However, there has not been any account taken of pregnancy terminations and birth defects on these trends. The current study sought to quantify these relationships using linked Western Australian administrative data for the years 1986–2010.The stillbirth rate in most high income countries reduced in the early part of the 20We analysed a retrospective, population-based cohort of Western Australia births from 1986 to 2010, with de-identified linked data from core population health datasets.p < .01), while the overall stillbirth rate remained static. The stillbirth trend was driven by deaths in the extremely preterm period , masking significant decreases in the rate of stillbirth at very preterm (28–31 weeks), moderate to late preterm (32–36 weeks), and term (37+ weeks). For singletons, birth defects made up an increasing proportion of stillbirths and decreasing proportion of neonatal deaths over the study period—a shift that appears to have been largely driven by the increase in late pregnancy terminations (20 weeks or more gestation). After accounting for pregnancy terminations, we observed a significant downward trend in stillbirth and neonatal death rates at every gestational age.The study revealed a significant decrease in the neonatal death rate from 1986 to 2010 (6.1 to 2.1 neonatal deaths per 1000 births; Changes in clinical practice related to pregnancy terminations have played a substantial role in shaping stillbirth and neonatal death rates in Western Australia over the 2½ decades to 2010. The study underscores the need to disaggregate perinatal mortality data in order to support a fuller consideration of the influence of pregnancy terminations and birth defects when assessing change over time in the rates of stillbirth and neonatal death. The ava century –4. Analy century . A subse century . In cont century , buildin century , 3. The  century .Better quality data can disaggregate to enable a more nuanced picture of mortality trends and reasons for change. Since the middle of last century, stillbirths and neonatal deaths have typically been reported together as perinatal deaths ,10. MoreWhen assessing the change over time in the stillbirth and neonatal death rates for high-income countries it is important to consider the influence of terminations of pregnancy. This is because legislative changes and a higher coverage of prenatal ultrasound screening have led to increases in the number of terminations performed in many jurisdictions in recent decades –13. In WAnother important issue to consider is the elevated stillbirth ,17 and nThe purpose of the current study was to use linked Western Australian administrative data for the years 1986–2010 to investigate whether the overall stillbirth and neonatal death rates follow the trends observed in other high-income jurisdictions, to explore differences between singleton and multiple births, and to assess the influence of pregnancy terminations and birth defects on these trends.This retrospective cohort study included all births with a gestational age of 20 weeks or more in Western Australia between 1986 and 2010, inclusive. Study data were primarily sourced from core population health datasets held by the Data Linkage Branch of the Western Australian Government Department of Health (DLB)—including the Midwives’ Notification System (MNS), Western Australian Register of Developmental Anomalies (WARDA), and the Birth Registration and Death Registration datasets . Information on birth outcomes  was sourced from the MNS and Births Registration datasets . The MNSThese data were linked together by the DLB by probabilistic linkage using common identifiers including name, address and the birthdate of the baby . MultiplIn Australia, the accepted definition of stillbirth is a birth of a baby showing no signs of life, of at least 400 g birthweight or at least 20 weeks gestation. This is generally operationalised in epidemiological studies as 20 weeks or more and accords with the limits of the available data—this range (≥20 weeks) has been applied here (we did not have access to records of stillbirths of less than 20 weeks gestation of 400 g or more birthweight). Stillbirths were identified using the birth status variable on both the MNS and Death Registration datasets, with the small number of discrepancies (26 cases) resolved via consideration of other indicators of the circumstances of birth from these datasets and information on the cause of death. The birth status on the MNS was given priority in ambiguous cases. In Western Australia, terminations of pregnancy are included as stillbirths if they occur at 20 weeks or more gestation.Neonatal deaths (death in the first 28 days of life) were identified using the information available in the Death Registration dataset in combination with the date of birth data from the MNS. The day of birth was nominated as day zero and in-scope neonatal deaths were identified as all non-stillbirth deaths with ages of 27 days or less.Information on pregnancy terminations at 20 weeks or more gestation was obtained from the WARDA and the cause of death text field on the Death Registration record. In Western Australia, all termination procedures are notifiable under the Health Act 1911. While no upper gestational age limit is specified in the legislation, the vast majority of terminations are conducted prior to 20 weeks . Late teThe WARDA was used to identify children with birth defects, and codes cases according to the British Paediatric Association extension of the International Classification of Diseases Version 9. Only those with a diagnosis code that reflected a ‘major’ birth defect were classified as having a birth defect for the purposes of this study—this includes cases that require treatment and/or result in disability or loss of function. A full list of birth defects diagnosis codes is available on the WARDA website .Consistent with World Health Organization guidelines , extremeβs) are reported). Univariable logistic regression was used to assess the relative odds of a stillbirth and neonatal death between groups with and without birth defects (odds ratios reported). The two sampled t-test was used to assess whether average annual mortality rates were significantly different across population groups (t statistic reported). Results with p < .05 are regarded as statistically significant.The stillbirth rate for each gestational age range was calculated as the number of stillbirths divided by the number of births in that particular gestational age range multiplied by one thousand. The neonatal death rate for each gestational age range was calculated as the number of neonatal deaths divided by the number of livebirths in that particular gestational age range multiplied by one thousand. Trends over time were analysed using linear regression, with the t-statistic used to assess statistical significance  with a gestational age of 20 weeks or more, including 4707 stillbirths (7.2 stillbirths per 1000 births) and 2076 neonatal deaths . Of these there were 652,381 births that had gestations of 28 weeks or more of which 2234 were stillbirths (3.4 stillbirths per 1000 births) and 1117 neonatal deaths . Thus, over half of all recorded stillbirths and nearly half of all neonatal deaths occurred among the 0.8 % of births (5159) that occurred between 20 and 27 weeks gestation. The mortality rates were highest at this gestation, including stillbirths and neonatal deaths .β = −0.08, p = .71). In contrast, the stillbirth rate for all births of 28 weeks or more gestation  and the neonatal death rates for all births of 20 weeks or more  and 28 weeks or more  gestation all significantly decreased over time .Figure t = 16.1, p < .01) than that for singleton births (6.7 per 1000 births). Similarly, the average annual neonatal death rate for multiple births (21.8 per 1000 livebirths) was significantly higher  than that for singleton births (2.7 per 1000 livebirths). Consistent with findings from other high-income jurisdictions, multiple pregnancy and twin pregnancy rates have significantly increased with time  with both appearing to peak in 2001  while the higher-order pregnancy rate has significantly decreased over time  with a maximum of 0.1 % in the year 1989 and a minimum of 0.01 % in 2010.Multiple births accounted for almost 3 %  of all births of 20 weeks or more gestation, although comprised 9 % of stillbirths (or 443) and 19 % of neonatal deaths (or 389). There were 9157 pairs of twins, 235 sets of triplets and 14 sets of higher-order births. The average annual stillbirth rate for multiple births (23.6 per 1000 births) was significantly higher . In contrast, the stillbirth rate for multiple births of 20 weeks or more gestation  and the neonatal death rates for singleton births  and multiple births  of 20 weeks or more gestation all significantly decreased over time .As with the stillbirth rate for all births of 20 weeks or more gestation, the stillbirth rate for singleton births of 20 weeks or more gestation did not significantly decrease between 1986 and 2010  and the proportion of births at moderate to late preterm  and extremely preterm  significantly increasing across time  (the proportion of very preterm singleton births did not change significantly). For singleton births, the distribution of stillbirths and neonatal deaths by gestational age has also shifted quite markedly over this period. The proportion of stillbirths associated with extreme prematurity  increased significantly  across time whereas the proportion of stillbirths associated with very preterm (28–31 weeks) , moderate to late preterm (32–36 weeks) , and term births (37+ weeks)  have all significantly decreased across time. The proportion of neonatal deaths associated with extreme prematurity also increased significantly . However, the proportion of neonatal deaths associated with very preterm , moderate to late preterm , and term births  did not significantly change across time  significantly decreasing  whereas the stillbirth rate for very preterm , moderate to late preterm , and term births  have all significantly decreased over time  over time across all these gestational age groups . There were no pregnancy terminations involving triplet, quadruplet or quintuplet pregnancies with 29 involving twin pregnancies (1.6 pregnancy terminations per 1000 births) and 767 involving singleton pregnancies (1.2 pregnancy terminations per 1000 births).