T1) and transverse (T2) relaxation times of phosphorus donors in bulk silicon with various electric field strengths up to near avalanche breakdown in high magnetic fields of about 1.2 T and low temperatures of about 8 K. We find that the T1 relaxation time is significantly reduced under large electric fields due to electric current, and T2 is affected as the T1 process can dominate decoherence. Furthermore, we show that the magnetoresistance effect in silicon can be exploited as a means to combat the reduction in the coherence times. While qubit coherence times must be much longer than quantum gate times, electrically accelerated T1 can be found useful when qubit state initialization relies on thermal equilibration.Modulation of donor electron wavefunction via electric fields is vital to quantum computing architectures based on donor spins in silicon. For practical and scalable applications, the donor-based qubits must retain sufficiently long coherence times in any realistic experimental conditions. Here, we present pulsed electron spin resonance studies on the longitudinal ( Also, several device designs within the donor-based framework have been proposed15 to enable topological quantum error correction. However, realizing two-qubit quantum operations using the exchange interactions as originally proposed by Kane in a scalable manner remains challenging due to the extreme sensitivity of the interaction strength to the donor displacement. To relax the requirement on the spatial precision, an architecture that exploits electric dipole interactions was recently proposed16. In this approach, the qubit is defined using the flip-flop energy splitting of the nuclear and electron spin states, and is called the flip-flop qubit. One and two qubit gate implementations require shifting the donor electron wavefunction to the ionization point, where the electron is shared halfway between donor and Si/SiO2 interface, via electric fields. This scheme allows for the larger inter-qubit spacing than the exchange-based method, which yields sufficient room to place classical control and readout components16. After all, the application of electric fields is ubiquitous in various proposals for donor-based quantum information processing. On the other hand, theoretical analyses of the single-donor flip-flop qubit with reasonable experimental parameters predicted considerable decrease of the qubit T1 relaxation time due to strong interaction with phonon-induced deformation potentials and the nontrivial valley-related characteristics of the electron-phonon interaction and the involved electronic states17. Yet, the effect of electric fields near ionization on the T1 and T2 times of donor spins in silicon with higher qubit densities is not clear-cut.Phosphorus donor spins in silicon (Si:P) are promising candidates for encoding quantum information due to outstanding coherence times and the availability of the mature semiconductor industry. Since the quantum computing architecture based on donor spins in silicon was proposed by Kane31P) donor electrons in bulk silicon under electric fields (E0) ranging up to near avalanche breakdown triggered by impact ionization using pulsed electron spin resonance (ESR). Two Si:P wafers with donor concentrations of about 1014–1015 P/cm3 are tested in the external static magnetic field (B0) strength of about 1.2 T and at temperatures near 8 K for good compromise between the detection sensitivity and the T1 relaxation time in the absence of electric field. The key findings are summarized as follows. The T1 relaxation time changes dramatically under strong electric field near (but before) the avalanche breakdown, and the coherence time T2 is limited by T1. This is attributed to the electric current (I) in the bulk silicon. However, due to magnetoresistance in silicon19, the amount of electric current varies with the orientation of the electric field with respect to the magnetic field. Therefore, the reduction in the relaxation times can be minimized by carefully determining the orientation.This work reports a detailed experimental study on the spin relaxation times of phosphorus . These concentrations correspond to about 59 to 166 nm inter-donor distance assuming uniform distribution. The electric field is formed along the [100] crystal orientation by applying voltage between two 50-nm-thick aluminum plates sputtered on each face of the wafer. The direction of E0 is coplanar to the external static magnetic field, and perpendicular to the oscillating microwave field (Bmw) as shown in Fig. The spin relaxation times of the donor-bound electrons are measured from two Si:P wafers, A and B, with phosphorus concentrations of 2.2 × 10T1 measurement experiments are single exponential regardless of the magnitude of the electric field. On the other hand, when E0 = 0, the T2 decay curve is better described by s(2τ) = exp[−(2τ/Ta2)n − 2τ/Tb2], where s(2τ) is the normalized electron spin echo signal with the interpulse delay τ20. However, we found that as the E0 value reaches certain regime, the T2 decay becomes a single exponential. In our measurements, the E0 values from which the coherence decay curves are single exponential are 0.22 V/μm and 0.13 V/μm for sample A and B, respectively. Moreover, at these points, the T1 relaxation times are significantly reduced. Figure T1 [(a) and (b)] and T2 [(c) and (d)] measurements for sample A with E0 = 0 and 0.22 V/μm at B0 = 1.2 T and 8 K. The inset in Fig. n estimated from fitting for several values of E0 in the non-single exponential regime ranges between two to three, agreeing with previously reported values attributed to nuclear-induced spectral diffusion20. The large difference between the time scale  of the figures on the left [(a) and (c)] and on the right [(b) and (d)] demonstrates the substantial increase of the relaxation rates when the electric field is turned on.For both samples, the electron spin echo signal decays in the E0 and the relaxation times is plotted in Fig. T1 is reduced by about three orders of magnitude at E0 ≥ 0.22 V/μm. The coherence decays fit well to single exponential in this regime, and T2 appears to be limited by T1. The solid line represents the magnitude of electric current between the metal plates, and shows the avalanche breakdown, a sudden transition to a low-resistance state, occurs at about 0.24 V/μm for this sample. Thus, E0 could not be increased beyond this point. Interestingly, the relaxation times change dramatically even though the current is about two orders of magnitude smaller than that at the breakdown. The inset in Fig. E0 at 10 K to demonstrate that the effect persists in a different temperature. In this temperature and donor concentration, T2 is limited by T1 as the T1 process dominates decoherence6. The relaxation times decrease rapidly as E0 is increased beyond 0.15 V/μm, similar to the behaviour observed at 8 K. The electric field dependence of the relaxation times is qualitatively confirmed with the sample B as shown in Fig. T1 and T2 do not exhibit noticeable changes until E0 is increased up to about 0.08 V/μm. But from beyond this point, T1 undergoes about two orders of magnitude reduction as E0 is increased up to about 0.19 V/μm. Meanwhile, the T2 decay converges to single exponential, and the spin coherence time appears to be limited by the T1 process in this regime. The experimental data provide clear evidence that the longitudinal relaxation time of electron spins in Si:P is reduced substantially even when the applied electric field is smaller than the breakdown field. On the other hand, the impact of the electric field on T2 independent from the T1 process is uncertain. The electric field effects on the spin relaxation times of the donor-bound electron in bulk silicon implies that the operating conditions of the Si:P quantum devices with higher donor densities can be limited due to accelerated decoherence. Hereinafter, we focus on the effect of the electric field on T1.The relationship between T1 is known to exist due to spin-phonon relaxation process22. As a first step towards understanding the source of the electric field dependence of the relaxation times, we measured the sample temperature and the electric current in a Si:P wafer between two metal plates with respect to E0 (see Methods). The measurement results depicted in Fig. T1 reduction in our measurements cannot be explained by the change in the sample temperature.In the temperature range in which the measurements are conducted, the strong temperature dependence of T1 in the crystal orientation with respect to B0 using B, the sample with more uniform donor distribution. In this study, the silicon crystal, and hence the direction of E0, were rotated around the x-axis defined in Fig. B0 was fixed. For each orientation, we conducted T1 measurements with E0 = 0, 0.15 V/μm, and at constant electric current of 20 ± 4 μA measured in the same direction as E0. To maintain the constant electric current at each orientation, the strength of E0 is adjusted by controlling the DC voltage. The results are shown in Fig. θ) corresponds to the change of the angle between E0 and B0 from the reference angle determined by the initial sample placement in the magnetic field. The T1 relaxation time is observed to be anisotropic in the crystal orientation, and hence the direction of E0, with respect to B0 in all experiments. For a fixed amount of E0, we observed that the electric current in [100] direction also varied with respect to the orientation between E0 and B0. As shown in Fig. E0 = 0.15 V/μm, the current is maximum near Δθ = 120°. Interestingly, T1 at this orientation is about an order of magnitudes smaller than that at other orientations. The anisotropic T1 is also observed when the current is fixed at about 20 μA as illustrated in Fig. T1 resembles that of the orientation dependence observed when the electric field is turned off , defined as [R(B) − R(0)]/R(0), where R(B) is the resistance in magnetic field B. The phosphorus density of sample B is just within the low doping regime where the MR for the perpendicular orientation (B0 ⊥ E0) is large26. For Si:P, the MR effect persists for the longitudinal orientation, i.e., 27. Therefore, the large electric current at a specific orientation (Δθ ≈ 118°) can be interpreted as a consequence of the minimum MR since E0 is parallel to B0.Figure E0 = 0.15 V/μm, although the electric field is uniformly raised for all orientations, the T1 time is significantly reduced only when the electric current is high. On the other hand, Fig. E0 with respect to the orientation, all relaxation times are about a factor of three smaller than the relaxation times at the same orientation without the electric field. These experimental results suggest that the acceleration of the longitudinal relaxation rate at strong electric field is related to the rise of the electric current in the Si:P crystal rather than the strength of the electric field.When 