In particular, understanding the risk/benefit of immunizations with respect to pathways resulting in preterm birth is of particular interest. Preterm birth results from a variety of pathways ranging from idiopathic to spontaneous etiologies. Because there is a diverse spectrum of possible causes of preterm birth, it is important to determine whether some of the pathways to preterm birth can be activated by interventions, including immunizations.The pathophysiology and pathways related to preterm birth represent diverse and complex processes. A critical principle is that spontaneous preterm births result from a spectrum of pathological processes that are initiated by specific molecular pathways, converging into a common pathway While preterm birth is being formally defined by another Brighton Collaboration working group and that definition will be incorporated into this document, the purpose of this exercise is to develop case definitions and guidelines for data collection, analysis, and presentation for the pathways to preterm birth. The etiologies of preterm birth can be grouped into four pathways that are considered the underlying events leading to preterm birth; they include: (1) premature preterm rupture of membranes (PPROM), (2) spontaneous preterm labor (PTL), (3) insufficient cervix (IC), and (4) provider-initiated preterm birth (PIPTB). Of note, the first three pathways are spontaneously occurring processes, while the fourth occurs when a decision is reached between a patient and her provider that iatrogenic initiation of labor is required for the health of the fetus, mother, or both. These four pathways are the adverse events of interest in this document, which will focus primarily on how researchers, in the context of vaccine trials, can determine that one of these four pathways has been activated, or an adverse event has occurred.The diverse array of etiologies, coupled with obscured and/or overlapping clinical and scientific definitions has led to inconsistent definitions of pathways leading to preterm birth. Moving toward a consensus definition is critical for the purposes of monitoring adverse events in vaccine trials and to standardize terminology for improved data collection. Issues related to defining and classifying preterm birth include: relying on gestational age estimates based on a variety of approaches and validity, distinguishing between clinical versus etiologic phenotypes of preterm birth, considering whether to include or exclude multi-fetal gestations or stillborn infants, and deciding how to separate or combine different pathways to preterm birth Literature searches related to immunization in pregnancy were performed to identify existing definitions and contributing factors for premature preterm rupture of membranes, preterm labor, insufficient cervix, and provider-initiated preterm delivery; the four pathways to preterm birth. For premature preterm rupture of membranes, no data were published on the incidence of this outcome in association with immunizations in pregnancy. The same was true for insufficient cervix and provider-initiated preterm delivery; no published incidence of these outcomes related to immunization in pregnancy were available, even when similar terms were included in the search . In the case of preterm labor, while almost 100 studies were found based on the search terms preterm labor and immunization, only three of the articles mentioned preterm labor in the text of the articles, with only one reporting the incidence of preterm labor in the setting of an immunization. That paper reported that following administration of influenza A (H1N1) 2009 monovalent vaccine, 294 adverse events in pregnant women were reported to the Vaccine Adverse Event Reporting System; two women experienced preterm labor, or 1% of the immunized population in the United States Existing case definitions for the term, ‘pathways to preterm birth’, do not exist. Description of preterm birth as a syndrome, however, is a common finding, and attempts have been made at standardizing the pathways to preterm birth Each of the four pathways to preterm birth as presented in this document do have existing case definitions in the literature. For example, premature preterm rupture of membranes has been defined as, “rupture of the fetal membranes before term and outside of the context of labor” 1.2http://www.brightoncollaboration.org/internet/en/index/process.html, the Brighton Collaboration Pathways to Preterm Birth Working Group was formed in 2015 and included members from clinical, academic, public health, and industry backgrounds. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html.Following the process described on the Brighton Collaboration Website To guide the decision-making for the case definition and guidelines, a literature search was performed using Medline, Embase and the Cochrane Libraries, including the terms: premature preterm rupture of membranes, preterm labor, insufficient or incompetent cervix, and immunization. The search resulted in the identification of 37 references. All abstracts were screened for possible reports of initiation of the pathways to preterm birth following immunization. All articles with potentially relevant material were reviewed in more detail, in order to identify studies using case definitions or, in their absence, providing clinical descriptions of the case material. This review resulted in a detailed summary of three articles, including information on the study type, the vaccine, the diagnostic criteria or case definition put forth, the time interval since time of immunization, and any other symptoms. As such, other literature on the pathways to preterm birth and immunizations in pregnancy, in general, were made available to working group members, which included 28 papers.1.31.3.1The decision to focus on individual pathways to preterm birth as opposed to preterm labor alone was based on the expectation that immunizations may have pathway dependent effects, and that there is a clinical need to understand how immunization may influence the occurrence of an outcome. Addressing the classification of preterm birth or delineation of pathways to preterm birth approaches the question why a preterm birth occurred in the most comprehensive manner possible, addressing a topic that has achieved little consensus in the literature.1.3.2Preterm birth is a complex syndrome that more easily defies definitional terms than conforms to them. Preterm birth is the only healthcare concept defined by an arbitrary time point rather than by a specific etiology or pathophysiology 1.3.31.3.3.1The term ‘fetal membranes’, or ‘membranes’, which are subject to rupture or tear either spontaneously or artificially during labor, refers to the chorion and amnion, two separate but juxtaposed layers that enclose the amniotic cavity 1.3.3.2Much like PTB and PPROM, PTL is also a syndrome associated with multiple mechanisms of disease. Analogous to PPROM, PTL is not simply activation of the mechanisms leading to labor in the preterm setting; rather, labor at term is the physiologic activation of parturition while preterm labor is the result of several possible disease processes and external stimuli leading to pathologic activation of the component pathways leading to labor and delivery 1.3.3.3In comparison to PPROM and PTL, little is known about the pathophysiology of insufficient cervix. Much of what is known about the condition is based on clinical research and associated risk factors, but less is known about the science. Factors that may increase the risk of cervical insufficiency include cervical trauma from prior surgery, such as cervical conization or loop electrosurgical excision procedures, mechanical dilation of the cervix during termination procedures, or a history of cervical laceration during delivery or prolonged labor that may damage the cervical tissue, although data confirming these associations are scant and inconsistent 1.3.3.4The global community has become focused on preterm birth and the burden it places on families, communities, countries, and healthcare systems. As such, non-spontaneous preterm births, or those that occur as a result of a healthcare provider's decision to deliver as opposed to a spontaneous process, have become a topic of particular interest because if they are avoidable, their prevention could reduce prematurity rates and complications. Review of the literature has suggested that 28–40% of all preterm deliveries are provider-initiated, and that the incidence of such deliveries may be on the rise, especially in high-income countries (HIC) 1.3.4Generally, diagnostics most frequently used in the levels of certainty for definitional inclusion of an event in one of the pathways to preterm birth include ultrasound and clinical evaluation. Ultrasound utilization includes determination of the amniotic fluid index as part of level 1 of certainty for PPROM, and transvaginal cervical length and dilation assessment as part of the definitions of level 1 of diagnostic certainty of preterm labor, and level 1 of diagnostic certainty for insufficient cervix. Neither amniotic fluid index nor cervical length/dilation assessment is of a particularly high level of difficulty for a routinely trained ultrasound technician in a setting where ultrasound is commonly used and regularly available. Therefore, routine training in both abdominal and transvaginal techniques should constitute standardization of ultrasound use in setting where ultrasound is highly utilized.Clinical examination presents a challenge to standardization as it is inherently a more subjective measure and may reflect a clinician's experience and level of training. For PPROM, clinical evaluation requires the ability to collect a history, visualize leakage of fluid, and determine arborization of cervical fluid on microscopy. For PTL, clinical skills are required to quantify uterine contractions, determine rupture of membranes, and assess cervical effacement and dilation by digital examination. The diagnostic certainty of insufficient cervix also requires clinical determination of cervical effacement and dilation by digital examination and ability to collect a detailed obstetric history. The final pathway, provider-initiated preterm birth, does not require any physical clinical skills, but does require the ability to collect an obstetric history with attention to the nuance of determining whether a preterm birth was facilitated by a provider. There is no method to standardize these clinical skills; it is the hope that with high quality training and experience similar outcomes would be achieved between providers, but standardization of these clinical diagnostics are likely to exhibit inter-provider variability.A number of commercially available products exist for diagnosing PPROM by testing vaginal discharge for amniotic fluid. These are listed as part of level 1 of diagnostic certainty for PPROM. There is no need for standardization across settings regarding which product to use, because while some products have better sensitivity and specificity than others, this is only one component of the definition, and in 90% of cases PPROM can be determined by history and gross evidence of rupture of membranes 1.3.5Preterm birth rates are highest in low and middle-income countries (LMIC) 1.3.6Multiple risk factors increase a woman's risk of preterm birth outside the context of vaccine research, and should be taken into account when outcomes data are analyzed in the setting of an immunization trial in pregnancy. For example, in the United States, race and socioecomic status have been implicated as risk factors of preterm birth, with race as an independent risk factor when studies control for socioeconomic status 1.3.7The case definition for pathways to preterm birth has been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, two additional diagnostic levels have been included in the definition, offering a stepwise increase of sensitivity from Level 1 down to Level 3, while retaining an acceptable level of specificity at all levels. In this way, it is hoped that all possible cases of pathways to preterm birth can be captured.It