β = 0.88, p < .01). The proportion of stillbirths that were terminations of pregnancy also significantly increased  across time.There has been an almost 4-fold increase in the pregnancy termination rate for singleton pregnancies of 20 weeks or more gestation between 1986 and 2010 , with about a quarter of births at this gestational age being terminations. The slight decrease in the rates at very preterm and at moderate to late preterm were not significant .As expected, the vast majority of pregnancy terminations of post-19 week singleton pregnancies occurred at 20–27 weeks gestation (709 of 767). Smaller numbers were recorded at 28–31 weeks (42), and 32–36 weeks (16), with none at 37 weeks or more gestation. As can be seen in Fig. β = −0.87, p < .01) over time  with the decrease in the neonatal death rate with the variation in the former explaining 36 % of the variation in the latter.Indeed, when pregnancy terminations are excluded, the stillbirth rate for extremely preterm singleton births significantly decreases  across time.Across the 1986–2010 period, there were 36,490 births  of 20 weeks or more gestation reported to have had a birth defect(s). Of these 30,122 (82.5 %) were reported as having a major birth defect(s)  which are the focus of the following analyses. There were no reports of a major birth defect(s) involving quadruplet or quintuplet pregnancies with 52 involving triplet pregnancies (73.8 cases per 1000 births), 1079 involving twin pregnancies (58.9 cases per 1000 births) and 28,991 involving singleton pregnancies (45.4 cases per 1000 births). The proportion of singleton, twin and triplet births with major birth defects has not changed significantly  and a 1377 % increased risk of neonatal death (p < .01). However, the stillbirth rate for singleton babies with a major birth defect(s) has increased  across time whereas the stillbirth rate for singleton babies without a major birth defect(s) and the neonatal death rate for singleton babies with as well as those without a major birth defect(s) have all significantly decreased  across time  was 42.3 per 1000 births and for twins with a major birth defect(s) it was 39.8 per 1000 births (none of the 52 triplets with major birth defect(s) was stillborn). The neonatal death rate for singleton babies with a major birth defect(s) was 24.7 per 1000 livebirths, for twins with a major birth defect(s) it was 57.9 per 1000 livebirths, and for triplets with a major birth defect(s) it was 19.2 per 1000 livebirths. Compared to singleton babies without a major birth defect(s), singleton babies with a major birth defect(s) had a 781 % increased risk of stillbirth  over time while the proportion of neonatal deaths involving major birth defects has significantly decreased  over time. Indeed the two are significantly negatively correlated  with the variation in the proportion of stillbirths involving major birth defects explaining 50 % of the variation in the proportion of neonatal deaths involving major birth defects.However, for singleton pregnancies of 20 weeks or more gestation, the proportion of stillbirths involving major birth defects has significantly increased  over time and this increase is significantly positively correlated  with the increase in the proportion of stillbirths involving major birth defects (R2 = 0.80). Thus the shift in perinatal deaths involving major birth defects from the neonatal period to the pregnancy/birth period (stillbirths) appears to have been largely driven by the increase in terminations of pregnancy. Indeed, when pregnancy terminations are excluded, the proportion of stillbirths involving major birth defects shows a significant decrease over time . Of the terminations of singleton pregnancies (of 20 weeks or more gestation) with major birth defect(s), 92.5 % (701) occurred in the extremely preterm period, 5.5 % (42) occurred in the very preterm period, and 2.0 % (15) occurred in the moderate to late preterm period.These findings suggest that a significant proportion of perinatal deaths involving major birth defects have shifted from the neonatal period to the pregnancy/birth period (stillbirths) between 1986 and 2010. Indeed, the proportion of singleton pregnancies (of 20 weeks or more gestation) with major birth defects that were pregnancy terminations has significantly increased (p < .01) and a 249 % increased risk of neonatal death (p < .01). The stillbirth rate for twins with major birth defect(s) has not significantly changed  across time whereas the stillbirth rate for twins without major birth defect(s) and the neonatal death rate for twins with as well as those without major birth defect(s) have all significantly decreased  across time. However, for twins, the proportion of stillbirths involving major birth defects has not significantly changed over time  nor has the proportion of neonatal deaths involving major birth defects .Across the 1986–2010 period, when compared with twins without major birth defect(s), twins with major birth defect(s) had a 97 % increased risk of stillbirth  for pregnancies that ended in birth at or after 28 weeks gestation, but no discernible change in the rate at 20–27 weeks gestation. In contrast, there has been a consistent decline in neonatal mortality over this period. We suggest that part of the decrease in risk of stillbirth at later gestations and neonatal death is due to a shift in mortality to earlier gestational periods.These trends are broadly consistent with those reported in other high-income jurisdictions –7, althoThere has been a significant increase in the rate of late pregnancy terminations (post-19 weeks gestation) in Western Australia—particularly from the mid-1990s—and this was primarily driven by terminations at 20–27 weeks gestation. Very few studies have investigated the contribution of pregnancy terminations to the stillbirth rate. Our evidence is consistent with the findings of a previous study in Northern England, and indicates that terminations of pregnancy account for an increasing proportion of stillbirths across time . This reIdentifying babies with and without a major birth defect(s) has provided a greater understanding of the reasons for the shift in the composition of perinatal mortality over time in Western Australia. The study has linked routine information on birth and death circumstances to a robust register of developmental anomalies, and highlighted that not only do singleton babies with a major birth defect(s) have a profoundly greater chance of being stillborn (than those without a birth defect) but that the risk has increased over time. This trend is in stark contrast to the stillbirth rate for singleton babies without a major birth defect(s) and the neonatal death rate for singleton babies with and without major birth defect(s)—which have all significantly decreased. Indeed, the variation (increase) in the proportion of stillbirths involving major birth defects explained 50 % of the variation (decrease) in the proportion of neonatal deaths involving major birth defects.While not empirically conclusive from our data, the study findings suggest that changes in clinical practice related to pregnancy terminations has played a substantial role in shaping stillbirth and neonatal death rates over time. Some of the decrease in risk of neonatal death and stillbirth risk for births at or after 28 weeks gestation across the study period is likely the result of a shift in mortality to earlier gestational periods. This shift appears to have been largely driven by an increase in the termination of pregnancies (at 20–27 weeks) with a diagnosed major fetal abnormality. It is important to note that the scope of the current study is, to a degree, limited by available data. The MNS excludes information on births that occurred before 20 weeks gestation, which is the period when the vast majority of terminations are performed ,31. It iThe study confirms that the proportion of multiple pregnancies increased through the 1980s and 1990s (appearing to peak in 2001), as has the likelihood of these babies surviving the perinatal period—these findings are broadly consistent with trends in other high-income jurisdictions . The treThe present study underlines the importance of disaggregating mortality data by stage and age of death and plurality. This enables a much more nuanced picture of the trends in mortality and helps identify trends that can be masked by a headline perinatal death rate figure. Despite the difficulties in accurately measuring gestational age , the curUp to two-thirds of stillbirths in high-income countries continue to be classified as unexplained –35. In WThe trends observed in Western Australian stillbirth and neonatal death rates over the years 1986–2010 in the current study are broadly consistent with those observed in other high-income jurisdictions. The stillbirth and neonatal death rates for all births of 28 weeks or more gestation and the neonatal death rate for all births of 20 weeks or more gestation all significantly decreased while the stillbirth rate for babies of 20 weeks or more gestation did not change significantly. Over half of all recorded stillbirths and nearly half of all neonatal deaths occurred among the 0.8 % of births that occurred between 20 and 27 weeks gestation. For singletons, the proportion of stillbirths involving major birth defects has significantly increased over time while the proportion of neonatal deaths involving major birth defects has significantly decreased with the results indicating that this shift appears to have been largely driven by the increase in pregnancy terminations at 20 weeks or more gestation. Our results highlight the importance of disaggregating perinatal mortality data to support a fuller consideration of the influence of pregnancy terminations and birth defects when assessing change over time in stillbirth and neonatal death rates.This research was granted ethics approval by the Western Australian Department of Health Human Research Ethics Committee (#2011/64) and the Western Australian Aboriginal Health Ethics Committee (#613). These ethical approvals support a waiver of consent on the basis that the study: (1) utilises routinely collected information from existing administrative datasets ; and (2) only has access to de-identified data, which are stored, analysed and disseminated according to strict protocols.Not applicable.The authors do not have permission to share the data used in this project, which were provided by the Data Linkage Branch of the Western Australian Government Department of Health under strict conditions.