16. Therefore, finding strategies to circumvent the escalation of the spin relaxation rates is critical. From above experimental studies, we found that the electric current, rather than the electric field, is responsible for the rapid change in T1. Then we experimentally verified that MR yields the electric current anisotropy in the orientation of E0 with respect to the external magnetic field. Therefore, if the angle between E0 and B0 is chosen properly, the electric current for a given E0 strength, and hence the reduction in the T1 time can be minimized. In particular, the electric field should not be aligned with the magnetic field. For instance, Fig. E0 is nearly parallel to B0 (Δθ ≈ 120°), T1 is about 0.1 ms for E0 = 0.15 V/μm, while when E0 is nearly perpendicular to B0 (Δθ ≈ 40°), T1 is about 0.7 ms for E0 = 0.45 V/μm. Thus, in this example data, the T1 time at one orientation can be about seven times longer than that at another orientation, although about three times larger E0 is used. Recall that in the absence of E0, the T1 time is the longest when B0 is applied along the [100] direction. Thus, we speculate that further T1 optimization is possible by using a silicon wafer grown in a direction such that the direction of B0 can be parallel to [100], but perpendicular to E0.The quality of the electron spin qubits in Si:P can be degraded considerably when large electric field is needed, due to the increased decoherence rate. In order to enhance the utility and the flexibility of the donor-based spin qubits, it is desirable to extend the high-fidelity qubit operating range to strong electric fields. Moreover, there exists an architectural proposal that demands the application of strong electric fields so that the electron spins are manipulated near the ionization pointT1 relaxation rate of the phosphorus donor electron spins in bulk silicon with low dopant concentration can be increased significantly under large electric fields due to electric current in the sample. The coherence time is also shortened as it is upper-bounded by T1. On the other hand, the amount of electric current is anisotropic in the E0 orientation with respect to the external magnetic field due to the MR effect. Thus, the reduction in the relaxation rates for a fixed electric field strength can be minimized by choosing the appropriate orientation. Although the decoherence rate must be minimized during quantum gate operations, the fast T1 relaxation can be exploited in a special instance. Namely, when the qubit initialization method relies on thermal equilibration, the fast relaxation rate is favoured for resetting the qubits. Furthermore, the ability to engineer the T1 relaxation rate can be useful for dynamic nuclear polarization since the increased T1 rate allows for the faster polarization of nuclear spins at the cost of the higher microwave pulse power for saturating the electron spin transitions28. Future work could extend the range of the experimental conditions, such as the magnetic field strength, the temperature, and the donor density. Our results also motivate further studies on the nuclear spin relaxation rates, as well as the case of the single donor spins in large electric fields.In summary, the 29Si) are used throughout the experiments. The first wafer (A) is quoted with the room temperature resistivity of 1–20 Ω⋅cm (about 2.2 × 1014−4.9 × 1015 P/cm3), and the thickness of 275 μm. The second wafer (B) has the room temperature resistivity of 7–13 Ω⋅cm (about 3.5 × 1014−6.5 × 1014 P/cm3), and is 300 μm thick. The wafers are cut to a size of approximately 1 × 15 mm to fit in a standard Q-band ESR tube.Two commercially purchased phosphorus doped (100)-silicon wafers with natural abundance (4.7% of All ESR experiments were carried out at Korea Basic Science Institute (KBSI) in Seoul, Korea. 34 GHz Q-band pulsed ESR data were obtained on a Bruker Elexsys E580 spectrometer using an EN5107D2 resonator. Cryogenic temperatures were achieved with an Oxford CF-935 cryostat and an Oxford ITC temperature controller.T1 is measured via inversion recovery experiment, and T2 is measured via Hahn echo decay experiment. The pulse sequence for the inversion recovery experiment can be expressed as π−T−π/2−τ−π−τ−echo detection. The delay, T, after the first π pulse was varied while τ was fixed, and the amplitude of the primary echo signal formed by the second and third pulses was measured. The pulse sequence for the Hahn echo decay experiment is π/2−τ−π−τ−echo detection, and the amplitude of the echo signal was measured as a function of the delay, τ. The π/2 and π pulse lengths were 16 and 32 ns, respectively, in both experiments.The current-voltage relations are measured using two multimeters (Fluke 287 True-RMS), each connected in parallel and in series with the silicon wafer for measuring voltage and current, respectively.2. A calibrated temperature sensor (Lakeshore DT-470-CU-13) was attached on top of the aluminum on one face of the wafer, and the other face of the wafer was in contact with the copper heat-sink of a low temperature probe. Then the probe was cooled using a helium-flow cryostat. The current was measured using a multimeter while external DC voltage was applied.The sample temperature dependence on the electric field strength was measured with an Si:P piece cut from A to an approximate size of 1 cm


Background: Adverse birth outcomes are related to unfavorable fetal growth conditions. A latent variable, named Favorable Fetal Growth Condition (FFGC), has been defined by Bollen et al., in 2013; he showed that this FFGC latent variable mediates the effects of maternal characteristics on several birth outcomes. Objectives: The objectives of the present study were to replicate Bollen’s approach in a population of newborns in Paris and to investigate the potential differential effect of the FFGC latent variable according to the neighborhood socioeconomic level. Methods: Newborn health data were available from the first birth certificate registered by the Maternal and Child Care department of the City of Paris. All newborns (2008–2011) were geocoded at the mother residential census block. Each census block was assigned a socioeconomic deprivation level. Several mothers’ characteristics were collected from the birth certificates: age, parity, education and occupational status and the occupational status of the father. Three birth outcomes were considered: birth weight (BW), birth length (BL) and gestational age (GA). Results: Using a series of structural equation models, we confirm that the undirected model (that includes the FFGC latent variable) provided a better fit for the data compared with the model where parental characteristics directly affected BW, BL, and/or GA. However, the strength, the direction and statistical significance of the associations between the exogenous variables and the FFGC were different according to the neighborhood deprivation level. Conclusion: Future research should be designed to assess the how robust the FFGC latent variable is across populations and should take into account neighborhood characteristics to identify the most vulnerable group and create better design prevention policies. Adverse birth outcomes (as low birth weight or preterm birth) remain a major public health concern due to the well documented association with neonatal mortality as well as both short- and long-term morbidity . In 2015Several authors advanced that adverse birth outcomes could be related to unfavorable fetal growth conditions, which could, in turn, have long-term health consequences at adult age ,7,8,9, pIn this context, a variable named Favorable Fetal Growth Condition (FFGC) has been defined in order to capture a variety of (un)favorable conditions related to environmental, genetic or epigenetic factors, dimensions that are all recognized to play a crucial role in prenatal development. Since the first scientific studies initiated in the 1990s, little attention has been devoted to investigating the existence of such a multi-dimensional variable. Recently, Bollen et al. investigated the possibility that the FFGC could exist and introduced it as a latent variable in a structural equation model in a Filipino islands infant’s cohort . This tyDuring the last decade, it was documented that neighborhood characteristics may modify the health impact of risk factors in term of coefficients significance and magnitude ,15. To oIn this context, one objective of our study was to replicate the approach developed by Bollen et al. (2013)  on a pop2. According to the national census in 2006, Paris, the capital of France, has a population of about 2,250,000 inhabitants and counts about 30,000 newborns per year. The year 2006 was chosen as it was the closest year to the newborn health data. The small-area level used for the analysis is the census block . These units, the smallest for which socio-demographic data from the census are available, were constructed in order to be as homogeneous as possible in terms of population size and socioeconomical profile. The city of Paris is subdivided into 992 census blocks with a mean population of 2199 inhabitants and a mean area of 0.11 kmNewborn health data are available from the first birth certificate registered by the Maternal and Child Care department of Paris (named PMI for ‘Protection Maternelle et Infantile’) . This ceSeveral mothers’ characteristics were collected, including age (in years), parity , level of education and occupational status. Occupational status was the only available characteristic for the father. Newborn birth at very preterm gestational age (<20 weeks) were excluded from the analysis because the babies only have a very small chance of surviving.younger) and above 35 years of age (older) are known to be two age groups at greater risk of adverse birth outcomes compared to women aged between 20 and 35 years (the referent age group). The initial quantitative parity variable was categorized as a binary variable (first pregnancy: yes or no: FirstP). Level of mother education was categorized into four groups: low (primary school), intermediate (secondary), middle , and higher education level (chosen as the referent age group given their high number in Paris). The occupational status of mother and father was categorized into two groups only characterizing ‘employed versus unemployed’  parents .We created three age groups of women according to a threshold defined in the literature : less thBW) in kilograms, length (BL) in centimeters and gestational age (GA) in weeks. As it is known that birth outcomes are gender differentiated , infant sex was included as a confounder (Girl), with male infants defining the referent group.Three birth outcomes were considered in this study: birth weight . We choose to categorize into 10 classes of deprivation in order to better capture the large range of socioeconomic inequalities existing in Paris. Thanks to our very large sample size, 10 categories constituted