needs to be re-emphasized that the grading of definition levels is entirely about diagnostic certainty, not clinical severity of an event. Thus, a clinically very severe event may appropriately be classified as Level 2 or 3 rather than Level 1 if it could reasonably be of an etiology not related to a pathway leading to preterm birth. Detailed information about the severity of the event should additionally always be recorded, as specified by the data collection guidelines.1.3.8The term “sudden onset” refers to an event that occurred unexpectedly and without warning leading to a marked change in a subject's previously stable condition. The term “rapid progression” is a conventional clinical term. An exact timeframe should not be offered since it would have to refer to a wide range of signs and symptoms without a scientific evidence base. Using an arbitrarily restrictive set point might bias future data collection unnecessarily.1.3.9Specific time frames for onset of symptoms following immunization are not included because pathways to preterm birth are most often activated outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the event, particularly in less developed or rural settings. In order to avoid selecting against such cases, the Brighton Collaboration definition avoids setting arbitrary time frames.1.3.10The Working Group decided against using ‘treatment’ or ‘treatment response’ toward fulfillment of the pathways to preterm birth case definition. A treatment response or its failure is not in itself diagnostic, and may depend on variables like clinical status, time to treatment, and other clinical parameters. Hence, the levels of diagnostic certainty definitions are designed to be broad enough to include cases presenting differently due to appropriate and early treatment initiation.1.4The case definitions are accompanied by guidelines, which are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve data comparability.1.5Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.2•Premature preterm rupture of membranes•Preterm labor•Insufficient cervix•Provider-initiated preterm birthPathways to preterm birth is a clinical syndrome characterized by any one or some combination of the following four pathways:For the purposes of presenting a case definition of pathways to preterm birth, each pathway will be considered individually and subject to all levels of diagnostic certainty.2.1•Patient is determined to be preterm as defined by the Brighton Collaboration definition•On presentation, patient is determined to not be in preterm labor, having ≤4 contractions per hour documented clinically or on tocodynometer, with <2 cm cervical dilation •Fluid can be noted to be clear, blood-tinged, meconium-tinged , purulent-tinged For all levels of diagnostic certainty:1.Clinical history of rupture of membranes AND2.Visible leakage of fluid on vaginal speculum exam AND3.Visible arborization (ferning) on microscopy of amniotic fluid OR4.Ultrasound with oligohydramnios (AFI <5 or MVP <2) AND5.a.Positive intra-amniotic dye-injection methodb.Positive result on amniotic fluid alpha-fetoprotein test kitc.Amniotic fluid pH measurement (nitrazine paper test)d.Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)e.Amniotic fluid insulin-like growth factor binding protein (IGFBP-1) test (Actim PROM test)Documented membrane rupture by a diagnostic test (one of the below options)Level 1 Diagnostic Certainty:1.Clinical history of rupture of membranes AND2.Visible leakage of fluid on vaginal speculum examination AND3.Visible arborization (ferning) on microscopy of amniotic fluid OR document membrane rupture by a diagnostic test (one of those listed above) OR4.Ultrasound with oligohydramnios (AFI <5 or MVP <2)Level 2 Diagnostic Certainty:1.Clinical history of rupture of membranes AND2.Visible leakage of presumed amniotic fluid; this may be on vaginal speculum examination (pooling in vagina), on inspection of the perineum (wet perineum due to leakage of fluid from the vagina), or fluid soaked cloth/clothes/sanitary padLevel 3 Diagnostic Certainty:2.2•Patient is determined to be have delivered preterm as defined by the Brighton Collaboration definitionFor all levels of diagnostic certainty:1.On presentation, >4 documented uterine contractions per hour as determined by a tocodynometer AND2.a.Cervical dilation 2 cm or greater at the internal os by digital examinationb.Cervical length of 1 cm or less by digital examinationc.50% or greater effacement by digital examinationDocumented change in length or dilation of cervix by physical examination or transvaginal ultrasound over a two hour period, with clinical criteria for documenting cervical change by exam including:Level 1 Diagnostic Certainty:1.Greater than 4 uterine contractions per hour as determined by a tocodynometer or clinical assessment AND2.a.Cervical dilation 2 cm or greater at the internal os by digital examinationb.Cervical length of 1 cm or less by digital examinationc.50% or greater effacement by digital examinationDocumented change in length or dilation of cervix by physical examination, with clinical criteria including:Level 2 Diagnostic Certainty:1.Greater than 4 documented uterine contractions per hour determined by clinical assessment AND2.Documented change in cervical examination (change in dilation or effacement) over a two hour periodLevel 3 Diagnostic Certainty:2.3•Patient is determined to be ≥16 weeks and <24 weeks gestation as defined by the Brighton Collaboration definitions of gestational age•Patient is determined to have advanced cervical dilation (>2 cm) resulting in either treatment with a cerclage  or preterm delivery•Patient is determined to not be in preterm labor, having ≤4 contractions per hour documented clinically or on tocodynometer For all levels of diagnostic certainty:1.Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by transvaginal ultrasound AND digital examinationLevel 1 Diagnostic Certainty:1.Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by digital examinationLevel 2 Diagnostic Certainty:1.Patient reports fetal delivery without any painful contractions2.History excludes other causes of mid-trimester deliveryLevel 3 Diagnostic Certainty:2.4•Patient is determined to be preterm as defined by the Brighton Collaboration definitionFor all levels of diagnostic certainty:1.Documentation in the healthcare record by a patient's delivering provider that there were no signs or symptoms of the spontaneous onset of preterm labor AND2.Documentation in the healthcare record by a patient's delivering provider that the patient needed to undergo induction of labor or cesarean delivery which led to the preterm deliveryLevel 1 Diagnostic Certainty:1.From recall, delivering provider confirms that there was an absence of any signs or symptoms of the spontaneous onset of preterm labor AND2.Delivering provider reports from recall that he or she decided that the patient needed to undergo induction of labor or cesarean deliveryLevel 2 Diagnostic Certainty:1.From recall, patient confirms that there was an absence of any signs or symptoms of the spontaneous onset of preterm labor AND2.Patient reports from recall that the healthcare provider indicated that she needed to undergo induction of labor or cesarean deliveryLevel 3 Diagnostic Certainty:3Pathways to Preterm Birth Working Group to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about pathways to preterm birth. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, a post-marketing surveillance or epidemiological study, or an individual report of a pathway to preterm birth having occurred. Also, as explained in more detail in the overview paper in this volume, these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation.It was the consensus of the Brighton Collaboration 3.1https://brightoncollaboration.org/public/resources/standards/guidelines.html; and data collection forms https://brightoncollaboration.org/public/resources/data-collection-forms.html.These guidelines represent a desirable standard for the collection of data on availability following immunization to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. The guidelines are not intended to guide the primary reporting of a pathway to yrs developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines. The Brighton Collaboration has developed guidelines for data collection iSource of information/reporter(1)Date of report.(2)Name and contact information of person reporting(3)Name and contact information of the investigator responsible for the subject, as applicable.(4)Relation to the patient .For all cases and/or all study participants, as appropriate, the following information should be recorded:ii1.Demographics(5)Case/study participant identifiers  or code (or in accordance with country-specific data protection laws).(6)Date of birth, age, and sex.(7)For infants: Gestational age and birth weight.For all cases and/or all study participants, as appropriate, the following information should be recorded:2.Clinical and immunization history(8)Past medical history, including hospitalizations, underlying diseases/disorders, pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma.(9)Any medication history (other than treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect. .(10)Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI)), in particular occurrence of a pathway to preterm birth as having occurred after a previous immunization.For all cases and/or all study participants, as appropriate, the following information should be recorded:Vaccinee/ControliiiDetails of the immunization(11)Date and time of immunization(s).(12)Description of vaccine(s) , diluent, and number of dose if part of a series of immunizations against the same disease).(13)The anatomical sites (including left or right side) of all immunizations .(14)Route and method of administration , other injection devices).(15)Needle length and gauge.For all cases and/or all study participants, as appropriate, the following information should be recorded:iv(16)For all cases at any level of diagnostic certainty and for reported events with insufficient evidence, the criteria fulfilled to meet the case definition should be recorded.Specifically document:(17)Clinical description of signs and symptoms of one of the pathways to preterm birth, and if there was medical confirmation of the event (i.e. patient seen by physician).(18)Date/time of onset,7(19)Concurrent signs, symptoms, and diseases.(20)•Values and units of routinely measured parameters  – in particular those indicating the severity of the event;•Method of measurement ;•Results of laboratory examinations, surgical and/or pathological findings and diagnoses if present.Measurement/testing(21)Treatment given for pathways to preterm birth, especially any antibiotics, corticosteroids, magnesium sulfate, or tocolytics, with attention to which specific drugs were given and in what dose. Mention should be made of whether a cervical cerclage was placed in the case of insufficient cervix as a pathway to preterm birth and if so, which type.(22)Outcome(23)Objective clinical evidence supporting classification of the event as “serious”.8(24)Exposures other than the immunization 24 h before and after immunization  considered potentially relevant to the reported event.The adverse eventv(25)•Biologic characteristics of the vaccine e.g. live attenuated versus inactivated component vaccines;•Biologic characteristics of the vaccine-targeted disease;•Biologic characteristics of pathways to preterm birth including patterns identified in previous trials ; and•Biologic characteristics of the vaccines .The duration of surveillance for pathways to preterm birth should be predefined based on(26)The duration of follow-up reported during the surveillance period should be predefined likewise. It should aim to continue to resolution of the event.(27)Methods of data collection should be consistent within and between study groups, if applicable.(28)Follow-up of cases should attempt to verify and complete the information collected as outlined in data collection guidelines 1–24.(29)Investigators of patients with activation of one of the pathways to preterm birth should provide guidance to reporters to optimize the quality and completeness of information provided.