The developmental origins of health and disease theory purports that early life factors determine long-term risks of death and disease. Historical studies, prospective birth cohorts such the UK ALSPAC birth cohort , and morIn contrast to the above ‘rapid growth tempo’ trajectory to later disease, poor childhood growth is also a risk factor for later health and survival. This ‘early childhood stunting’ trajectory is seen in older UK birth cohorts, such as the 1946 British Birth Cohort Study [


Metabolic acidosis is often encountered in a sick neonate and intestinal duplication with heterotopic gastric mucosa is a well-established condition. We present a previously unreported relationship between neonatal metabolic acidosis, resulting from transperitoneal absorption of hydrochloric acid, and a ruptured non- communicating ileal duplication cyst with gastric mucosal heterotopia. The neonate recovered rapidly after resection of the ileal duplication. We present this case to highlight a rare but surgically correctable cause of neonatal metabolic acidosis.  Causes of metabolic acidosis in the neonatal period include birth asphyxia, sepsis, cold stress, dehydration, congenital heart diseases , renal disorders  and inborn errors of metabolism. Necrotizing enterocolitis, bowel perforation and gangrene are some common surgical causes of neonatal metabolic acidosis.Intestinal duplications are uncommon congenital lesions that can occur anywhere from the mouth to the anus with an incidence of 1 in 4,500 autopsies [1]. The small bowel, particularly ileum (30% -50%) is the most common site of duplication cysts [2]. The clinical presentation is varied and includes obstructive symptoms (caused by mass effect) in a non- communicating duplication cyst or peptic erosion with gastro-intestinal bleed in a communicating duplication. A ruptured non-communicating, acid secreting ileal duplication cyst presenting with metabolic acidosis has not been reported, to the best of authors' knowledge.A nine hour old term female newborn born by normal vaginal delivery presented to the emergency department with abdominal distention and respiratory distress since birth. There was no antenatal history of maternal infections or birth asphyxia. The child had passed urine and meconium within an hour after birth. On examination the child was tachypneic (respiratory rate 80/min). The heart rate was 150/min and the digital peripheral oxygen saturation was (Sp02)88% on room air. The capillary refill was prolonged (> 3 sec). Normal breath sounds were heard bilaterally. The abdomen was distended and had a bluish hue. A presumptive diagnosis of sepsis was considered and the child was administered IV fluids, O2 by nasal prongs and IV antibiotics  after a blood culture. Inotropic (Dopamine) support was initiated. Blood gas revealed partially compensated metabolic acidosis with hyperchloremia and a normal anion gap.{ pH 7.32, Hco3 7.7, mmol/L, PCO2 15 .3mmHg , Acid Base Excess -16.2, Chloride 116 mmol/L, Hemoglobin 18.1g%,total count 27,424 cell/cc , serum sodium 125 mmol/L, potassium 5.0 mmol/L, anion gap 6.3 }. The CRP was 14.28 mg/L. The neonate continued to be tachypneic with irregular respiration and was intubated and ventilated.The neonate was passing normal meconium and plain X-ray  of the abdomen revealed non- dilated gas filled bowel loops indicating that intestinal obstruction was unlikely. Ultrasonogram of the abdomen reported ascites and on aspiration, hemorrhagic fluid was obtained; biochemical analysis detected acid hematin (5gm% at pH of 7.0). Serial blood lactate levels showed a rise from 2.5 to 3.1mmol/L. A provisional diagnosis of bowel gangrene was considered and laparotomy performed under general anesthesia. The peritoneal cavity was filled with copious hemorrhagic fluid. There was a non-communicating 10cm long ileal duplication cyst that was perforated . The proximal end of the cyst was closely adherent to the native ileum and the distal end was free. The distal end of the duplicated cyst was excised stripping the mucosa off the proximal segment that had a common wall with the native ileum. Histology revealed the presence of gastric mucosal heterotopia in the ileal duplication cyst . The child displayed prompt and dramatic postoperative resolution of the metabolic acidosis.{pH 7.39, Hco3 22.5 mmol/L, PCO2 38 mmHg, Base Excess -2.1, Chloride 107 mmol/L}. The child made a full recovery and was discharged on day 10 and has completed 2 yrs of uneventful follow up.Most small bowel duplications are non-communicating and about 50% may contain ectopic gastric mucosa; around 10% can have more than one heterotopic mucosa. One third of the small bowel duplication cysts are symptomatic in the neonatal period and more than 3/4ths of patients clinically manifest before 2 years of age . Ileal duplication cysts present with acute abdominal pain, bowel obstruction, intussusception, palpable mass, hemorrhage, and perforation [4]. Many are detected antenatally and remain asymptomatic. Acute presentations of ileal duplication cysts in newborn are rare. There have been presentations with severe respiratory distress [6] and bowel obstruction [7], atresia [8] and volvulus [9].This neonate presented with shock and metabolic acidosis; the most common differential diagnosis for this being sepsis. In this case, sepsis was unlikely due to the presence of hyperchloremic metabolic acidosis with a normal anion gap, a negative blood culture and sepsis screen (WBC count and CRP). The ruptured non- communicating ileal duplication cyst contained gastric mucosal heterotopia and acid hematin was detected in the acidic hemorrhagic peritoneal fluid . Acid hematin is the acid salt of HCl acting on hemoglobin [10]. A prompt and dramatic recovery after excision of the duplication cyst suggests a relationship. It is probable that the acid (HCl) secreted by the heterotopic gastric mucosa distended and ulcerated with subsequent perforation of the non-communicating ileal duplication. The resultant bleeding (hemoglobin within RBCs) from the perforated wall reacted with HCl to form acid hematin. The efflux of HCl into the peritoneal cavity led to its absorption into the blood stream resulting in hyperchloremic metabolic acidosis. Other causes of normal anion-gap hyper-chloremic metabolic acidosis in the newborn include conditions like renal immaturity, bicarbonate losses from renal sources , diarrhea, infusion chloride containing salts, acetazolamide therapy and pancreatic and urinary fistulae. These factors were not present in the neonate reported herein, and this case demonstrates a rare but surgically amenable cause of neonatal metabolic acidosis.Definitive treatment of ileal duplication cysts requires complete surgical excision, when feasible. A segmental resection of the involved bowel is usually required, because enteric duplication cysts are always mesenteric and share their blood supply and muscular wall with the adjacent bowel. The healthy normal bowel may be preserved by mucosal stripping of the duplication cyst.Source of Support: NilConflict of Interest: None


Reformulating opioid analgesics to deter abuse is one approach toward improving their benefit-risk balance. To assess sentiment and attempts to defeat these products among difficult-to-reach populations of prescription drug abusers, evaluation of posts on Internet forums regarding reformulated products may be useful. A reformulated version of OxyContin (extended-release oxycodone) with physicochemical properties to deter abuse presented an opportunity to evaluate posts about the reformulation in online discussions.The objective of this study was to use messages on Internet forums to evaluate reactions to the introduction of reformulated OxyContin and to identify methods aimed to defeat the abuse-deterrent properties of the product.Posts collected from 7 forums between January 1, 2008 and September 30, 2013 were evaluated before and after the introduction of reformulated OxyContin on August 9, 2010. A quantitative evaluation of discussion levels across the study period and a qualitative coding of post content for OxyContin and 2 comparators for the 26 month period before and after OxyContin reformulation were conducted. Product endorsement was estimated for each product before and after reformulation as the ratio of endorsing-to-discouraging posts (ERo). Post-to-preintroduction period changes in ERos  for each product were also calculated. Additionally, post content related to recipes for defeating reformulated OxyContin were evaluated from August 9, 2010 through September 2013.P<.001). A total of 37 recipes for circumventing the abuse-deterrent characteristics of reformulated OxyContin were observed; 32 were deemed feasible . The frequency of posts reporting abuse of reformulated OxyContin via these recipes was low and decreased over time. Among the 5677 posts mentioning reformulated OxyContin, 825 posts discussed recipes and 498 reported abuse of reformulated OxyContin by such recipes (41 reported injecting and 128 reported snorting).Over the study period, 45,936 posts related to OxyContin, 18,685 to Vicodin (hydrocodone), and 23,863 to Dilaudid (hydromorphone) were identified. The proportion of OxyContin-related posts fluctuated between 6.35 and 8.25 posts per 1000 posts before the reformulation, increased to 10.76 in Q3 2010 when reformulated OxyContin was introduced, and decreased from 9.14 in Q4 2010 to 3.46 in Q3 2013 in the period following the reformulation. The sentiment profile for OxyContin changed following reformulation; the post-to-preintroduction change in the ERo indicated reformulated OxyContin was discouraged significantly more than the original formulation (ratio of ERos=0.43, After introduction of physicochemical