a good compromised to keep enough statistical power and to group homogeneous census blocks in terms of level of deprivation.To characterize the neighborhood where mothers lived during pregnancy, we chose an estimate of socioeconomic deprivation at the census block scale. The index, based on previous work, was constructed using a principal component analysis . A totaA major goal of the current study was to test whether BW, BL, and GA are associated with a common latent variable named the Favorable Fetal Growth Conditions (FFGC), as concluded in Bollen et al. , or are Direct Effects Model—Unmediated Effects—The base SEM (Model 1) is depicted in BW, Birth Length: BL, and Gestational Age: GA). All the observed predictors’ variables are exogenous . The exogenous variables are allowed to correlate with one another as indicated by the long bar with the short arrows connecting them, except the variable ‘girl’; indeed, there is no hypothesis justifying a possible correlation between the sex of the newborn and the occupational status or the level of education, for instance. The arrows drawn between the set of exogenous observed variables and the set of health outcomes indicate the direct influence of one variable on another. Finally, in this model, we allowed errors in BW, BL, and GA to correlate with each other; this means that there is a residual association between the 3 health outcomes not captured by the exogenous variables introduced in the model.Indirect Effects Model—FFGC as a Mediator—In the second model (Model 2), a latent variable was added to Model 1 in order to consider possible mediation effects of exogenous variables on BW, BL, and GA, as proposed by Bollen  were close to 1. However, a more substantial gap is visible for BIC which, in Model 3, is lower than for Model 1 (780.7 vs. 818.8) and the difference is greater than 10. Model 3, which includes the FFGC latent variable as a mediator variable between the parents characteristics and the birth outcomes  and includes additional direct paths, appears to be the best model.The analysis of the overall fit statistics for the three models highlighted several interesting findings.Concerning the interpretation of Model 3, we examined both the sign and the significance of the regression coefficients . In thisp-value = 0.04).The mother characteristics  had statistically significant negative effects on FFGC. The level of education  also had a significant negative effect on the latent variable compared to the highest level of education, as well as the occupational status of the father (unemployedF), while, inversely, the occupational status of the mother (unemployedM) was positively associated with FFGC  was not significant; in addition, young mothers and those with a primary level of education were negatively related to FFGC.-For newborns living in the census blocks categorized in SES7, only the measures of parity (FirstP), maternal age (Older) negatively predicted FFGC see .However, there were two exceptions see :-For neFetal environment, which is known to be related with pregnancy outcomes ,21, is aThe main objective of our study was to apply this novel approach to another population, here newborns in the city of Paris (2008–2011). One original aspect of our study was to investigate whether results found on the overall population concerning the latent variable could vary according to the level of socioeconomic deprivation measured at the residential census blocks of the mothers. Comparing fit statistics from the model where parents’ characteristics directly affected BW, BL, and GA (Model 1) to one in which these effects were mediated by FFGC , we confirm that the latter provided a better fit for the data. One limitation, highlighted by Bollen et al.  in theiri) first, whether the FFGC Model was a better fit in each sub-group, and ii) secondly, whether the patterns of signs and significance of regression coefficient to predict FFGC were different between each sub-group. Our study found that a model with a latent FFGC variable fit the data better than a model without it, whatever the class of neighborhood socioeconomic deprivation. Hence, our study suggests that the existence of the latent variable characterizing favorable fetal growth conditions was not undermined by the level of neighborhood socioeconomic deprivation. However, our findings reveal that the strength, the direction and the level of significance of the association between the exogenous variables and the FFGC were different according to the level of neighborhood deprivation. Therefore, our study suggests that mechanisms and/or the strength of the mediating effect of the FFGC on adverse birth outcomes may be influenced by the level of socioeconomic deprivation; further investigations are needed to gather additional scientific evidence.Most interestingly, we stratified our analysis according to the neighborhood socioeconomic index estimated at the census block scale to test: The strengths and limitations of this study should be addressed here. The main strength of our study is the databases we used, with a high rate of completeness of the birth certificates (93% on average) and the large population size, resulting in a high statistical power when stratifying the statistical analysis by neighborhood deprivation category. However, one limitation related to the stratified analysis is the high number of missing values that we imputed using information available at the census block scale. Doing so, we increased the level of correlation between the distribution of individual characteristics and that of the neighborhood. Hence, we decreased between-subject variability within census blocks, especially among the most deprived census blocks in which the rate of the missing value was twice higher compared to the most privileged ones. However, our results consistently reveal significant relations with the FFGC variable; this may suggest that imputation values did not have a significant influence on this main result but rather much more on the measure of the associations and their level of significance between exogenous variables and the FFGC variable. Additionally, our study presents the advantage of consider three birth outcomes together in the same analysis while the majority of the epidemiological studies investigated each one separately when data of several outcomes were available. A methodological approach taking into account that correlation between the birth outcomes is more realistic, knowing, for instance, that small gestational age reduces the birth weight and height. While the development of the structural equation model has existed for a long time ,30,31, thttps://www.insee.fr/fr/statistiques/1288219). This may have influenced the association with the latent variable and needs to be investigated in other areas with various socioeconomic profiles. The main limitation of our study is the absence of certain mothers’ characteristics, such as maternal height and weight (or the body mass index), smoking habits or alcohol consumption during pregnancy; these factors are all known risk factors of adverse birth outcomes. However, we took into account individual and neighborhood socio-economic information, which are documented to be related to unhealthy behaviors; thus, we believe that we partially captured these missing risk factors thanks to these socioeconomic data, and thus minimized the resulting bias. Additional limitation of this study concerns the difficulty to extrapolate our findings to other French areas. Indeed, the Ile de France region is one of the French regions where the proportion of population with a high level of education is the highest (In addition, in our study, only one variable, occupational status, was available to characterize the socioeconomic position of the father. In future research, it could be very interesting, of course, to consider the level of education of the father and of the mother in the same analysis. In conclusion, our study supports the existence of a latent variable representing a FFGC-mediating variable between parents’ characteristics and newborn weight, length and gestational age. Future research should aim to confirm the existence of the FFGC latent variable, taking into account neighborhood characteristics using Multi-Level Structural Equations, which combine the analytic approaches of multilevel analysis and structural equation modeling in a two-stage process.


Infants with neonatal abstinence syndrome (NAS) initially experience neurologic excitability, poor feeding, and/or hyperphagia in the setting of increased metabolic demand. Because the longitudinal effects of these early symptoms and behaviors on weight trends are unknown, we sought to contrast weight gain patterns through age 1 year for infants diagnosed with NAS with matched controls.Retrospective cohort of 70 singletons with a gestational age of ≥37 weeks and an ICD-9 or ICD-10 diagnosis of NAS made ≤7 days after birth with institutional follow-up matched to patients without NAS. Infants were matched on gestational age (±2 weeks), birth weight (±20 g), sex (exact), and insurance type (exact). Quantile regression methods were used to estimate 10th, 25th, 50th, 75th and 90th percentiles of weight over time.The mean gestational age for an infant with NAS was 38.8 weeks . The mean birth weight was 3.141 kg . NAS patients had a median of 24 weights recorded between birth and 400 days . Patients without NAS had a median of 12 weights recorded . Growth curves were similar over the first 400 days of life. Patients with NAS had non-significantly higher and lower estimated weights for the 90th and 10th percentiles, respectively.Infants with a diagnosis of NAS grew similarly to controls during their first year. Given the frequently-encountered NAS symptoms of hyperphagia and irritability, future studies may evaluate whether early differences in caregiver feeding exist and whether they have longer-term impacts on growth. Neonatal abstinence syndrome (NAS) is a growing public health problem both nationally and globally –4. InfanStudies focused on caloric intake and growth of infants affected by NAS in the immediate neonatal period are inconsistent and sparse –9. WhileInfants affected by NAS are symptomatically irritable and difficult to soothe. These characteristics along with early hyperphagia may lead to the development of aberrant feeding behaviors by caregivers with a tendency towards feeding to comfort. While infants have an innate ability to control their caloric intake , 12, parN = 13,718) hospitalized at the Penn State Milton S. Hershey Medical Center  between July 2008 and March 2016 were queried. HMC is a tertiary care center with a level IV neonatal intensive care unit (NICU) and an active maternal-fetal medicine (MFM) program. Data extracted from the EMR included birth weight, type of delivery , sex, gestational age, singleton versus multiple birth, NICU stay, insurance status , receipt of drugs  during