(30)Reports of activation of any of the four pathways to preterm birth should be collected throughout the study period regardless of the time elapsed between immunization and the adverse event. If this is not feasible due to the study design, the study periods during which safety data are being collected should be clearly defined.Miscellaneous/GeneralGuidelines numbers below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences 3.2(31)Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis.The following guidelines represent a desirable standard for analysis of data on the occurrence of any of the pathways to preterm birth  to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting.(1)Level 1: Criteria as specified in the Pathways to Preterm Birth case definition(2)Level 2: Criteria as specified in the Pathways to Preterm Birth case definition(3)Level 3: Criteria as specified in the Pathways to Preterm Birth case definitionEvent meets case definitionAdditional categories for analysis(4)Reported Pathways to Preterm Birth with insufficient evidence to meet the case definition10(5)Not a case of Pathways to Preterm BirthEvent does not meet case definition(32)The interval between immunization and reported activation of a pathway to preterm birth could be defined as the date/time of immunization to the date/time of onsetEvent classification in 5 categories9(33)The duration of a possible Pathways to Preterm Birth could be analyzed as the interval between the date/time of onset(34)If more than one measurement of a particular criterion is taken and recorded, the value corresponding to the greatest magnitude of the adverse experience could be used as the basis for analysis. Analysis may also include other characteristics like qualitative patterns of criteria defining the event.(35)The distribution of data (as numerator and denominator data) could be analyzed in predefined increments , where applicable. Increments specified above should be used. When only a small number of cases is presented, the respective values or time course can be presented individually.(36)Data on Pathways to Preterm Birth obtained from subjects receiving a vaccine should be compared with those obtained from an appropriately selected and documented control group(s) to assess background rates of hypersensitivity in non-exposed populations, and should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials.Subjects with activation of a pathway to preterm birth by interval to presentation.3.3(37)All reported events of Pathways to Preterm Birth should be presented according to the categories listed in guideline 31.(38)Data on possible Pathways to Preterm Birth events should be presented in accordance with data collection guidelines 1–24 and data analysis guidelines 31–36.(39)Terms to describe Pathways to Preterm Birth such as “low-grade”, “mild”, “moderate”, “high”, “severe” or “significant” are highly subjective, prone to wide interpretation, and should be avoided, unless clearly defined.(40)n/N) (and not only in percentages), if available.Data should be presented with numerator and denominator .(41)The incidence of cases in the study population should be presented and clearly identified as such in the text.(42)If the distribution of data is skewed, median and range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided.(43)•The study design;•The method, frequency and duration of monitoring for activation of Pathways to Preterm Birth;•The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation;•The type of surveillance (e.g. passive or active surveillance);•The characteristics of the surveillance system ;•The search strategy in surveillance databases;•Comparison group(s), if used for analysis;•The instrument of data collection ;•Whether the day of immunization was considered “day one” or “day zero” in the analysis;•Whether the date of onset•Use of this case definition for Pathways to Preterm Birth, in the abstract or methods section of a publicationAny publication of data on Pathways to Preterm Birth should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify:These guidelines represent a desirable standard for the presentation and publication of data on Pathways to Preterm Birth following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology , of Improving the quality of reports of meta-analyses of randomized controlled trials (QUORUM), and of Meta-analysis Of Observational Studies in Epidemiology (MOOSE), respectively)


This study reports on a 67-year-old woman with partial Brown-Séquard syndrome due to a recurrent cervical neurenteric cyst at C3 to C4. The myelopathic symptoms reappeared 22 years after a previous shunting operation performed posteriorly with a silicone tube connecting the intradural cervical cyst cavity to the subarachnoid space. We have now succeeded in removing the cyst nearly completely with the anterior approach. The surgical procedure consisted of right vertebral artery exposure at C3 and C4 and a subtotal corpectomy of C3 followed by microdissection of the cyst, duraplasty, and iliac strut graft fusion. Spinal cord monitoring with motor-evoked potential studies helped us safely dissect the cyst wall tightly adhering to the spinal cord. Duraplasty with Gore-Tex patch-grafting in conjunction with postoperative lumbar subarachnoid drainage worked well in preventing a spinal fluid fistula. At two years after surgery, the patient showed a nearly complete return of function without any recurrence of the cyst. Spinal neurenteric cysts (SNCs) are relatively rare congenital lesions. The cysts tend to be located ventrally to the spinal cord in the cervical and thoracic regions . SurgicaA 67-year-old woman presented with the chief complaint of numbness and clumsiness in the right hand lasting 7 months. She managed to write but not functionally and could walk unaided but with some difficulty. Physical examination revealed partial Brown-Séquard syndrome with motor deficit, which predominantly affected the right upper limb and sensory impairment by a pinprick in the left upper and lower limbs. Muscle stretch reflexes, while generally responding normally, showed a hyperactive biceps reflex and a diminished ankle jerk bilaterally. What is noteworthy about the history of this case is that she had a shunting operation for the intradural cervical cyst using a silicone tube to create a communication between the cyst cavity and the subarachnoid space with a posterior approach 22 years ago. She recovered completely after the operation, without displaying any recurrence of symptoms originating from the cervical lesion for a period of more than 20 years.MRI of the cervical spine revealed an intradural extramedullary cystic mass lesion ventrally to the spinal cord at the C3 to C4 level with the spinal cord tightly stretched out over this ventral cyst . The conFollowing preoperative general anesthesia, we inserted a lumbar spinal drain percutaneously into the subarachnoid space to prepare for continuous CSF drainage after surgery involving durotomy . The draIntraoperative spinal cord monitoring consisted of stimulating the brain transcranially with corkscrew-type needle electrodes placed into the scalp 2 cm anteriorly and 5 cm laterally to the vertex on both sides and recording motor-evoked potentials (MEPs) from the bilateral tibialis anterior and the abductor hallucis with two monopolar needle electrodes inserted intramuscularly 2–4 cm apart . A trainA transverse incision on the right side was made at the level of the hyoid bone from just across midline to the sternocleidomastoid muscle laterally. After exposure of the anterior aspect of the vertebral bodies of C2, C3, and C4 with a standard approach, bilateral longus colli muscles were elevated from the vertebral bodies laterally, and the right transverse processes of C3 and C4 were exposed. By removing the anterior tubercles of the two transverse processes with a Kerrison rongeur, the vertebral artery was unroofed anteriorly to protect the artery during dissection of the cyst located with more right-sided extension. After the C3/4 disc was incised and removed, subtotal corpectomy of C3 and resection of one-third of the rostral portion of C4 vertebral body were carried out. Under the operative microscope, all bony cortexes were removed with a high-speed diamond-tipped burr, fully exposing the posterior longitudinal ligament (PLL). The uncovertebral joint was identified laterally on both sides, and right uncovertebral joint was resected completely with great care to avoid damage to the vertebral artery. The PLL was then removed cautiously from these areas, and the dura was revealed clearly. Epidural bleeding from venous plexus was controlled by bipolar electrocautery and a hemostatic agent. The dura was expanded and thin so that we could locate the exact position of the cyst through the dura without ultrasonic confirmation . A slighLumbar subarachnoid drainage of CSF was started immediately following surgery and continued until day 5 after surgery, with the patient kept in bed resting. The drainage with an average daily drain output of 200 ml worked well in preventing spinal fluid leak through the operative wound. On day 12 after surgery, the patient was allowed to ambulate with a hard cervical collar, which was kept in place for 3 months. The patient showed a progressive recovery of the myelopathic symptoms and eventually regained normal function at the 2-year visit, when she had a solid fusion on radiographs and showed neither signs of a cyst recurrence nor a CSF fistula on MRIs .Histopathological examination of the cyst demonstrated a cystic wall lined by cuboidal to columnar epithelial cells and those cells were periodic acid-Schiff (PAS) positive, all consistent with the diagnosis of SNC. According to Wilkins and Odom's histopathological classification , this cySNCs, rare congenital lesions , may resAs reported previously , 8, 9, aAccording to previous reports, surgical intervention for SNCs has been mostly approached posteriorly with laminectomy or laminoplasty despite their ventral location to the spinal cord . In factSome procedures deserve special mention as follows: (1) More right-sided extension of the cyst required the exposure of the right vertebral artery at C3 to C4 by removing the anterior tubercles of the two transverse processes, which facilitated a safe, complete removal of the lesion. (2) Microdissection failed to completely separate the anterior wall of the cyst from the dura, resulting in partial resection of the dura inseparable from the cyst wall followed by duraplasty to restore the CSF flow and prevent intradural scarring. The duraplasty using Gore-Tex patch-grafting of the dural defect in conjunction with postoperative lumbar subarachnoid drainage helped avoid CSF leak through the operative wound, thereby preventing CSF fistula. (3) Microdissection between the posterior wall of the cyst and the spinal cord surface failed to completely dissect off the cyst wall from its bed, even under high magnification, because of the tight adhesion. We managed to remove nearly the entire cyst wall, but a very small portion was left to avoid spinal cord compromise . This crWith an anterior approach, one can directly access SNCs located ventrally to the spinal cord. Selective use of a series of anterior procedures described here, based on proper diagnosis and surgical planning, could help us safely and nearly completely remove SNCs without complications.A recurrent SNC with myelopathy presented us with the technical challenge of safely removing the lesion in its near entirety. Although previous reports mostly employed a posterior approach for the initial surgical intervention for SNCs, the anterior strategy served better for microdissection between the spinal cord and the cyst wall under MEP monitoring, as indicated in this study. Partial exposure of the right vertebral artery necessary for covering MRI evidence of more right-sided cystic extension allowed for its adequate removal. Duraplasty in conjunction with postoperative lumbar subarachnoid drainage helped prevent spinal CSF fistula.