properties to deter abuse, changes in discussion of OxyContin on forums occurred reflected by a reduction in discussion levels and endorsing content. Despite discussion of recipes, there is a relatively small proportion of reported abuse of reformulated OxyContin via recipes, particularly by injecting or snorting routes. Analysis of Internet discussion is a valuable tool for monitoring the impact of abuse-deterrent formulations. Prescription opioid analgesics are an important component of pain management. Misuse and abuse of these medications, however, have created a serious and growing public health problem . The balMost abuse-deterrent technologies developed to date are designed to make product manipulation more difficult or to make abuse of the manipulated product less attractive or rewarding. Although in vitro and clinical studies indicate the efficacy of these technologies, postmarketing data are needed to evaluate their effectiveness. One of the early formulations intended to reduce abuse was a reformulated version of extended-release oxycodone , which was introduced to the market in August 2010. This product has physicochemical resistance to crushing and dissolution intended to present obstacles to abuse by nonoral routes of administration (ROA) . The launch of reformulated OxyContin provided a nationwide experiment to evaluate the impact of a product intended to reduce tampering in the real world ,9. To daIntroduction of reformulated OxyContin presents an opportunity to determine the utility of monitoring Internet data to evaluate reactions to this formulation among a difficult-to-reach population of prescription drug abusers who are not generally in contact with some authority . BecauseAlthough public Internet forums can be monitored unobtrusively and might reveal ways in which prescription drugs are being misused , there hIn the present work, we sought to understand how drug abusers reacted to the introduction of an intended tamper-resistant prescription opioid product to the market. We examined data from abusers who participated in Internet message boards to evaluate discussion of OxyContin before and after introduction of the reformulation. Specifically, we investigated these questions: (1) did the level of Internet discussion related to OxyContin change quantitatively over time following introduction of the reformulated version of the product, (2) within the OxyContin-specific discussion that did occur, was there a shift in the sentiment expressed by abusers who posted on these websites following the introduction of reformulated OxyContin, and (3) given concerns about efforts to generate and disseminate tampering methods intended to defeat the properties of reformulated OxyContin for use by unintended ROAs, could Internet discussion of such recipes be defined, identified, and monitored?The study aimed to evaluate the potential effect the introduction of the reformulation of OxyContin had on discussion within Internet-based recreational drug abuse message boards. Over the pre-post reformulated OxyContin timeframe, we conducted (1) a quantitative evaluation of message board discussion for OxyContin and comparators to capture the relative levels of discussion and any changes during the pre-post time period, (2) a qualitative coding of Internet post content and estimation of endorsement for OxyContin and comparators to determine any changes in the sentiment in favor of each medication for abuse purposes from pre to post OxyContin reformulation, and (3) in the period following the introduction of OxyContin, an evaluation of Internet post content related to tampering methods for defeating the abuse-deterrent properties of reformulated OxyContin. All research activities conducted for this study were exempt from Institutional Review Board review as determined by the New England Institutional Review Board.For the quantitative evaluation of discussion levels and content analysis/estimation of endorsement, Vicodin (hydrocodone) and Dilaudid (hydromorphone) were selected as comparators. These comparators represented a widely available and highly abused prescription opioid (Vicodin) and a high-potency opioid analgesic that is highly desirable for abuse (Dilaudid) . In ordeThe study sample consisted of Internet posts  copied from 7 publically accessible message boards that represent a population of drug abusers and their online communications regarding both illicit and prescription drugs. The websites were chosen based upon predefined criteria as described in McNaughton et al . All posFrom the database of saved Internet posts, all messages related to OxyContin , Vicodin, and Dilaudid written between January 1, 2008 and September 30, 2013  were identified through the use of standardized queries. These queries contained text-matching criteria that included common misspellings, slang, and wildcard characters as well as exclusion criteria to capture as many relevant posts as possible while minimizing the number of false positives  selected. It should be noted, however, that false positives could not be completely eliminated from the text-matching query results without manual review, which was not conducted for this analysis because of the magnitude of posts involved. The rate of discussion related to each product was then calculated as the number of product-specific posts identified per 1000 posts saved within the database per quarter.A formal content analysis was conducted on random samples of Internet posts related to OxyContin, Vicodin, and Dilaudid during the 26-month period before  and the 26-month period after the introduction of reformulated OxyContin  and identified through the use of the standardized queries. For this analysis, posts retained for coding in the preintroduction period pertained to the original formulation of OxyContin, whereas posts sampled and retained in the postintroduction period related specifically to reformulated OxyContin. Because the design involved comparison of discussion of original OxyContin in the preintroduction period and reformulated OxyContin in the postintroduction period, discussion of original OxyContin in the postintroduction period was not examined for this study. Using systematic query searches, product-specific Internet posts were randomly sampled from the archive. All coding was conducted as part of a larger dynamic postmarketing surveillance program, involving rolling sampling and content analysis of posts . Power analyses to determine the sample size needed to detect changes were calculated periodically throughout surveillance and changed over time resulting in somewhat different sample sizes in the preintroduction and postintroduction periods for this evaluation.The coding procedure and assessment of intercoder agreement used in this study is described in detail in McNaughton et al . BrieflyA mixed effects multinomial logistic regression was employed to model the probability of observing each of the 4 types of abuse-related Internet posts  per product. The fixed effects included a product indicator , time indicator  and product×time interaction. An author random effect was incorporated in the model to account for correlation among messages posted by the same author. The GLIMMIX procedure in SAS 9.3  was used to fit the model, producing the following statistics of interest:Probability of observing each type of abuse-related post  per product in the period before and after the introduction of reformulated OxyContin.Endorsement ratio (ERo) for each product in the period before and after the reformulation of OxyContin. The ERo provides a relative estimate of the extent to which a product was being endorsed during each time period by calculating a ratio of probabilities , commonly referred to as a relative risk .Post-to-preintroduction change in the ERo was estimated by calculating the ratio of ERos , commonly referred to as a relative risk ratio.Within-author correlation as estimated by intraclass correlation coefficients derived from the variance components .Of particular interest with respect to any purported ADF product is whether tampering methods, or recipes, are developed that allow individuals to readily defeat the abuse-deterrent properties of a new formulation. To evaluate this possibility, a review of recipe-related content was performed on Internet posts pertaining to reformulated OxyContin during the approximately 3-year period following the product’s launch . For this evaluation, a recipe was defined as a process  that enabled use of the product in a way other than intended  because ADFs are not formulated to prevent abuse by swallowing multiple tablets whole at one time ,5. WhileAll posts that referenced OxyContin during the approximately 3-year period were reviewed by a trained coder for recipe content related to the reformulated version of OxyContin. For each post that mentioned a recipe related to reformulated OxyContin, the coder assigned 3 codes: (1) the recipe profile, (2) the ROA mentioned in relation to the recipe profile, and (3) whether the author described the recipe as “feasible.” Feasibility was defined as being able to manipulate reformulated OxyContin for abuse via an unintended ROA . Utilizing the coded information, the total number of recipe-related posts, recipe profiles, and the frequency in which recipe profiles were first observed are presented. In addition, the ROAs mentioned in relation to feasible recipes are provided.Between January 1, 2008 and September 30, 2013 , 45,936 posts related to OxyContin  were identified in the database of 6,891,514 saved posts. Because the brand name of OxyContin did not change following the introduction of the reformulation, it was not possible to disambiguate references to original versus reformulated OxyContin in