delivery were 1.6-fold higher than those obtained at 26.1 ± 3.3 wk of gestation (P < 0.0001), and a positive association was found between IL-6 and both hepcidin and ferritin at delivery (P < 0.01). EPO was consistently correlated with hemoglobin (r = -0.36 and -0.43, P < 0.001), ferritin (r = -0.37 and -0.32, P < 0.0001), sTfR (r = 0.35 and 0.25, P < 0.001), TBI (r = -0.44 and -0.37, P < 0.0001), and serum iron (r = -0.22 and -0.16, P < 0.05) at mid-gestation and at delivery, respectively. EPO alone explained the largest proportion of variance in hemoglobin at 26.0 ± 3.3 wk of gestation (R(2) = 0.13, P = 0.0001, n = 113) and at delivery (R(2) = 0.19, P < 0.0001, n = 192). Pregnant adolescents are at high risk of anemia. EPO is a sensitive indicator of iron status across gestation, is not affected by systemic inflammation, and may better predict risk of anemia at term. The trial was registered at clinicaltrials.gov as NCT01019902.