The Oral Polio Vaccine (OPV or Sabin) is genetically unstable and may mutate to form vaccine-derived polioviruses (VDPVs).In 2014, two VDPVs type 2 were identified during routine surveillance of acute flaccid paralysis (AFP) cases. Consequently, a retrospective VDPV survey was conducted to ensure that there was no circulating VDPV in the country. All Sabin poliovirus isolates identified in Uganda 6 months before and 6 months after were re-screened; Sabin 1 and 3 polioviruses were re-screened for Sabin 2 and Sabin 2 polioviruses were re-screened for VDPVs type 2. The Poliovirus rRT-PCR ITD/VDPV 4.0 assay and sequencing were used respectively.The first two VDPVs type2 were identified in Eastern Uganda and the third was identified during the survey from South-western Uganda. These regions had low OPV coverage and poor AFP surveillance indicators.The retrospective VDPV survey was a useful strategy to screen for VDPVs more exhaustively. Supplementary surveillance methods need to be encouraged.The online version of this article (10.1186/s12985-018-0990-y) contains supplementary material, which is available to authorized users. VDPVs originate from OPV which has mutated in the gut. These mutant strains rarely cause outbreaks of paralytic poliomyelitis , 2 howevThe poliovirus evolution usually occurs in unimmunized populations with low OPV coverage . The polThere are 3 serotypes of polioviruses; poliovirus type 1 (PV1), poliovirus type 2 (PV2), and poliovirus type 3 (PV3). The mutated OPV can be classified according to the diversity of the virus capsid protein 1(VP1). Poliovirus undergoes an evolution rate of approximately 1% per year, which results in ~ 10 nucleotide differences in the 903 nt. VP1. The poliovirus ribonucleic (RNA) polymerase enzyme has an error rate of 1 per 1000 nucleotides per round of replication , 6, and The mutated polioviruses are classified as vaccine-related polioviruses (VRPVs) when there is a VP1 sequence divergence from the reference Sabin polioviruses of ≤1% for Sabin 1 and 3, and ≤ 0.6% for Sabin 2 , 11. WilVDPVs are classified into three categories; The first category are the circulating VDPVs (cVDPV) that are genetically linked and isolated from a) at least 2 individuals who may not be AFP cases but coming from different households or b) one individual and one or more environment samples or c) series of environmental samples from 2 or more sites or d) a single VDPV with documented evidence of circulation based on the genetic characteristics of the available VDPVs. The second category of VDPVs are the immune-deficiency-related VDPV (iVDPV). These are viruses isolated from persons with proven immunodeficiencies . The thicVDPVs are more transmissible and co-existence with OPV viruses may favor cVDPVs to become endemic while the OPV viruses get eliminated . Without. We report three aVDPVs type 2 that were sampled in 2014; two were detected during the routine AFP surveillance in 2014 and one was detected during a follow-up VDPV re-screening survey in 2016.From 2000 to 2015 cVDPV2 have been reported from 21 countries . These w(RD) cells and the human transgenic mouse (L20B) cell lines testing algorithm [Through the routine national AFP surveillance system, two VDPVs that were contacts to two AFP cases from Kamuli and Kween were identified. One stool sample was collected from the contacts and was delivered to the laboratory in a cold chain. The AFP case investigation questionnaire for poliomyelitis was used to obtain the demographic, clinical, immunization, and social data for the AFP cases while a contact investigation questionnaire was used for the contacts. The virus culture of stool specimens from the AFP cases and contacts were performed according to the World Health Organization (WHO) recommended rhabdomyosarcoma lgorithm .A detailed field investigation for the Kamuli and Kween contacts that were identified as VDPVs was immediately conducted by the national rapid response team in close collaboration with district rapid response team to confirm whether there was circulating VDPV or not in these districts. The contact for Kamuli AFP is referred to as VDPV number 1 (VDPV no1) and the contact for Kween AFP is referred to as VDPV number 2 (VDPV no2). In order to determine the etiological and clinical status of AFP cases and contacts, the following were performed: review of the case investigation questionnaires, interview with key persons, detailed clinical examination of the cases, a 30 house-hold clinical survey with stool sampling from the original AFP cases, and contacts to VDPV no. 1 and VDPV no. 2. Furthermore the AFP cases whose contacts had VDPVs were investigated; a visit was made to the major health facilities, traditional healers, and local health authorities. The OPV immunization coverage and AFP surveillance indicator of the affected districts were also reviewed.Stool specimens were collected from four and five contacts of VDPV no1 and no2 respectively to screen for undetected VDPVs. Two additional stool specimens were collected for poliovirus screening from the VDPV no1 and VDPV no2 within a time of 48 h’ at intervals of 28 and 15 days from the time of first virus isolation respectively. One additional stool specimen was collected from the original AFP cases. The s.. All the specimens were transported in a reverse cold chain and investigated for polioviruses in the WHO accredited polio laboratory at Uganda Virus Research Institute (UVRI). Blood specimens were also collected for immunological evaluation from the VDPV no1 and VDPV no2.A total of 93 Uganda specimens, that had Sabin isolates and were reported 6 months before and 6 months after the 2 VDPVs were retrospectively screened for VDPVs. The viruses that were primarily detected as Sabin 1 and 3 polioviruses were re-screened for the presence of Sabin 2 using a more sensitive Poliovirus rRT-PCR ITD and VDPV 4.0 assays. The viruses that were initially detected as Sabin 2 polioviruses were further characterized by sequencing to rule out the presence of VDPV2.Viral isolation was performed in accordance with the WHO recommended procedures . BrieflyThe isolates from the L20B cell line that grew on the RD cell line were further characterized using the poliovirus dual-stage rRT-PCR ITD assay . BasicalRe-screening for the Sabin 2 poliovirus among isolates collected before and after detecting the first two VDPVs was performed using the superior ITD/VDPV rRT-PCR 4.0 kit at NICD for those initially detected as Sabin 1 + 3 using the dual-stage ITD/VDPV rRT-PCR assay. The samples that had been previously detected as Sabin 2 isolates were sequenced and this was performed at NICD, South Africa.The viral RNA was extracted using the QIAmp Viral RNA manual extraction kit according to the manufacturer’s instructions .o/second to 60 °C and extension at 60 °C for 2 min).The cDNA synthesis reaction of the VP1 region was performed in a 50 μl reaction mixture as described ); Ten miA polymerase chain reaction (PCR) product of 1.1 kb was run on 1% agarose gel and the remaining product was purified using QIAquick PCR purification kit . The conCycle sequencing reaction was performed in a 10 μl reaction as follows: 1.0 μl of the DNA template was added to the sequencing mix containing 2.0 μl of Big Dye Reaction mix, 2.0 μl of 5X Sequencing Buffer, 1.0 μl of primer 3.2 picomole/μl, and 4.0 μl nuclease free water. Amplification consisted of 25 cycles . The sequenced products were purified using the BigDye Xterminator Purification kit (Thermo Fisher Scientific). The following sequencing primers were used: Y7, 246S, 247S, PV2S, PV4S (3.2 picomole/μl) for the sense orientation and Q8, PV10A, PV1A and 253A (3.2 picomole/μl) for the antisense orientation . The samIt was not possible to amplify the virus material from the standard 6 discs from all the filter papers (FTA cards) that were saturated with the inactivated virus on the first attempt. Twelve instead of 6 discs were punched from the FTA cards and resulted in good PCR signals. During the extraction process, the virus might have been exposed to a second inactivation process and could explain the low virus yield that was obtained from the 6 discs.Two contacts of two AFP cases from Kamuli and Kween districts of Uganda were both confirmed VDPV2 on 03rd November 2014. In the manuscript, the viruses are identified as VDPV no1 and VDPV no2, respectively. A third VDPV2 from an AFP case was later confirmed on 04th May 2016 from Kisoro district located in South-western Uganda in a specimen from a one month old baby. A polio suspected virus was reported on virus culture. The subsequent ITD/VDPV assays displayed a VDPV result curve that was misinterpreted and scored a Sabin 2 poliovirus and not a ‘possible’ VDPV2. As a result the VDPV2 was missed at this stage. The first two contacts were detected during the routine national AFP surveillance activity using the WHO adapted AFP surveillance protocol whereas the third VDPV was detected during the retrospective VDPV screening performed in 2016. Stored frozen isolates of 2014 were investigated. These samples were obtained from cases that were fairly well distributed over the country  and two mutations at the amino acid level (R103K and I143T). The VDPV from from Kisoro contained 7 mutations with a VP1 variation from the reference Sabin of 7.8%. It shared two mutations at the amino acid level R103K and K160E with Kamuli and Kween and K160E with Kamuli. At the nucleotide level is shared mutations at G308A, and A505G  of the specimens from the AFP cases that were re-screened for Sabin 2 and VDPV2 in the retrospective VDPV study and the 4 and 5 secondary contacts of VDPVs no1 and no2 were negative for the serotype 2 polioviruses. One specimen was collected from the original AFP cases on follow-up and also one specimen from the secondary contacts which could have compromised on virus recovery. Only one virus out of the 93 was a type 2 poliovirus that had not been detected initially. Results from poliovirus dual-stage rRT-PCR ITD/VDPV kit that was used for the index testing and the ITD rRT-PCR 4.0 kit that was used for the re-screening were concordant; previously detected Sabin 2 polioviruses were not re-run on ITD but were sequenced to screen for VDPV2s. Only one VDPV type 2 from the previously detected Sabin 2 polioviruses was identified on the second screening.The three VDPVs shared the R103K mutation that could be linked to a natural selection process. The mutation I143T was common to Kamuli and Kween and has been reported in all the polioviruses that were detected from stool specimens of AFP cases