the postintroduction period without review of each post, which was not conducted for this analysis. In addition, 18,685 posts related to Vicodin, and 23,863 posts related to Dilaudid were identified. When evaluated by quarter, the proportion of OxyContin-related posts fluctuated between 6.35 and 8.25 posts per 1000 posts during the period before the release of reformulated OxyContin (Q1 2008 through Q2 2010) before increasing to an observed 10.76 posts per 1000 posts in Q3 2010 with the launch of reformulated OxyContin on August 9, 2010 . FollowiOf the 16,588 posts sampled, 5365 (32.40%) were identified as false positives and removed from the final sample . The higP<.001)  and following (postintroduction period) the introduction of reformulated OxyContin is presented in P<.001) .P<.001) indicating that the ratio of encouraging-to-discouraging discussion for Vicodin in the period following the introduction of reformulated OxyContin was significantly greater than in the period before the reformulation (P<.001) in the postintroduction period than in the preintroduction period. These changes in the ERo estimate for Vicodin and Dilaudid, however, appear to be because of a reduction in posts coded as discouraging rather than an increase in encouraging posts. In relation to the post-to-preintroduction period ratio of the ERos for Vicodin and Dilaudid compared to OxyContin, however, the magnitude of the change for Vicodin and Dilaudid was 3.91 times greater (P<.001) and 4.95 times greater (P<.001) than OxyContin, respectively. The post-to-preintroduction period ratio of the ERo estimates for Vicodin compared to Dilaudid was not statistically different (P=.12). These results suggest that the endorsing and discouraging sentiment profile for OxyContin before and after the introduction of the reformulation changed significantly more than the endorsing and discouraging sentiment profile of Vicodin and Dilaudid.Changes in the sentiment profiles of Vicodin and Dilaudid were also observed before and after the introduction of the reformulated version of OxyContin. In relation to Vicodin, the ERo was 1.66 times greater in the postintroduction period than in the preintroduction period , 19,659 posts related to OxyContin  were identified and reviewed by trained coders . Of thesIn total, 37 unique recipe profiles were identified during the approximately 3-year period, 32 of which were denoted as feasible at least once . Within When considering the 498 reformulated OxyContin-related posts that referenced a feasible recipe profile, various ROAs were mentioned in relation to use of the manipulated product . Oral usNovel methodologies for evaluating the impact of prescription opioid products with abuse-deterrent properties on abuse-related behaviors are needed. This study presents an Internet-focused approach to examine discussion on recreational drug abuse Internet forums regarding reformulated OxyContin, the first widely available reformulated opioid product on the market. Systematic monitoring and review of content from online message boards before and after the introduction of reformulated OxyContin allowed for evaluation of (1) discussion about OxyContin and 2 comparators, (2) relative endorsement of OxyContin and comparators, and (3) discussions around manipulation of reformulated OxyContin through recipes.Overall, the findings presented here suggest that the introduction of reformulated OxyContin had an impact on discussion of OxyContin on message boards frequented by prescription drug abusers. Quantitative analysis indicated that the volume of discussion related to OxyContin increased in the quarters leading up to the launch of the reformulated version of the product and subsequently decreased to levels lower than those observed in the period before the reformulation. In contrast, the level of discussion associated with the selected comparators  remaineThe analyses of sentiment built upon prior work  by applyPrior to the launch of any reformulated product, like reformulated OxyContin, concern existed that the product would be greeted with numerous attempts by abusers to defeat the product’s tamper-resistant mechanism. A particular concern was that any truly successful recipe would be widely and rapidly disseminated online . ResultsFindings from this study should be considered in light of its limitations. Querying Internet posts based on selected keywords is incomplete and does not identify all discussion potentially related to a particular topic. Although the methodology described here has the advantage of providing a systematic and consistent approach over time, it is possible that some discussion associated with OxyContin was missed in this analysis. For example, discussion containing references to the product via terms such as “it,” “that drug,” or “what Joe is using,” in which an individual is making an inference or reference within a conversation may have been missed. This may have introduced selection bias in the sample of posts used. However, it seems unlikely that such bias would result in having completely missed or underestimated significant discussion or topics related to the introduction of reformulated OxyContin and the potential change in OxyContin-related discussion over time.For the formal content analysis and estimation of endorsement, a high false positive rate was observed for reformulated OxyContin during the postintroduction period , which was primarily attributable to 2 issues. The slang term “OP”  is also an acronym commonly used on message boards to refer to the “original poster” or the first author to write a post in a thread. Furthermore, because the brand name of the product did not change following reformulation, the search-string queries often yielded posts that, even with human review , could not be clearly identified as pertaining specifically to reformulated OxyContin. Although both of these factors contributed to the high degree of false positives, removal of the non–OxyContin-related content as well as ambiguous references to OxyContin that could not be verified as related to the reformulated version of the product ensured that the sample of posts included for analysis in the postintroduction period reflected the target product  and would, therefore, minimize the effect of misclassification on the results.It should be noted that references to feasible recipes in this study refer to an author reporting that he/she was able to manipulate reformulated OxyContin and then use it for recreational purposes. Such reports cannot be verified . However, individuals who participate in the examined forums represent stable communities of drug users and are self-policing so that posted information that is inconsistent with others’ experience tends to be “corrected” by the online community. Additionally, reports of feasible recipe use do not necessarily indicate that the desired effect was achieved as a result of the manipulation. Claims of having abused a manipulated product, whether by an oral or a nonoral route , does not mean that the effects were equivalent to, better than, or worse than use of the original product. Although one might expect that the overall poorer sentiment observed for reformulated OxyContin suggests dissatisfaction, the present study did not directly examine satisfaction with results of tampering.Strengths of this study should be highlighted and include (1) the duration of the study period allowed for a large sample size and examination of trends over time, (2) systematic coding of posts with acceptable interrater reliability, (3) the use of operational definitions of recipe profiles that established a standardized methodology for evaluation of Internet content, (4) the ongoing archiving and storage of Internet posts over time allowed the retrospective evaluation of data and avoided bias introduced by forum moderators deleting older posts for reasons of their own , and (5) the integration of quantitative (number of Internet posts), content , and qualitative analyses (manipulation recipes) provided a comprehensive approach to understanding the reactions of recreational abusers to the introduction of a tamper-resistant product.This study illustrates the value of analyzing Internet discussion on recreational drug use forums to evaluate the impact of introducing a possible tamper-resistant opioid formulation. Introduction of reformulated OxyContin into the marketplace correlated with changes in discussion of abuse-related behavior among recreational abusers as reflected by changes in online conversation levels, reversal of sentiment about the product, and emergence of manipulation-attempt recipes, consistent with findings from other studies showing reductions in abuse and diversion -11. Thes