birth hospitalization, total number of inpatient and outpatient visits within 13 months after birth, and weights and lengths entered in the EMR during inpatient or outpatient visits. Where data were missing from searchable fields of NAS patients, they were manually extracted from the clinical chart. For all transferred newborns with a diagnosis of NAS (N = 127), pre-transferal data were obtained by physically reviewing outside records.In this retrospective cohort study, electronic medical records (EMR) of all newborns  and the ICD-10 code P96.1 . Each NAS patient was matched to 1 patient without NAS on gestational age (±2 weeks), birth weight (±25 g), sex, and insurance  using a greedy matching algorithm . While tWe used a quantile regression model appropriate for longitudinal data to estimate 10th, 25th, 50th (median), 75th, and 90th percentiles of weight (measured in kg) as a function of time after birth. The penalized fixed-effects model in the R package “Regression Quantiles for Panel Data (rqpd)” was used to estimate the percentile curves . The modTo estimate non-linear percentile curves, we used restricted cubic splines  with knoWe conducted 2 subgroup analyses. First, we compared percentile curves of patients who did and did not receive pharmacologic therapy for NAS. Second, we compared patients with NAS who received pharmacologic therapy to their matched controls. The same methods were used as above with the following changes: λ was set to 20 and only 4 total knots were used (instead of 5) for patients with NAS who did not receive pharmacologic therapy due to the smaller number of weights recorded for this subgroup.Among the 234 neonates with a diagnosis of NAS and documented inpatient stay at our center, 70 (30%) met all inclusion criteria and were included in the final analysis Fig. . Thirty-Fifty (71%) of the NAS patients were < 1 day old at the time of NAS diagnosis. An additional 14% were diagnosed on the day following birth, and the remaining 14% of patients were diagnosed between ages 2–5 days. Thirty-six (51%) of NAS patients did not receive pharmacologic treatment. Among NAS patients who required pharmacologic therapy, nearly all (97%) received treatment with morphine with 4 patients (12%) requiring the addition of a second agent  to manage their symptoms. One patient received treatment with phenobarbital alone.Patients with NAS had a total of 2072 weights recorded between birth and 400 days of age  compared to 974 weights recorded  during the same time period for matched controls. The majority (61%) of the weights for patients with NAS were recorded during the initial birth hospitalization with a median of 12 weights recorded during the birth hospitalization and a median of 9 weights recorded between newborn discharge and 400 days. In contrast, for matched controls, the median number of weights recorded during the birth hospitalization was 3, and a median of 10 weights were recorded between newborn discharge and 400 days.Figure N = 34) and those who did not (N = 36). Differences between groups were non-significant for each percentile. In a separate subgroup analysis, Fig. In a subgroup analysis, Fig. This retrospective, pilot analysis of data from a single center failed to reveal significant growth differences between birth and 1 year among those infants diagnosed with NAS when compared with matched controls. Further subgroup analysis of those NAS infants pharmacologically treated compared to matched controls did not demonstrate growth differences. These results conflict with our a priori hypotheses, which reflected known feeding difficulties and hyperphagia among infants with NAS.Pediatric growth is a complex, multifactorial process influenced by genes, nutritional intake, the environment, overall health, and socioeconomic status (SES). In the newborn period, the NAS population is unique in its nutritional needs. The hypermetabolic state resulting from symptoms of withdrawal in combination with poor feeding places this patient population at risk for excessive weight loss in the neonatal period , 9. WhilInstead, consistent with a previous investigation by Vance et al. , we founIt is reasonable to presume differences may exist in the growth of this population for a number of reasons. Similar to previous study findings , 17, NASHowever, the burden of NAS is experienced by members of all socioeconomic statuses, and deprivation alone is not the only reason to suspect variance in growth. There is compelling evidence to suggest early feeding behaviors affect childhood eating habits and weight , 26. HypThere are a number of limitations to our study. Our data are retrospective and gathered from a single center with a fairly homogenous population. Many patients ultimately received their post-discharge care outside the HMC system, and the resulting sample size is small and may conceal actual differences that exist in growth of this vulnerable population. Additionally, utilizing a hospital database for research depends on correct ICD coding. Failing to assign the relevant diagnostic code for an infant who displays symptoms of NAS may lead to a falsely-low appreciation of the true extent of this syndrome at our institution. Conversely, inappropriately assigning a diagnosis of NAS to an infant being observed for NAS may lead to improper selection of the desired study population. Indeed, in our dataset, over half of the patients with a diagnosis of NAS did not receive pharmacologic management, suggesting that their symptoms were mild or they were inaccurately assigned such a diagnosis. Future research using a larger database with access to long-term follow-up data may clarify whether differences in growth exist between patients affected by NAS and their non-affected counterparts.Infants with a diagnosis of NAS grew similarly to matched controls in this small, retrospective sample from a single center. Future studies may evaluate whether early differences in caregiver feeding exist, and if so, whether they have longer-term impacts on growth of these infants.


Double emulsions were prepared with sunflower oil containing 10 to 70 g kg−1 PGPR in the oil phase, and were monitored for droplet size distribution, morphology, encapsulation efficiency (EE) and oxidative stability over time.Worldwide iron deficiency in diets has led to a growing interest in the development of food‐compatible encapsulation systems for soluble iron, which are able to prevent iron's undesirable off‐taste and pro‐oxidant activity. Here, we explore the use of double emulsions for this purpose, and in particular, how the lipophilic emulsifier  concentration influences the physicochemical stability of water‐in‐oil‐in‐water (WFresh double emulsions showed an initial EE higher than 88%, but EE decreased upon storage, which occurred particularly fast and to a high extent in the emulsions prepared with low PGPR concentrations. All double emulsions underwent lipid oxidation, in particular those with the highest PGPR concentration, which could be due to the small inner droplet size and thus promoted contact between oil and the internal water phase.Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.These results show that a too high PGPR concentration is not needed, and sometimes even adverse, when developing double emulsions as iron encapsulation systems. © 2019 The Authors.  Iron deficiency is one of the most common global nutritional deficiencies and an important factor responsible for anaemia.1/O/W2) double emulsions are suitable to encapsulate water‐soluble compounds.Among the plethora of food‐compatible encapsulation systems, water‐in‐oil‐in‐water  has not been investigated yet, it is well established that the PGPR concentration affects the EE value in such systems. For instance, a double emulsion is considered reasonably stable if EE is ∼95% (or above) and decrease to 70–80%, maximally, after a few weeks of storage.1/O/W2 double emulsions targeted to ferrous sulphate encapsulation.It is thus clear that some aspects still need to be elucidated in order to bring double emulsions towards food applications for soluble iron encapsulation: for instance, we should strive for minimizing PGPR concentration, since FAO regulations put a maximun on daily intake of 7.5 mg of PGPR per kilogram of body weight,d‐Glucose monohydrate was purchased from VWR Chemicals  and n‐hexane was purchased from Actu‐ALL Chemicals . Acetic acid  100% anhydrous was purchased from Merck Millipore . Ultrapure water obtained from a Millipore Milli‐Q system  was used throughout the study.Sunflower oil was purchased from a local supermarket  and used without further purification. Ferrous sulphate heptahydrate was obtained from Merck Millipore . Para‐anisidine of analytical grade, polyoxyethylenesorbitan monolaurate (Tween 20), and 2‐propanol were purchased from Sigma‐Aldrich . PGPR was purchased from Quest International . 1/O) emulsion, the aqueous phase contained 1 mol L−1 ferrous sulphate heptahydrate. The oil phase was prepared by mixing sunflower oil with different PGPR concentrations: 10, 25, 50, and 70 g kg−1 in the oil phase, at 200 rpm for 30 min at room temperature, followed by a 30‐min rest. Then, 25% v/v of the inner aqueous phase was drop‐wise dispersed into the oil phase using a rotor‐stator homogenizer  at 11 000 rpm for 4 min.For making the primary water‐in‐oil . The pressure vessel was connected to a nitrogen source and set to 400 kPa.The external aqueous phase was prepared with 2 mol L1/O/W2 double emulsions were kept in cylindrical plastic tubes at room temperature for further analysis. Samples to measure lipid oxidation were kept in the dark at room temperature.The freshly made W1/O emulsion and W1/O/W2 double emulsion was determined by static light scattering . In the case of the primary W1/O emulsion, sunflower oil was used as the continuous phase and the following conditions were applied: particle refractive index of 1.330, droplet absorbance of 0.01, dispersant refractive index of 1.465,1/O/W2 double emulsion, ultrapure water was used as a continuous phase and the following conditions were applied: particle refractive index of 1.465, droplet absorbance of 0.01, dispersant refractive index of 1.330, obscuration between 5% and 10%. The droplet size distribution was measured in fresh W1/O/W2 double emulsion and after 1 and 7 days of storage at room temperature. Before measuring, the samples were gently agitated to ensure homogeneity. Results were expressed as the Sauter mean diameter (d32) and span value (δ).Droplet size distribution of the primary W1/O emulsions, and in fresh W1/O/W2 double emulsions, or after 1 and 7 days of storage at room temperature. The samples were gently agitated to ensure homogeneity. Then a drop of the sample was placed on a microscopic slide and covered with a slip. To visualize the primary emulsion the samples were diluted ten times with sunflower oil. Images were captured with an AxioCam MRc 5 camera at a magnification of ×400.Light