in an Afghanistan study . The nucThe wild poliovirus 2 was eradicated ahead of wild poliovirus 1 and 3. Wild Poliovirus 1 (WPV1) and Wild Poliovirus 3 (WPV3) are being eradicated later because the OPV1 and 3 are less immunogenic than OPV2 . In ordeThe third VDPV was from a baby in Kisoro district and contained mixed bases characteristic of iVDPV , 38. UnfIn the 2014–2015 VDPV rescreening, a survey was conducted in 33 district and 93 AFP cases were tested; nineteen (20.4%) were Sabin poliovirus 2, 28 (30.1%) Sabin poliovirus 1 and 46 (49.5%) were Sabin poliovirus 3. Sabin 2 was least prevalent which is not surprising because OPV2 is more immunogenic than OPV1 + 3. However what is surprising, VDPV2s are more common than VDPV1 or 3. The Sabin 2 poliovirus could be associated with sub-optimal secondary excretion or spread which result in partial secondary immunization giving a chance to the virus to evolve. Understanding more about the Sabin poliovirus 2 evolution remains an important area for investigation and could enhance the understanding of the pathogenesis of the live attenuated vaccines .The emergence of VDPVs under ideal good hygienic conditions, high IPV coverage and high population immunity has not been demonstrated  however,One additional isolate was confirmed an aVDPV during the VDPV survey. The VDPV survey enhanced VDPV detection in the country.Additional file 1:Recommendation for publication. Recommendation from the Ministry of Health. (PDF 42 kb)Additional file 2:Consent to manuscript content and creative commons public license, Approvals from the co-authors. (PDF 116 kb)Additional file 3:The Phylogeny of VDPVs from Uganda, Republic of Democratic Congo (RDC/DRC), Nigeria and Madagascar. (PDF 140 kb)


The strongest associations were for maternal secondary education, showing an increase of 0.6–0.7 z scores in height‐for‐age and weight‐for‐age at 2.5 and 8.5 years and 0.3 kg/m2 in fat and lean mass compared to no education. There was a positive association with conditional growth in the highest asset score group and secondary maternal education, and generally no association with land ownership. Our results show that SES at birth is important for the growth of children, with a greater association with fat mass. The greatest influence was maternal secondary education.Socioeconomic status (SES) is associated with childhood anthropometry, but little is known about how it is associated with tissue growth and body composition. To investigate this, we looked at components of SES at birth with growth in early and mid‐childhood, and body composition in a longitudinal study in Nepal. The exposure variables  were quantified from questionnaire data before birth. Anthropometry data at birth, 2.5 and 8.5 years, were normalized using WHO reference ranges and conditional growth calculated. Associations with child growth and body composition were explored using multiple regression analysis. Complete anthropometry data were available for 793 children. There was a positive association between SES and height‐for‐age and weight‐for‐age, and a reduction in odds of stunting and underweight for each increase in rank of SES variable. Associations tended to be significant when moving from the lower to the upper asset score, from none to secondary education, and no land to >30 dhur (~500 m CHconditional height (CH)CRWconditional relative weightHAZheight‐for‐age z‐scoreSESsocioeconomic statusWAZweight‐for‐age z‐score1Socioeconomic status (SES) is associated with nutritional status in children in low‐ and middle‐income countries  and wealth  during different periods in childhood, not only for immediate health but also for longer term health and education  and mid‐childhood (2.5–8 years), and body composition at 8.5 years.Socioeconomic components at birth determine childhood anthropometry, conditional growth, and body composition.Maternal secondary education showed the strongest association with child growth and body composition.SES associations with body mass at 8.5 years were mostly attributable to fat mass variability.22.12 and, with a population of 754,777, is the fifth most populous state in Nepal. Janakpur is the district capital and has a population of 98,446  at birth, 2.5 and 8.5 years, respectively; 9%, 59%, and 29% were stunted (height‐for‐age ≤ 2 z scores) at birth, 2.5 and 8.5 years, respectively  in purchasing power parity, ranking it 102nd in the world  and the Nepal Health Research Council (Reference 51/2011).2.3z scores for weight‐for‐age (WAZ) and height‐for‐age (HAZ), adjusted for sex. We defined stunting and underweight as HAZ and WAZ < −2 z scores, respectively. Longitudinal child growth was defined as conditional height (CH) and conditional relative weight (CRW) at two periods, 0–2.5 and 2.5–8.5 years, using the method described by Adair et al. (z scores), whereas CRW accounts for previous weight and height, and current height values . CH can be considered a marker of skeletal growth and CRW a marker of soft tissue growth. The inclusion of birth data in the 8.5‐year relative growth analysis had no effect on the model.WHO Child Growth Standards for children under five  at this age was calculated as weight (kg) divided by squared height (metres). Lean mass index (LMI) and fat mass index (FMI) were calculated as in Equation 2), and >30 dhur. Maternal education was classified as no education, primary, and secondary or higher education. Categories of SES variables are referred to in Tables 2–4 as levels 1 to 3 denoting their ascending order.Asset score, maternal education, and land ownership at birth were included as ordinal data. The two middle categories of asset score were merged due to low numbers, resulting in three levels WHO, . Land owWe investigated the association between SES and child growth using multiple regression, controlling for the antenatal trial allocation. No other confounders were included in the models as the socioeconomic variables were the most distal in our conceptual model of putative relationships. We studied the association between SES and child growth in three different ways. First, we used linear regression to assess separately the relationship between each of asset score, maternal education, and land ownership, as exposure variables, and anthropometric indices HAZ, WAZ, or body composition variables, BMI, fat mass index, and lean mass index, as outcome variables. Second, we used logistic regression to estimate the odds of stunting or underweight for each of the same exposure variables. Lastly, we used linear regression to assess the association between CH and CRW and each of the exposure variables. Statistical analysis was done in Stata .3p < .0001) and their mothers had some education (p < .0001) but were otherwise similar to those retained in the study. The mean ages at follow‐up at the three time points were 0 (<72 hr of age), 2.5, and 8.5 years. At 8.5 years of age, just over half the children were underweight and approximately one third were stunted. Figure z scores between birth and 8 years of age, respectively. Compared to HAZ, WAZ reduction was lower in this period, but infants were relatively lighter at birth. For HAZ, there appeared to be some recovery between 2.5 and 8.5 years of age, whereas WAZ showed a steady decline.Table 3.1The most consistent pattern of associations was between maternal education and HAZ, where each level increase of maternal education showed a positive increase on HAZ values at all ages. A similar but more attenuated pattern was observed for assets score, where positive and significant increases for HAZ values were observed for all levels at 2.5 years of age and only at the higher level at 8.5 years of age. Land ownership showed a less clear pattern, where only high levels of land ownership showed a positive increase on HAZ.A similar pattern of associations was observed with the odds of being stunted at different ages. Maternal education showed the most consistent protective effect against stunting at all ages. Greater assets score levels at birth were protective against stunting mainly at 2.5 years but also at 8.5 years for the higher level of assets score.Only the higher levels of all three SES proxies showed a positive increase in conditional height growth between 0 and 2.5 years of age, and only the higher levels of maternal education and assets score between 2.5–8.5 years of age.3.2Maternal education showed the most consistent association with WAZ. Each level increase of maternal education showed a significant increment of WAZ at all ages, except at birth when comparing primary education versus no education. Again, a similar pattern was seen with assets score but only the higher levels of land ownership showed a positive increase in WAZ at 2.5 and 8.5 years.For the odds of being underweight, we observed that at most ages, only the higher levels of maternal education or assets score showed a protective effect against being underweight in children. Greater levels of land ownership before birth did not show a protective effect against being underweight.The higher levels of maternal education had a significant positive association with greater conditional growth in weight on both periods, 0–2.5 and 2.5–8.5 years.3.3The SES proxies did not show a significant effect on relative leg length. Only the greater level of each SES proxy showed a positive increase in BMI values at 8.5 years. When compartmentalising that positive effect into its two components, fat and lean mass, all three SES proxies showed a significant positive increase of fat mass, but only maternal education showed a significant positive increase of lean mass.4Our results are consistent with the findings of others, namely, that the family's SES collected at birth is an important factor affecting the anthropometric status of children. Generally, all SES proxies showed a positive association with HAZ and WAZ at 2.5 and 8.5 years, with mixed results at birth. Most of the associations were in the same direction, from the poorest to the intermediary to the least poor level. However, not all SES proxies had the same pattern of associations with the different types of child growth. We observed the most consistent pattern of associations for maternal education, whereas land ownership showed the least clear pattern. We have shown that SES is associated with the growth of skeletal tissue  and of soft tissue . Furthermore, our results indicate that SES associations with body mass at 8.5 years were mostly attributable to fat mass variability, though maternal education was also associated with lean mass.Children in our sample