Analyses were adjusted for demographic, clinical, and environmental covariates, and stratified by community type . In cities, higher greenness (tertiles 2–3 vs. 1) was protective for both preterm  and small for gestational age birth , but not birth weight or Apgar score. We did not observe associations between greenness and birth outcomes in adjusted models in boroughs or townships. These results add to the evidence that greener cities might be healthier cities.Living in communities with more vegetation during pregnancy has been associated with higher birth weights, but fewer studies have evaluated other birth outcomes, and only one has been conducted in the Eastern United States, in regions with a broad range, including high levels, of greenness. We evaluated associations between prenatal residential greenness and birth outcomes  across a range of community types using electronic health record data from 2006–2013 from the Geisinger Health System in Pennsylvania. We assigned greenness based on mother’s geocoded address using the normalized difference vegetation index from satellite imagery. We used propensity scores to restrict the study population to comparable groups among those living in green  The biologist E.O. Wilson developed the theory of biophilia, which postulated that, since human beings evolved out of nature, they have a biologically-ingrained affinity for nature . Indeed,The majority of studies on greenness and birth outcomes have been conducted in urban areas where absolute levels of greenness are low (NDVI < 0.4) and are often limited to within-city comparisons in small geographic areas. To our knowledge, only one other study has examined the relationship between greenness and birth outcomes across a range of communities, encompassing the full spectrum of rural to urban areas in a large geography in the United States . Associai.e., participant subgroups in green areas with few or no comparable counterparts in less-green areas and vice versa). We addressed concerns about violations of the positivity assumption  by (1) performing analyses separately by community type; and (2) using propensity scores derived from machine learning [We sought to evaluate the relationship between prenatal exposure to greenness and birth outcomes in a range of Pennsylvania communities. Such analysis, which included participants from diverse communities, while adjusting for individual and neighborhood-level confounders, may lead to practical violations of the positivity assumption , we chose to treat them as confounders in our analysis as we considered this the primary direction. We used the conceptual framework to guide our covariate selection, model building, and interpretation of results. We proposed a conceptual framework outlining the mechanisms by which greenness might affect birth outcomes : by alte2, respectively. The Geisinger primary care population is representative of the general population of the region [We used electronic health record (EHR) data on mothers who delivered neonates at one of two labor and delivery-equipped Geisinger Health System hospitals between 1 January 2006 and 31 January 2013. Geisinger’s primary catchment area covers nearly 40 counties, containing a range of self-governed Pennsylvania communities, including suburban and rural townships, moderate-to high-density boroughs, and cities, with median population densities ranging from 34 to 738 to 1360 people per kme region . The InsInternational Classification of Diseases, Ninth Revision codes V27.x and V30.x. We linked these mothers to their neonates in the EHR, primarily using medical record numbers, but also with addresses, names, and dates . We geocoded the mother’s most recent address using ArcGIS 10.2  with a series of basemaps [n = 622 neonates, n = 433 deliveries), with primary addresses outside Pennsylvania (n = 492), those we could not geocode (n = 1389), non-singleton births (n = 1019), stillbirths (n = 13), and neonates with serious birth defects (n = 74), birth weights <500 g (n = 22), or gestational ages <22 weeks (n = 8) [We identified mothers who gave birth and infants born at Geisinger from primary and non-primary care records using basemaps . We thenbasemaps . This mibasemaps . We exclWe identified four birth outcomes: term birth weight (≥37 weeks), small for gestational age birth, preterm birth (<37 weeks gestation), and low 5 min Apgar score (<7). We used physician-estimated gestational age, which was determined based on mother-reported last menstrual period and 20 week ultrasound. We extracted birth weight and 5 min Apgar score from the EHR vitals file and labor and delivery notes (free text), and a separate labor and delivery database maintained continuously by nursing personnel. Small for gestational age was assigned based on an internal reference of babies born at Geisinger between 2006–2013 . NeonateWe obtained demographic characteristics from the EHR. These included neonate sex, gestational age, season and year of birth; maternal age, race/ethnicity, primary care status (primary or non-primary), smoking status during pregnancy, pre-pregnancy body-mass index, parity, number of antibiotic orders during pregnancy, and receipt of Medical Assistance, a means-tested program often used as a surrogate for low family socioeconomic status (SES) ,29. SmokExposure to green, natural areas around each home address was estimated using NDVI, a satellite-image based vegetation index. Chlorophyll in plants absorbs visible light for use in photosynthesis, while leaves reflect near-infrared light. NDVI calculates the ratio of the difference between the near-infrared region and red reflectance to the sum of these two measures, and ranges from −1.0 to 1.0, with larger values indicating higher levels of vegetative density ,39,40. Fvs. less green communities . This could result in model extrapolation rather than adjustment in evaluating our primary associations of interest. We also hypothesized that the association between greenness and birth outcomes might operate differently in different community types. To make the compared groups more similar on greenness and covariates, we first stratified our analyses by community type  and then confined analysis to comparable patients. The distribution of greenness differed by community type . We werei.e., propensity scores [To restrict our analysis to comparable mothers we evaluated the predicted probabilities of greenness as a function of baseline covariates including maternal age, race/ethnicity, alcohol and tobacco use, number of prenatal clinical visits, receipt of Medical Assistance, and UNGD exposure, and others. We compared the distributions of the predicted probabilities (y scores ) of liviy scores , an ensey scores ,44 The SPlots confirmed different distributions of predicted probabilities of high greenness exposure (vs. tertile 1) and four birth outcomes using linear and logistic regression, depending on outcome, accounting non-independent observations due to neonates nested within mothers  and mothers nested within communities in our estimated standard errors [vs. no), smoking status during pregnancy (never vs. ever), pre-pregnancy body mass index , parity (nulliparous vs. multiparous), receipt of Medical Assistance , number of antibiotic orders during pregnancy, distance to nearest major road (meters), drinking water source , the number of unconventional natural gas wells drilled prior to birth within 20 km of the home, exposure to swine operations, block group walkability (continuous), and CSD (quartiles). We tested all two-way interactions between model covariates and retained those that significantly improved model fit. We also specifically evaluated whether CSD or receipt of Medical Assistance modified relations between residential greenness and birth outcomes by including interaction terms. We used quadratic and cubic terms to assess non-linear relationships.We evaluated associations between residential greenness (tertile 2–3 d errors . Adjustea priori hypotheses about confounders and likelihood ratio testing (p < 0.05). Residual semivariograms showed that model residuals did not exhibit spatial autocorrelation. In the original population data missingness was minimal (0%–5.8% on outcomes and 0%–5.2% on confounders) and in the restricted population data was not missing on confounders and again minimal for outcomes (0%–5.0%), thus we excluded mothers from models when they were missing data. Statistical analyses were implemented using Stata version 13  and R version 3.1.1  and the R SuperLearner package [Models were selected using  package .To evaluate the sensitivity of associations to choices about NDVI metric and residential environment size, we calculated greenness exposure based on mean and maximum greenness during pregnancy in 250 m and 1250 m radii. To test sensitivity to the greenness cutpoint we also evaluated associations dichotomizing greenness at the community-specific 20th-percentile (comparing <20th-percentile to ≥20th-percentile). Finally, we evaluated the association between continuous NDVI and birth outcomes in both the original and restricted population.From January 2006 through January 2013, a total of 16,184 mothers delivered 20,598 infants at two Geisinger Health System hospitals. After exclusion, we had a sample size of 16,913 mother-infant pairs. The use of propensity scores to further restrict to exchangeable groups left 12,821 infants  born to 10,787 mothers . The medWe did not observe significant associations between residential greenness and term birth weight or 5 min Apgar score in any community type , though In a sensitivity analysis, we observed high correlation (Spearman > 0.7) between mean and maximum residential greenness defined by 250 m and 1250 m radii. Analysis produced similar associations for both buffer sizes (results not shown). In evaluation of sensitivity of results to decisions regarding NDVI cutpoints, a division at the 20th percentile yielded similar associations to the primary analysis (results not shown). Analysis in the restricted population with a continuous NDVI variable suggested a statistically significant relationship between continuous NDVI and preterm birth in cities . AdditioIn an analysis of birth outcomes across a range of communities, from rural to urban, in Pennsylvania, we found that higher levels of residential greenness, in cities only, were associated with lower odds of preterm and small for gestational age births. The analysis presented challenges, for reasons often not recognized or acknowledged in environmental epidemiologic studies. Specifically, we had to address structural confounding by restricting the analysis to mothers with comparable counterparts while controlling for numerous spatially correlated exposures. Prior studies of greenness in