microscopy  images were taken in primary WEPGPR) in a given volume of W1/O emulsion, considering a theoretical PGPR surface coverage (ΓPGPR) of 1.2 mg/m2mPGPR tot is the total mass of PGPR (in grams) in a given volume of emulsion, Vwater is the volume of aqueous phase, and r is the water droplet radius (d32/2).We calculated the theoretical excess fraction of PGPR  in solutions of the same composition as the external aqueous phase (glucose and Tween 20).The EE value was determined by direct conductivity measurements in the double emulsions  according to Sahin Cw2) relative to the maximum released concentration of iron   hydroperoxides1/O/W2 double emulsion were mixed with 950 μL 2‐propanol. This first sample was further diluted ten‐fold with 2‐propanol. The obtained sample was centrifuged at 1200×g for 4 min. The absorbance spectrum of the supernatant was recorded between 200 and 310 nm with a UV‐visible spectrophotometer , using a blank consisting of 2‐propanol and water in the same ratio as in the measured sample. Measurements were done on fresh emulsions, after 4 h, 1 day and 7 days storage at room temperature. The concentration of the CD hydroperoxides was calculated using the measured absorbance at 233 nm and their molar extinction coefficient at 233 nm (27 000 M−1 cm−1), and expressed as mmol kg−1 of oil.For the determination of CD hydroperoxides, 50 μL of W1/O/W2 double emulsion. Then the emulsion was mixed with 2.5 mL hexane/isopropanol . The upper hexane phase was centrifuged at 1200×g for 4 min and the supernatant was collected to measure the absorbance at 350 nm (Ab), using pure hexane as the blank. Then, 0.5 mL of the upper hexane phase was mixed with 0.1 mL of 2.5 g L−1 para‐anisidine in acetic acid solution. The blank was hexane mixed with the same para‐anisidine solution, in similar proportions. After 10 min the absorbance (As) of the samples was measured at 350 nm. The pAV was calculated as Eqn m is the mass of oil per millilitre of hexane phase.The determination of the pAV started with weighing 1 g of W−1 sunflower oil, 5 g kg−1 Tween 20 and 2 mol L−1 glucose in the aqueous phase) was prepared with 12.9 × 10−3 mol L−1 iron in the aqueous phase . Iron was dispersed at the aqueous phase under magnetic stirring at 100 rpm. The aqueous phase was prepared as described earlier. The oil was drop‐wise dispersed into the aqueous phase under magnetic stirring at 700 rpm for 15 min. The obtained coarse emulsion was then passed through a premix membrane emulsification system three times using the same parameters as described in earlier. This mixture corresponds to a situation in the W1/O/W2 double emulsion where all the water and iron would have been released from the inner water droplets to the external aqueous phase.Double emulsions without iron were prepared as a control. Besides, a simple oil‐in‐water (O/W) emulsion . The normality of the data was tested with Kolmogorov–Smirnov test. Means from samples prepared with different PGPR concentrations within the same storage time were compared by one‐way analysis of variance (ANOVA) with Tukey's 1/O/W2 double emulsions prepared with different PGPR concentrations was monitored over storage time at room temperature. The physical stability was assessed considering droplet size distribution, microscopy images, and EE. The formation of primary and secondary lipid oxidation compounds was used to analyse chemical stability.The physicochemical stability of W1/O emulsions prepared with the lowest and the highest PGPR concentrations tested. It is clear that W1/O emulsions prepared with 70 g kg−1 PGPR showed smaller droplets compared to W1/O with 10 g kg−1 PGPR. Figure 1/O emulsions prepared with different PGPR concentrations. A bimodal distribution was seen for W1/O emulsions with higher PGPR concentrations, with a first peak between 0.1 and 0.14 μm and a second peak between 1 and 1.5 μm. The polydispersity also increased when PGPR concentration was increased  resulted in decreasing the droplet size of W/O emulsions. To make physically stable double emulsions, it is preferable to have W1/O emulsions with small droplet size, to avoid rapid droplet sedimentation. In fact, a slower sedimentation rate can prevent the water droplets coming into close contact with the sedimentation layer, which reduces coalescence rates.Márquez et al.−1. This would imply that in our case, emulsions made with PGPR concentration equal to or above 25 g kg−1 would contain excess PGPR as reverse micelles in the oil phase. Moreover, the ability of free PGPR to aggregate and form reverse micelles has been described by the formation of spontaneous water droplets in oil phase even at low PGPR concentration (5 g kg−1) without homogenization.The peak around 0.1 μm could correspond to reverse micelles . Dickinson et al.. Therefore, those measurements are useful to obtain an estimation about the size and size distribution of the droplets but should be interpreted with caution. We checked the particle size distribution of O/W emulsions prepared in the same conditions as the double emulsions, except that the dispersed phase was now only oil, instead of a W/O emulsion. The particle size distribution and corresponding d32 and d43 values are presented in the Appendix  retained most of the iron encapsulated after 1 day. However, after 7 days of storage, the EE decreased to ∼50% in these double emulsions. Therefore, it seems that low PGPR concentrations lead to rapid release of iron, but that beyond a certain PGPR concentration  no further improvement can be achieved from an EE point of view. The pronounced release of iron in double emulsions prepared with low PGPR concentration after 7 days may be explained by sedimentation of larger water droplets within the oil droplets. Such a sedimentation would bring the water droplets closer to each other, and to the oil droplet surface, facilitating the release of water and iron to the external aqueous phase .−1  in fresh double emulsions compared to double emulsions without iron, independently of the PGPR concentration  the CD hydroperoxides only increased considerably after 168 h of storage.The formation of CD hydroperoxides was monitored over time in double emulsions with iron. After 4 h of storage, no substantial formation of CD hydroperoxides in double emulsions with iron could be detected, but after 24 h of storage CD hydroperoxide concentration increased significantly in double emulsions with 10 to 50 g kg−1) compared to double emulsions with lower PGPR concentrations, which continued to increase over time. At low PGPR concentrations, there was a significant increase only after 24 h of storage. For all double emulsions, the pAV seemed to level off after 24 h of storage.Nevertheless, there was no difference in the pAV in the fresh emulsions prepared with various PGPR concentrations  in emulsion systems can accelerate the decomposition of pre‐existing hydroperoxides, forming ferric iron (Fe3+) and alkoxyl radicals. Furthermore, Fe3+ can further react with hydroperoxides to form Fe2+ and peroxyl radicals.et al.2+ to O/W emulsions rapidly decreased the oxygen concentration compared to the addition of Fe3+, due to the fast rate of oxidation of Fe2+ to Fe3+ by pre‐existing lipid hydroperoxides in the system. This can explain the fast decomposition of CD hydroperoxides seen for double emulsions with iron, followed by a level‐off.The increase in lipid oxidation observed in our study was attributed to the presence of iron in the double emulsions, since it was substantially promoted compared to double emulsions with no iron. It is well known that the redox cycling of iron is a relevant mechanism to accelerate lipid oxidation. Ferrous iron  was added. Surprisingly, they found that when iron was encapsulated in the inner droplets of the W1/O/W2 emulsion, i.e. separated from the O/W fish oil droplets, the latter oxidized more than when iron was present in the external water phase, i.e. in direct contact with the fish oil droplets. Although no obvious explanation for this finding could be proposed, the authors hypothesized that corn oil itself could have oxidized because of the presence of iron in the inner water droplets, which could have catalysed the subsequent oxidation of the fish oil, although the latter was not in direct contact with iron.To test the potential effect of iron release in the external aqueous phase on lipid oxidation, we prepared simple O/W emulsions with iron present in the aqueous phase, to mimic a situation where all the inner water droplets would have been released to the external aqueous phase. We noticed that there was an increase in the formation of CD hydroperoxides over time , due to reverse micelles formed with non‐adsorbed PGPR that removed hydroperoxides from the droplet surface. When iron (Fe2+) was added to the W/O emulsions the hydroperoxides decomposition went faster at lower PGPR concentrations, which supports the hypothesis of the partitioning of hydroperoxides into reverse micelles.Finally, it has also been described that surfactant micelles can remove hydroperoxides from the interface and limit lipid oxidation.−1 PGPR concentration. Double emulsions with high PGPR concentration had smaller water droplets, thus a larger interface area that probably promoted lipid oxidation. We conclude that from a physical stability perspective, a high PGPR concentration was enough to keep most of the iron encapsulated before 7 days of storage, after which the EE decreased. From a chemical stability perspective, all double emulsions were unstable. A higher PGPR concentration increased the formation of secondary lipid oxidation products. Therefore, we assumed that the physicochemical changes observed in these double emulsions certainly hamper their suitability as iron encapsulation systems. An optimal PGPR concentration needs to be combined with strategies to reduce iron lipid oxidation and increase EE. This could next be a basis to tailor a physicochemical stable W1/O/W2 double emulsion for iron encapsulation.The present study investigated the physical and chemical stability of double emulsions containing iron in the inner water droplets. Regarding the physical stability, even a high PGPR concentration was not sufficient to fully prevent the release of iron to the external aqueous phase over storage. Yet increasing PGPR concentration did help in some respect, but only up to a certain concentration, above which no further increase in EE could be obtained. We hypothesized that the transport of iron was mostly due to the coalescence of the inner water droplets with the external aqueous phase at low PGPR concentration, and mostly due to transport via reverse micelles at high PGPR concentrations. The PGPR concentration also had an effect on lipid oxidation. The formation of CD hydroperoxides increased over time in all double emulsions, and pAV increased more substantially in double emulsions with 70 g kgThe authors declare no competing financial interest.


Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors.Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach.p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed . The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group . No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman . The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2–5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes.Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome  individual participant data meta-analysis (IPD-MA) were to assess the effect of repeat prenatal corticosteroids when given to women at high, ongoing risk of preterm birth on important clinical outcomes and whether treatment effects varied depending on participant and treatment factors.The aims of the Prenatal Repeat Corticosteroid Eleven randomised trials with 4,857 women and 5,915 infants were identified as including women at ongoing risk of preterm birth after an initial course of prenatal corticosteroids who were allocated repeat prenatal corticosteroids or placebo or no placebo treatment and in which outcomes for the infant were reported and included.Overall, repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course did not reduce the risk of serious health outcomes for the infant but did reduce the need for respiratory support, although birth weight z-scores were reduced. Exposure to more repeat courses and greater total dose of corticosteroids was associated with a reduction in serious outcome and less need for respiratory support for the infant but also greater reduction in body size at birth. There were no differences in rates of maternal sepsis. At childhood follow-up, no differences in neurodevelopment were seen between those exposed to repeat prenatal corticosteroids and those not, although weight z-scores and systolic blood pressure measurements were lower in the exposed group.Treatment effects varied little by reason for preterm birth, the number of fetuses in utero, the gestational age when repeat treatment was given, or the time prior to birth that the last dose was given.Repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduce the likelihood of their infant needing respiratory support after birth and lead to other respiratory benefits.To provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited if possible. We suggest a maximum of three repeat treatments and a total dose of between 24 mg and 48 mg.Reductions in weight z-scores and systolic blood pressure seen at childhood follow-up are of uncertain clinical importance and warrant further study.Adoption of repeat prenatal corticosteroid treatment used in this way could lead to both significant health benefits for infants at ongoing risk of preterm birth after exposure to an initial course of corticosteroids while minimising any reduction in body size. Respiratory distress syndrome, caused by surfactant deficiency, is a common complication of preterm birth and a major cause of early neonatal mortality and morbidity . InfantsUse of repeat prenatal corticosteroids for women who remain at risk of preterm birth to prevent neonatal morbidity was first suggested in the early 1970s . The CocInternational IPD-MA Study: assessing the effects using the best level of Evidence (PRECISE) Group was formed to undertake an individual participant data (IPD) meta-analysis (MA) of the data from eligible trials. This approach has the advantages of allowing for exploration of interactions between treatment and characteristics at a participant level and enables examination of differential treatment effects between subgroups  and [antenatal or prenatal] and [corticosteroid* or steroid* or glucocorticoid* or betamethason* or dexamethason* or hydrocortison*]. Date of last search was 20 January 2015. The WHO/CTRP portal was accessed to identify any recently completed or ongoing trials. There was no language restriction on searches. Trialists within the PRECISE Group were asked if they knew of any unpublished or other trials.Eligibility of identified trials was assessed independently and unblinded by two members of the PRECISE Project Team (PFM and TKM). Any differences regarding eligibility were resolved by discussion.The Chairperson of the PRECISE Project Team (CAC) contacted the investigators of all eligible studies to invite them to join the PRECISE Trialist Group and to include IPD data from their trial in the IPD-MA. Prespecified variables were developed and defined by the PRECISE Trialist Group. Investigators were asked if these variables were available or could be derived for their study, and a coding system was developed.Deidentified data were collected on all randomised women. These included baseline data for descriptive purposes and analyses  and details of the intervention planned and given  together with the infant, childhood, and maternal outcomes to allow the planned analyses.The data from the individual trials were recoded as needed and stored in a secure database only accessible by the PRECISE Data Management Group. The individual trialists were asked to verify their coded data prior to analyses. Data were checked for internal consistency, extreme or missing values, errors, and consistency with published reports. Randomisation methods and intervention details were cross-checked against trial protocols, clinical record forms, and published reports for all trials. The PRECISE biostatistician (MV), project coordinator (TKM), and data manager (SZ) liaised with the trialists to check any inconsistencies and missing data. The final IPD dataset prepared from each trial was sent to the trialist for verification before being included in the full PRECISE dataset. Data items collected are published elsewhere  S2 TextS2 Text.Risk of bias for each study was assessed using the Cochrane Collaboration risk of bias tool  by two mThe primary prespecified outcomes for the infant were serious outcome ; use of respiratory support ; and birth weight z-scores.The primary prespecified outcome for the child was death or any neurosensory disability at childhood follow-up .The primary prespecified outcome for the woman was maternal sepsis .Secondary outcomes were prespecified in the PRECISE IPD-MA protocol  S2 TextS2 Text.The statistical analysis plan was prepared by the PRECISE Data Management Group and agreed by the PRECISE Trialist Group. One-step IPD-MA analyses were conducted on the checked IPD from all the trials. All randomised participants with outcome data available were included in the analyses, performed on an intention-to-treat basis by treatment allocation at randomisation.p values. Continuous outcomes were analysed using linear regression models, and results were presented as differences in means with 95% CI and two-sided p values. Correlations between outcomes due to multiple births were taken into account using generalised estimating equations (GEEs) for infant and child outcomes. Differences in treatment effect between prespecified subgroups were assessed by testing a treatment-by-subgroup interaction term within the model. A treatment-by-trial interaction term was included in the model to assess heterogeneity of treatment effect across trials. When excessive statistical heterogeneity in treatment effect or inconsistency across trials was detected, then the rationale for combining trials was questioned and the source of heterogeneity explored.Binary outcomes were analysed using log binomial regression models with results presented as RRs with 95% CIs and associated two-sided p < 0.05 level. NNT was calculated as the inverse of the absolute risk reduction (ARR): NNT = 1/ARR, where ARR = Control Event Rate minus Experimental Event Rate.For growth outcomes, z-scores were calculated at birth, hospital discharge, and follow-up based on WHO Child Growth Standards and British 1990 reference data, reanalysed 2009 ,19. For Analyses presented do not correspond to published estimates from individual trials in every case because trialists may have defined outcomes differently or prespecified different criteria for inclusion or exclusion of data from their analysis. Discrepancies between published estimates and PRECISE estimates do not imply that one or the other is incorrect.Eleven randomised trials were identified from the search, and each provided data for the IPD-MA –34, withFive trials were from the US ,26,27,33Individual study protocols varied in relation to the amount and number of doses used in a course of repeat treatment, the interval between courses, and the latest gestation that repeat treatment courses could be given. In most trials, a course of treatment was two doses, usually given 24 hours apart, although for two trials, a course of treatment was a single dose ,30. SeveOverall the risk of bias was low across the included studies, with some variation between the trials .p = 0.33) , with no significant heterogeneity ( = 0.33) .p = 0.64) , with no significant heterogeneity ( = 0.64) . The NNTp = 0.80).There was a significantly lower birth weight z-score in infants exposed to repeat prenatal corticosteroids compared with unexposed infants  , with noThere was no statistically significant effect of treatment with repeat prenatal corticosteroids on the risk of death or neurosensory disability for the child .For the primary maternal outcomes of maternal sepsis, no statistically significant effect was seen with repeat corticosteroids using the data available for the IPD .No statistically significant differences were seen for many of the secondary infant outcomes . Fewer iFor the children, no statistically significant differences were seen for the outcomes of death, neurosensory impairments, any neurosensory disability, major neurosensory disability, child behaviour, or respiratory disease at follow-up; however, weight z-scores and systolic blood pressure were lower .p-value for heterogeneity was <0.0001, indicating differences between the studies not accounted for by random variation, such as differences in the placebo used . For the composite outcome of adverse effects of corticosteroid therapy, the ebo used . There wWhen sufficient data existed, subgroup comparisons were conducted using the five primary outcomes for the infant, child, and mother, as well as the individual components of each composite outcome. Not all planned subgroup analyses were possible because of unavailability of data. When subgroup analyses were possible, not all trials had data to contribute.The prespecified participant