started life, on average, underweight and a little shorter than reference children of similar age and sex (de Onis et al., Generally, SES proxies did not show a protective effect against being stunted or underweight at birth, but its protective effects were seen later in life. Interestingly, the protective effects were seen more clearly against stunting than against underweight. As expected, the most consistent pattern of associations between SES proxies and child growth and body composition was seen when moving from the lowest to the highest level of SES. Maternal secondary education appeared to have the strongest effect and was the only exposure that affected lean mass. In our results, changes in fat mass were more amenable to changes in SES.Our definition of growth was not just a change in height or weight, but a deviation from expected values. The associations were generally greater for both conditional height and weight gain in the early life period, as might be expected as socioeconomic factors before birth will wear off over time.The supporting information summarises the evidence from longitudinal studies that have investigated the association between the socioeconomic marker as in our study, and growth. Positive associations were seen between asset ownership and child growth in Ethiopia, India, Peru, Vietnam (Krishna et al., Maternal education was the strongest explanatory variable, particularly for skeletal growth in early childhood. Cross‐sectional studies across multiple countries have shown a positive association of maternal education with offspring height, or a negative association with stunting (Lakshman et al., The importance of land ownership varies by location and from family to family. The association with growth varies according to geography, climate, type of land, and the dependence on land for income or food. There is a paucity of studies examining the relationship between the distal factor of land ownership and child growth. Lourenco et al. found a positive association between land ownership and child growth; however, this was only in later child growth and not early growth (Lourenco et al., 4.1We acknowledge that SES is a complex concept to define and that there are many alternative methods (Howe et al., In summary, our findings suggest that SES at birth affects the growth of children, with maternal secondary education having the greatest positive effect. We suggest that interventions to improve SES prior to the birth of the child would help to improve growth and would be of long‐term benefit.The authors declare that they have no conflicts of interest.The study was designed by DD, DO, JCKW. Data collection was managed by DD; BPS, DSM, NS, AC provided management of the field site; DD, RMD analysed the data; DD, DK wrote the first draft. All authors were involved read and criticised drafts of the manuscript.Supplementary Table 1: Review of literature showing longitudinal studies that describe the effects of an asset‐based index of household wealth, land ownership or maternal education on child anthropometry and growthClick here for additional data file.


Despite the widely recognized association between the severity of early preterm birth (ePTB) and its related severe diseases, little is known about the potential risk factors of ePTB and the sub-population with high risk of ePTB. Moreover, motivated by a future confirmatory clinical trial to identify whether supplementing pregnant women with docosahexaenoic acid (DHA) has a different effect on the risk subgroup population or not in terms of ePTB prevalence, this study aims to identify potential risk subgroups and risk factors for ePTB, defined as babies born less than 34 weeks of gestation.N = 3,994,872) were obtained from CDC and NCHS’ 2014 Natality public data file. The sample was split into independent training and validation cohorts for model generation and model assessment, respectively. Logistic regression and CART models were used to examine potential ePTB risk predictors and their interactions, including mothers’ age, nativity, race, Hispanic origin, marital status, education, pre-pregnancy smoking status, pre-pregnancy BMI, pre-pregnancy diabetes status, pre-pregnancy hypertension status, previous preterm birth status, infertility treatment usage status, fertility enhancing drug usage status, and delivery payment source.The analysis data (Both logistic regression models with either 14 or 10 ePTB risk factors produced the same C-index (0.646) based on the training cohort. The C-index of the logistic regression model based on 10 predictors was 0.645 for the validation cohort. Both C-indexes indicated a good discrimination and acceptable model fit. The CART model identified preterm birth history and race as the most important risk factors, and revealed that the subgroup with a preterm birth history and a race designation as Black had the highest risk for ePTB. The c-index and misclassification rate were 0.579 and 0.034 for the training cohort, and 0.578 and 0.034 for the validation cohort, respectively.This study revealed 14 maternal characteristic variables that reliably identified risk for ePTB through either logistic regression model and/or a CART model. Moreover, both models efficiently identify risk subgroups for further enrichment clinical trial design. Preterm birth occurs in 9.57% of all U.S. births each year [http://www.who.int/mediacentre/factsheets/fs363/en/). Preterm birth increases the risk of many severe health outcomes. Infants born preterm are more likely to experience early death than are infants born at term [http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm) [Preterm birth, also known as premature birth, is the birth of a baby at less than 37 weeks of gestational age  . Moreoverth.htm) , 9 and wrth.htm) –12. Earlrth.htm) , 14. TheSeveral recent studies have explored the risk factors for ePTB –18. ReseBased on findings from previous studies on preterm birth and our future research interest, the specific aim for this study is to identify potential risk subgroups and risk factors for the main outcome, ePTB, defined previously as babies born prior to 34 weeks of gestation , 24. We http://www.cdc.gov/nchs/data_access/Vitalstatsonline.htmThe ePTB population data used for these analyses were obtained from the National Vital Statistics System’s 2014 Natality public data file, compiled by the Centers for Disease Control and Prevention’s (CDC) National Center for Health Statistics (NCHS). Since federal law mandates national collection and publication of births and other vital statistical data, all births occurring and registered within the U.S. in 2014 were collected directly from the 50 U.S. states, New York City, and the District of Columbia (DC) . The oveAfter excluding 3303 cases for which the gestation period from the original 2014 Natality public data file was unknown, the final analysis file for the current study included 3,994,872 records. Since the main outcome variable is ePTB, a binary flag variable representing the ePTB status  was created in the analysis file. The analysis file included selected maternal demographic characteristics considered relevant to ePTB, such as mothers’ age, mothers’ nativity, mothers’ race, mothers’ Hispanic origin, marital status, mothers’ education, delivery payment source. Delivery payment source was included as an additional covariate that may provide additional information on the implications of socioeconomic status for ePTB. Maternal pre-pregnancy characteristics and medical history were also included in the ePTB risk factor analysis. These factors included smoking status, body mass index (BMI), diabetes status, hypertension status, previous preterm birth status, infertility treatment usage status and fertility enhancing drug usage status. In total, 14 maternal variables from the database were used as risk predictors in statistical models. The father’s demographic characteristics were not considered for this study.A total of 142,851 (3.58%) observations from the analysis file contained at least one missing value for some of the predictors and those predictors were categorized as “missing.” Predictors with responses of “Unknown,” “Not Stated,” “Not Applicable,” and “Other,” were categorized together as shown in the descriptive statistics listed in Tables The large sample size allowed for independent training and validation cohorts. The overall sample was divided randomly into a training cohort (70%) and a validation cohort (30%), stratifying by ePTB status to ensure a balanced partition. Descriptive statistics were summarized to compare the demographic and pre-pregnancy information between the two cohorts of data. The training sample was used to build models via both logistic regression and CART and the validation sample was used to evaluate the models obtained from the training cohort.In order to investigate the association of ePTB with the potential risk factors, a multivariate logistic regression model was applied to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI). All predictors entered the model and they were selected via backward elimination. We set the significance level to stay in the model for a predictor to 0.05. A further simplified logistic regression model was fitted using 10 covariates to explore risk subgroups of ePTB. The predicted probabilities were calculated for the validation cohort based on the simplified model obtained from the training cohort. Based on the validation cohort, the calibration plot was generated to compare the average predicted probabilities and the average observed probabilities. The c-index was calculated to identify the model discriminatory capacity in terms of the training and validation cohorts.CART model can be a very useful complement to a logistic regression model because the CART model can identify unknown interactions among the risk factors of ePTB. CART is a nonparametric method that derives hidden patterns in data by constructing a series of binary splits on the outcome of interest –29. The p ≤ 0.05 as the statistically significant level. The CART analysis was executed in SAS Enterprise Miner Workstation 13.1 [All statistical tests were two-tailed with ion 13.1 , and allN = 2,796,411) and 30%  of the total sample were generated for each cohort, respectively. The frequencies and related percentages of each predictor were similar after the random split stratified by the ePTB status, indicating that the partition is well-balanced  and 3,860,863 cases of baby birth ≥ 34 weeks of gestation. The characteristics of the subjects stratified by ePTB