cities did not have to deal with this methodological complication. As studies of contextual and community influences on health increase in their geographic scope, they will continue to run into complex data problems including issues of structural confounding. We provide an example of how to use machine-learning based propensity scores and stratification to study communities ranging from urban to very rural while reducing the possibility that the associations were explained by either model extrapolation or confounding due to a number of important environmental exposures and conditions.In addition to the methodological contributions we also add data from outside cities to the greenness and birth outcome literature. In our study, greenness only conferred benefits in cities. This could suggest that in communities with higher absolute levels of greenness, for example boroughs and townships, additional greenness does not benefit neonate health.Greenness exposure may provide opportunities for physical activity, lower psychophysiological stress and depression, increase social interactions, and lower exposure to noise, air pollution and extreme temperatures . These pet al. [p = 0.05). An analysis of 64,705 singleton births in Vancouver, Canada showed that a 0.1 increase in NDVI was associated with a 5% decrease  in the odds of a moderately preterm (30–36 weeks) birth [Two prior studies reported greenness as protective of preterm birth. In Southern California, Laurent et al.  found ths) birth , adjustiet al. [Three studies have also reported that greenness is protective for small for gestational age birth. The Vancouver study found that a 0.1 increase in NDVI was associated with a 3% (95% CI: 0%–6%) decrease in small for gestational age birth . Donovanet al.  found thet al. .et al. (2014) observed a similar effect size, 20.6 g  per 0.1 unit increase in NDVI. Our findings were also similar in magnitude compared to those seen in other studies [et al. and Ebisu et al. in the U.S. [Most studies of greenness and birth outcomes have reported that NDVI is associated with continuous birth weight ,9,10,12.t al. 201 observed studies ,9, but lthe U.S. . Differei.e., Medical Assistance) or CSD. Since more mothers on Medical Assistance resided in cities and cities in general had higher levels of community deprivation, it is possible that we did not observe effect modification by family SES and community deprivation since we stratified analyses by community type.Prior studies have reported stronger associations of greenness with birth outcomes among individuals with low SES or living in poorer communities ,5,6,9. WOur study had limitations. First, while stratifying our analysis by community type and restricting to comparable populations to prevent model extrapolation was a key strength, this methodology prevented us from testing interactions between community type and greenness, or greenness and overall CSD or modeling NDVI as a continuous variable in our main analysis. We cautiously present linear associations between continuous NDVI and birth outcomes in the Despite these limitations, our analysis offered improvements over past studies. A main contribution is limiting analysis to the area of common support, which prevented reliance on model extrapolation. The EHR provided detailed patient data  and accurate outcome ascertainment. Our NDVI exposure summarized exposure across pregnancy by averaging NDVI by trimester. We were able to assign a suite of confounders including information on drinking water source, industrial agriculture, and unconventional gas wells not available in other analyses. Although it is possible that including some of these factors may have over-controlled for exposure, each was hypothesized to act primarily as a confounder and was included based on substantive knowledge. We observed an association between higher levels of greenness and lower odds of preterm and small for gestational age birth only among city-dwelling mothers. This finding was observed after restriction to mothers with similar probabilities of residing in areas with greenness and adjustment for a host of spatially correlated social and environmental exposures. Future environmental epidemiology studies that include participants from a range of communities should consider the issue of non-positivity in analyses. While more research is needed to identify the specific mechanisms through which greenness may impact birth outcomes, planners and policy makers should consider incorporating additional vegetation in urban areas.


The shift in epidemic trends in recent years in Romania shows new problems in regard of HIV vertical transmission, firstly in intravenous drug user's mothers co-infected with hepatitis viruses and with social problems, and secondly the children of young mothers with an old HIV infection and long antiretroviral therapy history.We studied all HIV perinatal exposed children routinely followed up in the Paediatric Department of the National Institute of Infectious Diseases, since January 1st 2006 till December 31st 2012. The analyses consisted of describing the birth defects and association with certain risk factors: gender, mother's age at birth and exposure to antiretrovirals in the first trimester of pregnancy.We analyzed 244 children born to HIV-infected mothers. The incidence of HIV infection was 16.39%. The rate of birth defects was 39.34% (96/244 cases). The most frequent findings were cardiac malformations (47/96), followed by musculoskeletal defects (24/96), neurologic defects (20/96), urogenital malformations (13/96), digestive tract defects (3/93), metabolic disorders (2/96) and genetic disorders (2/96). We found nine cases of severe congenital anomalies: complex heart defect, total congenital aganglionic megacolon, anal imperforation, Dandy-Walker syndrome, gangliosidosis, Niemann-Pick syndrome, Down syndrome, true hermaphroditism and cleft palate. Two children died during first year of life due to severe malformations. 9% of cases had associated malformations. The gender rate was in favour of males in group with birth defects (58/38) and with no birth defects (82/66). The median age at birth in mothers was 22 years, similar in both groups. The highest mean age at birth was in offspring's mothers with neurologic congenital defects 25, 15 years old, but is not statistically significant (p=0.1). In the studied period the highest number of birth defects were found in 2012, 37 children, compared with less than 15 in previous years . In our studied patients the risk of birth defects was not statistically associated with HIV transmission or with exposure to antiretrovirals before and in first trimester of pregnancy (p=0.88).The rate of birth defects among HIV-exposed children was not significantly associated with antiretroviral exposure, but we identify very rare and severe congenital conditions. We have noticed also a trend to increasing number of birth defects in 2012 among studied patients compared to previous years.


We sought to prospectively study the association between antenatal emotional distress and gestational length at birth as well as preterm birth.We followed up 40,077 primiparous women in the Norwegian Mother and Child Cohort Study. Emotional distress was reported in a short form of the Hopkins Symptom Checklist-25 (SCL-5) at 17 and 30 weeks of gestation. Gestational length at birth, obtained from the Medical Birth Registry of Norway, was used as continuous  and categorized (early preterm (22–31 weeks) and late preterm (32–36 weeks) versus term birth (≥37 weeks)) outcome, using linear and logistic regression analysis, respectively. Births were divided into spontaneous and provider-initiated.Of all women, 7.4% reported emotional distress at 17 weeks, 6.0% at 30 weeks and 5.1% had a preterm birth. All measurements of emotional distress at 30 weeks were significantly associated with a reduction of gestational length, in days, for provider-initiated births at term. Emotional distress at 30 weeks showed a reduced duration of pregnancy at birth of 2.40 days for provider-initiated births at term. An increase in emotional distress from 17 to 30 weeks was associated with a reduction of gestational length at birth of 2.13 days for provider-initiated births at term. Sustained high emotional distress was associated with a reduction of gestational length at birth of 2.82 days for provider-initiated births. Emotional distress did not increase the risk of either early or late preterm birth.Emotional distress at 30 weeks, an increase in emotional distress from 17 to 30 weeks and sustained high levels of emotional distress were associated with a reduction in gestational length in days for provider-initiated term birth. We found no significant association between emotional distress and the risk of preterm birth. Preterm birth  is a common but serious pregnancy complication Since the nineties a growing awareness that maternal antenatal stress may influence gestational length at birth and preterm birth in particular has led to a large number of studies, as the comprehensive review of Dunkel Schetter & Glynn indicates The influence of maternal psychological distress and stress hormones on the risk of preterm birth is not well defined, although patterns are beginning to emerge provider-initiated” and defined as induction of labor or elective caesarean section without premature rupture of membranes Research on both gestational length at birth and preterm birth are of interest. Using gestational length at birth as a continuous variable adds statistical power and may reveal associations not detected when using cut-offs, such as early and late preterm birth. A shortening of gestational length at birth by a day, or couple of days can be detected using a