level characteristics that were analysed were the reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, gestational age when first trial treatment course was given , the time prior to birth that the last dose of trial treatment course was given, the number of courses received, the interval between courses, and the total dose received.There were few clear differences in treatment effects among subgroups of reasons the women were considered at risk of preterm birth. Reductions in birth weight, head circumference, and length due to receiving repeat corticosteroids were greater when the reason for being at risk of preterm birth was preterm labour than when it was not . For thoThere were no significant differences in treatment effects among the subgroups by the number of fetuses in utero .Reductions in birth weight, head circumference, and length were significantly greater for infants whose mothers had received corticosteroids at an earlier gestational age. Women starting treatment at earlier gestations were a subgroup who also received higher total exposure overall .There were no significant differences in treatment effects for any of the major outcomes according to categories of time prior to last dose of treatment until birth .The number of courses of repeat prenatal corticosteroids received varied by trial due to the different treatment protocols. The number of courses also varied by participant characteristics such as the gestational age at which study treatment commenced, with women commencing at an earlier gestational age having more time to receive more courses of treatment provided birth did not occur. Half of the children in the analyses were exposed to only one course of treatment. Only 3% of children were exposed to six or more courses of treatment. CIs for this subgroup were therefore wide because of the smaller number of participants in the analysis. Because the number of courses received was a postrandomisation measurement, these analyses were considered exploratory, although still clinically important, comparisons. For the primary outcomes of serious outcome and use of respiratory support for the infant, treatment effects differed according to the number of courses of repeat treatments received. Benefits of repeat corticosteroid were observed for infants who were exposed to between 2 to 5 courses of repeat corticosteroids compared with infants exposed to only a single repeat course or 6 or more repeat courses. There were greater reductions in birth weight and length z-scores for infants exposed to 4 or more repeat courses and in head circumference for infants exposed to two or more repeat courses .The minimum interval between repeat treatment courses varied by trial because of the different treatment protocols and different participants. Intervals between repeat courses of 1–7 days and 8 or more days showed a reduction in serious outcome and the use of respiratory support for infants exposed to repeat courses compared with a single repeat course. For the other outcomes, apart from death at any time, no obvious differences were seen between groups for different minimum interval between repeat treatment courses .The dose of trial treatment received varied by trial because of the different trial protocols and also because of the number of courses of treatment actually received. Differences in treatment effects were seen for serious outcome for the infant, use of respiratory support, death at any time, and head circumference depending on the total dose received. Benefits of repeat corticosteroids were seen for serious outcome for the infant and for use of respiratory support with larger doses (>24 mg) and for death at any time with total doses between >24 mg to 48 mg of repeat corticosteroid compared with total doses received of ≤24 mg . Head ciThe major findings from the PRECISE IPD-MA are that for women at risk of preterm birth, use of repeat prenatal corticosteroids following an initial course 7 or more days previously does not reduce the risk of serious outcome for their infant but does reduce the risk of their infant needing respiratory support after birth. The number of women who need to be treated to prevent one infant needing respiratory support is 21 (95% CI 14 to 41). This benefit is associated with their infant being less likely to have respiratory distress syndrome, having less severe respiratory disease, and being less likely to require resuscitation at birth, surfactant treatment, and oxygen supplementation. These respiratory benefits are not at the expense of any short-term complications for the mother. However, z-scores for weight are significantly lower in infants whose mothers receive repeat prenatal corticosteroids (mean difference 80 g), as are z-scores for head circumference and length at birth and the proportion of infants born small for gestational age. The clinical significance of the reduction in birth weight z-scores is unclear. There appear to be no longer-term clinical benefits or harms of repeat prenatal corticosteroids in childhood, as assessed by neurosensory disabilities, respiratory outcomes, or behaviour, and few differences in body size, although weight z-scores are lower by ‒0.11 SD (95% CI ‒0.19 to ‒0.03). The clinical importance of this reduction in weight z-score at early childhood follow-up, in the absence of clear evidence of effects on head size, length/height, or neurosensory outcomes is unclear. There is also a small reduction in systolic blood pressure of uncertain clinical importance. Ex-preterm survivors have higher blood pressure in late adolescence or early adulthood than do term controls , which mThe results from this IPD-MA are consistent with the aggregate meta-analysis in the Cochrane review assessing the use of repeat prenatal corticosteroids in women who remain at risk of preterm birth after an initial course of corticosteroids . The newIn three subgroup analyses involving postrandomisation events , differences were seen between subgroups. The risk of a serious outcome for the infant and the need for respiratory support were reduced when exposed to at least 2 repeat treatment courses and to total doses of more than 24 mg of repeat treatment. Death at any time was reduced with exposure to total doses of between >24 mg to 48 mg.The number of repeat prenatal corticosteroid treatment courses and the total dose of repeat prenatal corticosteroids also affected body size z-scores at birth, with exposure to increasing numbers of repeat treatment courses or larger total doses associated with greater reductions in growth. There were greater reductions in birth weight for infants exposed to 4 or more repeat courses. To provide clinical benefit with the least harm in women who remain at high risk of preterm birth 7 or more days after an initial course of corticosteroids, it would seem prudent to limit the use of any repeat corticosteroids to a total dose of between >24 mg to 48 mg and a maximum of 3 repeat courses of treatment.IPD-MA is recognised as the gold standard for systematic reviews . One of In this way, we were able to include IPD from all the known completed randomised trials of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their infants. The IPD-MA findings provide the best available evidence for decision makers at this time.We have recently updated the search for trials (date of search 22 January 2019). No additional randomised trials of repeat prenatal corticosteroid treatment given 7 or more days after an initial course of prenatal corticosteroids were identified. Two of the trials have reported health outcomes in later childhood, one at 5 years  and the Not all trials collected or were able to provide data for all of the prespecified subgroups. This limited the power to be able to detect overall or subgroup differences because event rates are low for some important maternal, infant, and childhood clinical outcomes. Neonatal hypoglycaemia was not reported in any of the trials but has recently been linked with use of antenatal corticosteroids in the late preterm period , so it sThe PRECISE IPD-MA found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduces the likelihood of their infant needing respiratory support after birth and leads to other respiratory benefits. Body size measurements at birth are lower in infants whose mothers had received repeat prenatal corticosteroids, and the reductions in weight z-scores and systolic blood pressure seen at childhood follow-up are of uncertain clinical importance. No longer-term clinical benefits or harms are seen in childhood for neurosensory disabilities, respiratory outcomes, or behaviour.Prenatal corticosteroids are easy to administer, relatively inexpensive, and are effective at reducing the need for respiratory support that preterm infants often require. Recommendations to use repeat prenatal corticosteroids when indicated are now included within the WHO recommendations on interventions to improve preterm birth outcomes  and seveIt is reassuring that the respiratory benefit is seen among varying reasons for risk of preterm birth, in singleton and multiple pregnancies, and across a range of preterm gestational ages when repeat treatment courses are first given and times prior to birth the last repeat treatment is given. Because the benefits of reduced serious outcome and need for respiratory support for the infant are accompanied by a reduction in measures of body size at birth that are related to the number of repeat treatment courses and total dose of repeat prenatal corticosteroid treatment given, it would seem prudent to limit the use of repeat corticosteroids in women who remain at high risk of preterm birth to a total dose of between >24 mg to 48 mg and a maximum of three repeat courses of treatment.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TablePTB, preterm birth.(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 TableGA, gestational age.(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S1 TextPRISMA, Preferred Items for Reporting for Systematic Review and Meta-analysis.(DOCX)Click here for additional data file.S2 TextRepeat prenatal corticosteroid prior to preterm birth: a systematic review and IPD-MA for the PRECISE study group Study Protocol. IPD, individual participant data; MA, meta-analysis; PRECISE, Prenatal Repeat Corticosteroid International IPD-MA Study: assessing the effects using the best level of Evidence.(PDF)Click here for additional data file.