status are shown in Table p = 0.169), 30-34 years, and ≥ 35 years, respectively. Mothers born outside of the U.S. were less likely to experience ePTB compared to mothers born in the U.S. with an adjusted OR (95% CI) of 0.880 . Black mothers and American Indian/Alaskan Native/Asian or Pacific Islander mothers were more likely to have an ePTB compared to White mothers with adjusted OR (95% CI) of 1.773  and 1.096 , respectively. Mothers of Hispanic origin had a slightly higher ePTB prevalence compared to mothers of non-Hispanic origin with an adjusted OR (95% CI) of 1.033 . ePTB was more likely to occur in the unmarried mother population compared to married mothers with an adjusted OR (95% CI) of 1.326 .Table p = 0.873). In addition, since all the observations with missing predictors were all from the same subset, for the following parameters after mothers’ education, missing observations were automatically excluded from the analysis, and the corresponding parameters were automatically set to 0 due to they are from the same subset.Mothers with an associate degree or some college credit and mothers with a bachelor’s degree or higher education were less likely to experience ePTB compared to mothers with a high school/general educational development (GED) or less education. The corresponding adjusted OR (95% CI) for each subgroup was 0.842  and 0.713 , respectively. Results from the subgroup with missing mother’s education were non-significant (p = 0.047), with an adjusted OR (95% CI) of 0.983  compared to mothers with underweight and/or normal BMI. However, the opposite result was obtained for the obese subgroup with an adjusted OR (95% CI) of 1.127 , compared with the underweight and/or normal BMI mothers. For other pre-pregnancy risk factors , mothers in each risk sub-category were more likely to have a higher prevalence of ePTB compared to mothers who did not have the abovementioned risk factors. The corresponding adjusted OR (95% CI) were 1.183 , 1.776 , 1.984 , 3.004 , respectively.Some maternal pre-pregnancy characteristics and medical history factors were also found to be related to ePTB. For Pre-pregnancy BMI, mothers in the overweight subgroup had a slightly lower prevalence of ePTB , the numerical differences were small.In addition, mothers who used infertility treatment were much more likely to experience ePTB than those who had not used the infertility treatment, with an adjusted OR (95% CI) of 5.103 . On the other hand, a different outcome was observed with the usage of fertility enhancing drug. Mothers who used fertility enhancing drugs were less likely to have an ePTB compared to women who did not, with an adjusted OR (95% CI) of 0.820 . Compared to women whose payer was Medicaid, the adjusted OR (95% CI) were 0.965  and 1.079  for women who had private insurance and self-pay, respectively. Mothers with private insurance had a slightly lower prevalence of ePTB; whereas mothers with self-paid delivery had a slightly higher prevalence of ePTB. Although the After examining results from the 14-predictor model, four covariates - mothers’ nativity, mothers’ Hispanic origin, fertility enhancing drug usage status, and delivery payment source - were excluded for having minimal effects on ePTB and to explore further a smaller set of potential risk subgroups for ePTB. Moreover, the same C-index (0.646) was obtained from both logistic regression models with either 14 or 10 predictors based on the training cohort , the average predicted and observed probabilities were 1.92% and 1.83% respectively, with a range of 0.55% for the predicted probability. A typical mother from this potential subgroup was between 30-34 years old, with a designation as white, married, with a bachelor’s degree or higher education level, non-smoking, underweight to normal weight (BMI ≤24.9) before pregnancy, without notable pre-pregnancy risk factors , and without infertility treatment. The second subgroup  had an average predicted and an average observed probability of 2.46% and 2.33% respectively, with a range of 0.52% for the predicted probability. Mothers from the second potential subgroup shared very similar characteristics with a typical mother from the first subgroup, with the exception of age  and slightly lower education level (associate degree or some college credit). The average and range of predicted probability for the third subgroup  were 3.22% and 0.95%; and the observed probability was 3.24%. Similar to trends observed from the second subgroup (in comparison with the first subgroup), a typical mother from the third subgroup was younger (≤ 24 years old) and with less education (≤ high school or GED/unknown). Lastly, the average predicted and observed probabilities for the highest risk subgroup  were 6.02% and 6.07% respectively, with the predicted probability range of 60.6%. Mothers in this high-risk subgroup exhibit much different characteristics from the other three subgroups. They tended to be younger (≤ 24 years old), Black, unmarried, with a high school/GED or less education level, and generally obese (≥ 30.0 BMI). Moreover, compared to the other three subgroups, a relatively higher percentage of mothers in this high-risk subgroup had pre-pregnancy diabetes, hypertension, previous preterm birth, and infertility treatment usage.For the CART model, sub-categories were collapsed for a couple of risk factors. The missing subgroup of previous preterm birth status was combined with the “no” group; and the race category of American Indian/Alaskan Native/Asian or Pacific Islander was combined with the White group. Based on a pre-specified stopping rule of having the terminal node size no less than 0.5% of the total sample and the binary Gini splitting rule, the CART tree was created to explore the unknown interactions among the risk factors and identify potential risk subgroups Fig. . Overalln =16,750), indicating a higher risk of ePTB for Black mothers with a preterm birth history. The correspondent percentage of this subgroup from the validation cohort is 15.02% . This subgroup totally accounted for 0.60% of the overall 2014 U.S. births. 8.96% and 8.70% of mothers with a preterm birth history and a race designation as White had an ePTB experience from training  and validation , and the subgroup birth prevalence (SBP) was 2.07%. Women without a preterm birth history who were Black had an ePTB experience of 5.37% ; while 2.75% of mothers without a preterm birth history who were White had an ePTB experience . The correspondent rates for the identical subgroups from the validation cohort are 5.35%  and 2.76% . These two subgroups accounted for 15.44% and 81.89% of the overall birth data, respectively.From training cohort, 14.41% of mothers with a preterm birth history and a race designation as Black had an ePTB experience . Three subgroups  had an increased probability of ePTB compared to the subgroup without a preterm birth history who were White.This large sampled pioneer study aimed to explore potential risk factors and their interactions, and identify subgroup for the ePTB population via both logistic regression model and the CART model. Several important findings emerged from the current study. First, a subset of the most important and relevant covariates have been identified among the 14 risk factors examined, such as race, diabetes history, hypertension history, preterm birth history, and infertility treatment usage. Second, although logistic regression model identified a set of 10 predictors for the prevalence of ePTB, the CART model was able to examine multiple and complicated interactions among the selected predictors. The CART model clearly identified that the subgroup with a preterm birth history and a race designation as Black had the highest risk for ePTB. Third, although not presented in the current work, the risk ratios (RR) of a particular subgroup from the CART terminal nodes can be calculated to compare with the RR of other subgroups via the observed probabilities. RR also indirectly can inform the risk factors for ePTB.Previous preterm birth status and race were the most discriminating predictors for ePTB by the CART model, while another eight predictors were identified by the logistic regression analyses. As a well-known traditional statistical approach, logistic regression provided predicted probabilities based on the important demographics and characteristics for ePTB; however, it cannot identify complicated interactions among risk factors. On the other hand, the CART model presents a more straightforward picture of the potential high risk subgroups for ePTB for whom targeted prevention efforts can be implemented. Moreover, each subgroup accounted for a different percent of the overall simple size. Thus the difference in ePTB prevalence among the four subgroups identified by the CART model was much larger than that identified by the logistic regression model. Coupling both statistical approaches provides more efficiency for analyzing the overall objective of this study. It also further exemplifies the statistical analysis for similar studies.Additionally, from a long-term perspective, this pioneering study provides valuable information and direction for our further targeted subgroup enrichment clinical trials aiming at decreasing the prevalence of ePTB among the interactive risk subgroups via supplement pregnant women with DHA.There are some limitations with this study. Some risk factors contained missing values and/or values of “Not Applicable”, “Unknown,” and “Not Stated,” which added complexity to the proposed analyses. However, data management is unavoidable for any concrete project, and we face the same issue for such a large database regarding birth data for the whole country. The solution taken was from an objective and general perspective, which could deduce the reasonable and acceptable results. Additionally, the risk predictors explored in this paper mainly from mothers’ demographics factors and Maternal pre-pregnancy characteristics, and it does include more highly specific biomarkers. This is due to no such predictors collected in the analysis database. Potentially, this limitation may lead to the relatively low c-index for both models. Further application and reference for these two models should be precautioned.This study revealed 14 maternal characteristic variables that can be used reliably to identify risk factor subgroups for ePTB either through a logistic regression model and/or a CART model. Moreover, both models may be used efficiently to identify high risk subgroups for further enrichment clinical trial design.


Performance on visiting rotations during the senior year of medical school is consistently cited by residency program directors as a critical factor in selecting residents. Nevertheless, the frequency with which visiting rotations are undertaken and the associated financial costs they impose have not been systematically examined.Under the auspices of the Electronic Residency Application Service, a survey was sent in March 2015 to all U.S. applicants for residency programs in the 2014-15 academic year. Students were asked how many visiting rotations they performed; the estimated cost of performing each rotation; their perception of their educational value and primary motivation for performing them; and the Match outcome of their residency application.The survey was completed by 2817 applicants, yielding a response rate of 11.3 %. 1898 applicants (67.4 %) performed visiting rotations: 647 applicants (30.0 %) performed one; 640 (22.7 %) performed two; 322 (11.4 %) performed three; and 289 (10.3 %) reported four or more. When accounting for potential response bias, the true prevalence of away rotators was estimated to be 58.7 % of all fourth-year medical students (95 % CI 54.0–63.4 %). The mean number of rotations for participating students was 2.1. Most students performed rotations equally as an audition for residency placement and for education, with some of the more competitive subspecialties reporting more of an audition experience. The mean estimated cost for performing a single rotation was $958. Thirty-six percent of applicants reported matching at an institution where they had rotated, either their home institution or one at which a visiting rotation was performed.Visiting rotations are prevalent, expensive, and only partly educational. As such, these rotations may impede optimal use of the senior year of medical school and limited student financial resources. We haveThere is, of course, a good reason for the popularity of visiting rotations among students: namely, the popularity of visiting rotations among program directors who select residents. Surveys of program directors –9 demonsDespite the apparent increasing importance of visiting rotations in residency placement, we have found no reports of the overall prevalence of these visiting rotations; and while there have been reports on their purported benefits , we haveUnder the auspices of the Electronic Residency Application Service  an anonymous web-based survey was sent in March 2015 to all U.S. applicants for allopathic residency programs in the 2014-15 academic year. This survey asked students how many visiting rotations they performed; the estimated dollar cost of performing each visiting rotation; their perception of the educational value of these rotations; and the match outcome of their residency application.P = 0.05. Statistical analysis was performed using Microsoft Excel .Pearson’s chi-square test was used to examine the goodness-of-fit of the distribution of respondents disclosing their primary specialty in which they applied and the actual distribution of applicants within each specialty nationally, as gathered by the National Resident Matching Program® . SignifiTo evaluate potential non-response bias, we distributed a second survey 2 weeks later to those students who did not originally respond asking how many visiting rotations they performed. Using a variable response propensity model  to correThe survey was completed by 2817 applicants, yielding a response rate of 11.3 % , indicating that our sample was not overly influenced by any particular specialty. Visiting electives were most prevalent among neurological surgery and plastic surgery applicants, with 100 % of survey respondents performing one or more visiting rotations. Over 90 % of emergency medicine, orthopaedic surgery, and otolaryngology applicants each performed at least one visiting rotation. Visiting rotations were least prevalent among internal medicine (43.5 %), psychiatry (47.7 %), and diagnostic radiology (48.3 %) applicants.There were 1540 respondents (54.7 %) who reported the specialty in which they primarily applied  were deemed by respondents to have value for both learning and job hunting Table . Very feOverall, among all survey respondents, 36 % of applicants reported matching at an institution at which they had been seen previously, either their home institution or one at which a visiting rotation was performed Table . OrthopaWhen examining only those survey respondents performing visiting rotations, 42 % matched at an institution where they rotated, either their home institution or at an institution where a visiting rotation was performed. Within the specialties, psychiatry applicants who performed at least one visiting rotation matched most frequently at an institution where they had been seen previously (58 %), which was closely followed by orthopaedic surgery (57 %), radiation oncology (55 %), and family medicine (54 %) applicants. The specialties matching least frequently at an institution where they had been seen previously were general surgery (28 %) and neurology (28 %).The mean estimated dollar cost for performing a single visiting rotation was $958. As expected for specialties in which higher numbers of visiting rotations were performed, neurological surgery applicants reported the highest mean total expenses for visiting rotations performed Fig. ; $3,465,Visiting rotations are prevalent, with a corrected rate of 58.7 % of survey respondents reporting performing one or more. The high prevalence of visiting rotations may be a good thing. To start, students can learn, reconnoiter and audition. Further, by visiting, applicants can demonstrate their sincere interest in the visited institution. Visiting rotations also may allow the host institution to examine what might be termed the applicants’ “affective strengths and weakness” — elements of their personality, such as extraversion, agreeableness, openness, conscientiousness and absence of neuroticism . These fSimilarly, by noting the applicant’s decision to visit, the institution may reasonably (and more accurately) infer interest in the program., Asking residents about their commitment is of course forbidden. As noted by the AAMC , “It is Despite the benefits of visiting rotations, there are problems to consider. For one thing, these rotations have a high dollar cost. In addition, visiting rotations have a high opportunity cost , 19, 20 It is likely that in some fields applicants may view the visiting rotation as a de facto requirement: as noted, in competitive specialties such as plastic surgery, neurological surgery, orthopaedic surgery, emergency medicine, and otolaryngology, nearly all applicants performed visiting rotations, and in those fields there was a greater tendency to report the visiting rotation experience as having a greater audition component. At competitive programs, selection committees may believe that only those students who have been seen –either as part of a visiting rotation or as a home institution course—are eligible for further consideration.Performing the mean number of visiting rotations can be expensive. Whereas the average applicant spent approximately $2,000 on visiting rotations, many applicants spent in excess of $5,000 and $10,000 on these visiting rotations. Moreover, this estimate does not include costs the home institution may impose, to say nothing of the costs, financial and other, that are incurred attempting to arrange rotations that are not ultimately undertaken.We acknowledge limitations to our study. While the number of respondents was large and well distributed, there very well may be selection bias, in which those students who performed a visiting rotation would be more likely to participate. In an effort to mitigate such non-response bias, and to estimate the true prevalence of away rotations among fourth-year medical students, we distributed a second survey to those students who did not response the first time. As expected, this cohort of respondents performed fewer visiting rotations than the original respondents. Using a variable response propensity model, we deduced that the proportion of all students that performed zero visiting rotations, including early respondents, late respondents, and non-respondents, was 41.3 % (95 % CI 36.6–46.0 %), indicating that the true proportion of all fourth-year medical students performing a visiting rotation was 58.7 % (95 % CI 54.0–63.4 %). With a slightly higher percentage of students reporting performing visiting rotations, the first survey responses were slightly biased toward students performing visiting rotations.Also, because no demographic information was collected, we cannot be sure that the sample we have reflects the student population at large. It would have been more informative to collect information on the geographic region of the students’ schools; the size and organization (public vs private) of the medical school; and the presence or absence of a residency program in the desired field at the individual respondent’s school. It also would have been more informative to collect information on the duration of the rotation, as clearly a 4 week rotation imposes a larger opportunity cost  than one only 2 weeks in length.The rating system we used for the educational/audition value of the rotation probably suffers from a central tendency bias: namely, the predisposition of many respondents, in general, to avoid the extremes of the rating scale and thereby (incorrectly) favor scores near the midpoint. Even with that potential limitation, comparisons within specialties may be interesting nonetheless, as the bias would apply equally to all. It must be noted, further, that contrasting the educational versus audition value of the rotation is not the only dimension on which fair comparisons may be made. For example, rotations may be taken to compensate for a deficiency of the home institutions’ offerings, and limiting the analysis to this single vector may omit some salient costs and benefits.Last, the cost estimates are just that: estimates. It is certainly possible that individual respondents may have distinct ideas as to what “counts” as a rotation-related expense. For instance, a student may consider only those food costs above and beyond that which would have been spent at home  whereas some may have considered the entire food expense.More than that, these estimates are given many months after the fact, a feature that introduces a bias  owing to the reliance on memory.Despite these limitations, this study may help inform a needed discussion. Currently, only about 10 % of applicants perform 4 or more visiting rotations. Nonetheless, it is easy to imagine a burgeoning “arms race”  in whichVisiting rotations are prevalent, expensive, and only partly educational. As such, these rotations may impede optimal use of the senior year of medical school and limited student financial resources.