Previous research indicated that birth order was associated with physical health outcomes in adulthood. However, evidence on its association with mental health was lacking. The aim of this study was to investigate if birth order was associated with mental wellbeing and psychological distress at mid-life, stratified by gender, and taking into account confounding factors in childhood and adulthood.The sample consisted of 9,354 participants of the 1970 British Cohort Study (BCS70). The Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), the Malaise Index and attending a doctor’s consultation in the past year for a mental health issue at age forty-two were used to assess mental wellbeing and psychological distress in midlife. Birth order was ascertained via a parental questionnaire and referred to the numerical birth position of the participants. The associations between birth order, mental wellbeing and psychological distress were tested using linear and logistic regression adjusting for birth characteristics: smoking during pregnancy, maternal age, mother’s marital status, father’s employment, region of birth, parental years of education and parental social class, and factors at age 42: years of education, employment status and partnership status. Potential mediating variables including breastfeeding and birthweight at birth and parental separation and conduct disorder measured at age ten were also taken into account.We find no evidence to support an association between birth order and midlife psychological distress or attending a doctor’s consultation in both men and women. In unadjusted analysis, there was an association between birth order four and above and a reduced WEMWBS score of -0.79  in men only. This association was attenuated after adjusting for birth characteristics and mediators at birth  but was maintained once conduct disorder at age 10 was accounted for . However, this association was attenuated once again after adjusting for employment status, years in education and partnership status in adulthood .In this study, birth order was not associated with psychological distress or having a mental health issue at midlife. Accounting for employment status, years of education and partnership status in adulthood attenuated the relationship between birth order and mental wellbeing. The WHO defines mental health as a ‘state of wellbeing in which every individual realises his or her own potential, can cope with the normal stresses of life and can work productively and fruitfully’ . High leVarious psychosocial and socioeconomic circumstances through an individual’s lifecourse, are associated with mental wellbeing and psychological distress in adulthood , 3. Howenot being the first-born child, whilst sociological theories suggest being the first-born child can have sociological and developmental advantages. The developmental origins of health and disease hypothesis emphases the influence of the fetal environment during pregnancy. The fetus learns to adapt to the environment it expects to enter once outside of the womb, by first adapting to the environment within the womb [Theoretical hypotheses regarding the role of birth order have emphasised either its impact on biological conditions within the womb, or the social and environmental conditions a child is raised in. Theoretically, social and biological theories lead to contradictory expectations regarding the association between birth order and adult outcomes. Biological theories emphasise the biological advantage of the womb , 9. Chilthe womb . The prithe womb .A first-born child is likely to grow up in a more restricted uterine environment compared to subsequent pregnancies . For exaSociological theories focus on resource depletion as a pathway through which children of lower birth orders may receive increased resources and investment compared to subsequent siblings. The eldest sibling represents a better Darwinian bet for survival and reproduction and as such, parents bias investment and resources, both consciously and unconsciously towards the eldest child . FurtherTo our knowledge there are no existing studies that have investigated birth order, mental wellbeing and psychological distress in midlife. Within a developed country context, birth order has been extensively studied with regards to the development of schizophrenia and has been found to be an independent risk factor for the illness –22. The Two studies using the 1970 British Cohort Study (BCS70) found contrasting evidence. One found an association between exposures in fetal life including low birthweight (P <0.05), early gestational age (P<0.05) and low weight gain (P <0.05) and psychological distress at age twenty-six . HoweverPrevious studies have also found differences in association when stratified by gender. –22. The We examined the association between birth order and three mental health outcomes: midlife (age 42 years) mental wellbeing, adult psychological distress and attending a doctor’s consultation, accounting for potential mediation by factors at birth, in childhood and confounding by birth characteristics and factors at age forty-two.The 1970 British Cohort Study (BCS70) has followed 17,096 participants across England, Scotland and Wales born in a single week of 1970, collating information at nine different time points across the life course. A user guide for the dataset can be found at the Centre for Longitudinal Studies . The cohWithin the BCS70 there were 8,578 respondents with valid data on the Malaise Index at and 8,070 with valid data on the WEMWBS at forty-two. This represents 50.5% and 47.49% of the original birth cohort for the Malaise Index and WEMWBS respectively. Previous research using weights to adjust for lost cases, multiple imputation and attrition within the BCS70 were found not to improve the efficiency of models and had weak predicative powers . WeightsMental health was measured using three instruments; the Malaise Index measuring psychological distress, the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) measuring mental wellbeing, and a direct question asking participants whether they had attended a doctor’s consultation in the past year for a mental health issue.The WEMWBS was designed to capture the presence of positive mental states, with all questions being presented in a positive manner. The scale is comprised of fourteen-questions with five response likert-scale for each question. The responses to each question were summed to produce a single score between fourteen and seventy. A higher WEMWBS score reflects higher levels of positive mental well-being. The scale also indicates a high level of reliability  and displays content and criterion validity and acceptable test-retest reliability . The meaThe Malaise Index is based on the Malaise Inventory ; an estaWithin the final measure participants were asked to state if they had been to see a doctor or a specialist for a mental health issue in the past year from the time they completed the survey. The measure was treated as a binary outcome with responded either answering ‘yes’ or ‘no’. The decision to analyse this alternative outcome were to test the limitations of the self-reported measures of mental wellbeing and psychological distress, replacing them with a more objective measure of mental health.Birth order within this study refers to the numerical position a child was born into the family. The measure was derived by subtracting the total number of miscarriages and stillbirths from the total number of pregnancies, to produce the number of live births prior to the participant’s birth. This information was self-reported, collected at the time of the participants birth.Several childhood factors previously found to be associated with mental wellbeing and psychological distress in adulthood were analysed as potential mediators. A self-reported measure of breastfeeding duration and an objective measure of birth weight were recorded at birth. Children are significantly and increasingly less likely to be breastfed as birth order increases (P<. 0.00) . BreastfBeing of birth order one and having no subsequent siblings increases the risk of family dissolution (P < 0.01) , 46. PsyBirth characteristics refer to exposures directly associated to the parents of the participants, must have occurred prior to the participant’s birth and were measured in the birth surveys. Birth characteristics accounted for included—maternal age, maternal smoking, parental education, mother’s marital status, father’s employment, parental social class and region of birth. Social class is strongly associated to negative health outcomes, larger family formations and increased sibship size . MaternaThe conceptual diagram included in Firstly, descriptive statistics were conducted on the outcome variables. Logistic regression was carried out on the Malaise Index and the doctor’s consultation variable as binary outcomes, whilst. linear regression was used to analyse the WEMWBS. Model 1 tested the unadjusted association between birth order, mental wellbeing, psychological distress and doctor’s consultation. Model 2 tested the association between birth order and the three outcomes adjusting for birth characteristics . Model 3 added mediators measured at birth to model 2 (birthweight and level of breastfeeding). Model 4 added mediators measured at age ten to model 3 . Model 5 additionally included confounders at age forty-two . The associations were analysed independently for men and women.Tables Model one in Tables Model four in Tables Model five presented the fully adjusted model, showing the association between birth order, mental wellbeing and psychological distress, adjusting for birth characteristics and mediators at birth, age ten and confounders in adulthood. We find no evidence for a significant association between birth order and the WEMWBS, the Malaise Index or doctor’s consultation, for men or women. For men, the association between birth order four plus and the WEMWBS previously seen in model one and model four were attenuated when adulthood confounders were adjusted for .This study found no evidence to support the hypothesis that birth order was associated with mental wellbeing and psychological distress in midlife after considering confounding and mediating factors. There was little evidence to indicate differences in effect estimates when stratified by gender. Including conduct disorder at age ten attenuated the relationship between birth order and mental wellbeing at age 42. Adulthood socioeconomic confounders also attenuated any significant association between birth order and midlife outcomes.The results did not support the resource depletion hypothesis. Investing increased resources into the surviving eldest child might have been a ‘Darwinist best bet’ in an historical era when childhood mortality was high and sibship sizes were large. However, the BCS70 were born in an era where childhood mortality was low and fertility dropped dramatically, while resources may have been more evenly distributed amongst siblings. Further, this study did not support previous findings including Barclay & Kolk study of 509,984 people in Sweden who indicated a relative gender effect of birth order on mortality that was greater among women  than among men  . One expThis analysis found that socioeconomic confounders in adulthood including employment, partnership status and educational attainment were strongly associated with mental wellbeing and psychological distress at midlife, however early life factors were weakly associated. A potential explanation is that the long lead time between factors at birth, at age ten and the outcomes has resulted in any potential effect becoming diminished overtime. A second hypothesis, is that there may be other childhood mediators, unexplored within this study that are more important for predicting mental wellbeing. The finding that conduct disorder is associated with mental wellbeing in midlife postulates the conclusion that further research should focus on the development of personality types and behaviour across childhood.In contrast to our findings, earlier work found associations between birth order and physical health in adulthood including, hospitalisation (P<0.01) amongst a sample of 10,394 British children  and mortOur findings were similar to other studies that has found no evidence to support an association between birth order and other health outcomes in adulthood including both alcoholism  and anorThere are several strengths of this analysis. These include the large sample size of the study, utilising one of the four major British birth cohorts, which is representative of the UK national population, although attrition may render the sample less representative than the initial birth sweep. Previous research into the BCS70 has found that attrition is greater for the mobile, disadvantaged men, participants whose fathers had a manual occupation or mothers with lower levels of education . This weThe analysis also used three independent and alternative measures of mental wellbeing and psychological distress—capturing a more accurate and complete understanding of mental wellbeing and psychological distress in midlife. However, these measures of mental wellbeing are limited due to their self-reported nature. The analysis has also been limited in being unable to tease out the separation effects between birth order and maternal age; two variables that are strongly correlated to one another. The study also failed to capture the consequence of changing family structures within its definition of birth order. Birth order may have included sibships formed from several partnerships, whilst the analysis did not account for length of birth intervals, nor distinguished the gender of the previous births.In summary, this study indicated that birth order may not be associated to mental wellbeing or psychological distress at midlife, for men or women. With the exception of conduct disorder childhood mediators were only weakly associated with adult mental wellbeing and psychological distress. However, socioeconomic and partnership status in adulthood appeared to be significant in attenuating any association to mental wellbeing and psychological distress at midlife.We conclude that on the evidence of this study the development of mental wellbeing is not a predefined pathway stemming from birth order. Instead, mental wellbeing and psychological distress results from individualised exposures across the life course. There is also a genetic component linked to the mental wellbeing and psychological distress that was not explored within this study.Future research should use refined population cohort study data, with improved attrition rates and substantial pre-birth health markers, including an assessment of parental mental health, to test the conclusions drawn from this study. Future research should also look to develop and incorporate more objective measures of psychological distress and mental wellbeing.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S1 Fig(PDF)Click here for additional data file.