continuous variable Another issue, which has been poorly investigated to date, is the role of the pattern of prenatal stress as a possible predictor of reduced gestational age at birth. Research indicates that levels of anxiety and depression vary during pregnancy, with higher levels at the beginning and lower levels at 30 weeks gestation The Norwegian Mother and Child Cohort (MoBa) is a nationwide population-based prospective cohort study of pregnant women. It included measurements of emotional distress on two occasions in pregnancy as well as a large number of relevant covariates. The aim of our study was to estimate the association between antenatal emotional distress in the second and third trimester, and of a pattern of either increasing or sustained high levels of emotional distress, with gestational length at birth as well as increased risk of preterm birth. All of these associations were assessed for provider-initiated births versus spontaneous births.www.fhi.no). The current study is based on version 6 of the quality-assured data files released for research in 2011. Our study included 45,769 primiparous women with a singleton pregnancy who gave birth between 22 and 44 weeks of gestation. We excluded 1,383 women for whom information on emotional distress at 17 weeks was missing completely and 1,302 women who gave birth to a baby with serious congenital malformation(s). Another 118 cases were excluded due to birth weights 3.0 standard deviations (SD) above or 3.5 SD below gender- and gestational age-adjusted national reference values The MoBa study, conducted by the Norwegian Institute of Public Health www.fhi.no/moba).The Regional Committee for Medical Research Ethics in South-Eastern Norway  and the Norwegian Data Inspectorate approved the study. Informed written consent was obtained from each participant. The protocol for this study was submitted to the Norwegian Institute of Public health who upon approval supplied the researchers of this study with anonymized data through contract , at around 17 weeks  and 30 weeks' gestation . Although such a measurement cannot replace a clinical interview, previous research The actual and the estimated date of delivery  was obtained from the MBRN database, and used to calculate gestational length at birth in days. For the 798 (1.8%) women for whom no ultrasound based EDD was available, gestational length at birth was calculated using the last menstrual period. Preterm birth was defined as birth before 37+0 weeks (259 days) of gestation, as opposed to term birth at or after 37+0 weeks. Preterm birth is often categorized into <28 weeks, 28–<32 weeks and 32–<37 weeks 2), and history of spontaneous abortion (<22 weeks gestation) were obtained from the MoBa questionnaire at 17 weeks gestation. The gender and birth weight of the new-born were obtained from the MBRN database. Major fetal malformations were derived from the variable “serious congenital malformations” from MBRN records. We defined a “late medical risk” variable which included risk factors occurring during pregnancy. These consisted of pregnancy-induced hypertensive disease as registered in the MBRN records, self-reported urinary tract infection(s) and episodes of fever after 21 weeks from the MoBa questionnaire at 30 weeks. Since more than 99% of the MoBa participants were of Caucasian origin, ethnicity was not a relevant confounding factor in our study. The variable “start of birth” was used to differentiate between provider-initiated births, i.e. starting with induction of labor or elective caesarean section without preterm rupture of membranes, and spontaneous births, i.e. starting with contractions or spontaneous rupture of the membranes Maternal age, education, marital status, smoking, maternal pre-pregnancy body mass index .(DOCX)Click here for additional data file.


We also performed bivariate genetic correlation analyses between (i) whole CC DTI measures and (ii) whole CC DTI measures with total brain WML burden. Across the DTI measures for the whole CC, MD and RD shared 84% of the common genetic variance, followed by MD- AD (77%), FA - RD (52%), RD - AD (37%) and FA – MD (11%). For total WMLs, significant genetic correlations indicated that there was 19% shared common genetic variance with whole CC MD, followed by CC RD (17%), CC AD (16%) and CC FA (5%). Our findings suggest that the CC microstructure is under moderate genetic control. There was also evidence of shared genetic factors between the CC DTI measures. In contrast, there was less shared genetic variance between WMLs and the CC DTI metrics, suggesting fewer common genetic variants.The current study sought to examine the relative influence of genetic and environmental factors on corpus callosum (CC) microstructure in a community sample of older adult twins. Analyses were undertaken in 284 healthy older twins  from the Older Australian Twins Study. The average age of the sample was 69.82 (SD = 4.76) years. Brain imaging scans were collected and DTI measures were estimated for the whole CC as well as its five subregions. Parcellation of the CC was performed using Analyze. In addition, white matter lesion (WMLs) burden was estimated. Heritability and genetic correlation analyses were undertaken using the SOLAR software package. Age, sex, scanner, handedness and blood pressure were considered as covariates. Heritability (h Many of the previous reports only studied the whole CC as a single unit or divided it into two (genu & splenium) or three  regions. However, the CC has no clear anatomical boundaries WM lesions (WMLs) are a marker of WM pathology and are commonly observed as hyperintense regions in T2-weighted or fluid attenuated inversion recovery (FLAIR) scans in older adults. WMLs are thought to reflect small vessel disease but their aetiology is incompletely understood In this study, we estimate the relative influence of genetic and environmental factors on DTI measures for the entire CC and for five parcellated regions using the method of Chao et al., The study was approved by the Australian Twin Registry, University of New South Wales, University of Melbourne, Queensland Institute of Medical Research and the South Eastern Sydney and Illawarra Area Health Service and written informed consent provided by all participants. Participant's information was de-identified and anonymized prior to analysis.The current study is comprised of 142 twin pairs  drawn from the longitudinal Older Australian Twin Study (OATS) with available brain imaging data. The mean age of the sample used in this study was 69.82 (+/− 4.76) years with ages ranging from 65 to 85. All participants were Caucasian. In the current analysis, individuals with a consensus diagnosis of dementia were also excluded.Briefly, OATS recruited twins aged 65 years and above who were registered with the Australian Twin Registry and through recruitment drives across the three eastern states of Australia – New South Wales, Queensland and Victoria. Other inclusion criteria were ability to complete questionnaires in English and having a consenting co-twin. Individuals were excluded if they were diagnosed with any progressive malignancy or other life threatening illness or acute psychiatric disorder. The study was approved by the relevant ethics committees and written informed consent provided by all participants. The full details of the study have been published elsewhere Participants completed an extensive face-to-face interview, which included demographic, medical and health information. Data on alcohol consumption, tobacco smoking and diabetes were obtained by self-report questionnaires MRI data were obtained on three 1.5 Tesla scanners and a 3 Tesla scanner owing to the multi-site nature of this study. Co-twins were imaged on the same scanner. We used Siemens Magnetom Avanto and Sonata scanners  with similar years of manufacture and upgrade in centres 2 (Victoria - 97 participants) and 3 (Queensland- 79 participants), respectively. In centre 1 , we initially used a 1.5 T Philips Gyroscan scanner  (83 participants) and subsequently a 3 Tesla Philips Achieva Quasar Dual scanner (25 participants). The acquisition protocols and parameters were tested and matched between the centres through standardization of spatial resolution and slice thickness, using a 3D phantom to correct geometric distortions and using five volunteers who were scanned on the four scanners 2), together with a non-diffusion-weighted acquisition b0. For each DWI scan, 55 axial slices were collected. The field of view was 240 mmx240 mmx137.5 mm with acquisition matrix 96×96, and slice thickness 2.5 mm with no gap between the slices, yielding 2.5 mm3 voxels of isotropic sizes. Two extra non-diffusion-weighted (b0) EPIs were separately acquired and then combined with DWI scans for higher SNR. TR = 7115 ms and TE = 70 ms and b1 = 1000 s/mm2 were used for the 3 Tesla Philips Achieva Quasar Dual scanner at Centre 1 while the other DWI parameters were the same.Diffusion weighted MRIs (DWI) scans were used for computing the diffusion tensor imaging (DTI) measures. DWI sequences were performed using a similar protocol for the 1.5 Tesla scanners in the three centres. To increase the signal-to-noise ratio (SNR), all of the subjects were scanned twice for DWI sequences in the same MRI session. A single-shot echo-planar imaging (EPI) sequence  was used. Diffusion sensitizing gradients were applied along 32 non-collinear directions  and 3D T1-weighted MRIs scans for the computation of white matter lesion (WMLs) volumes. 3D T1-weighted volumetric sequence was performed using a similar protocol in the three centres with in-plane resolution = 1×1 mm, slice thickness = 1.5 mm, slice number = 144, TR = 1530 ms, TE = 3.24 ms, TI (Inversion time) = 780 ms, and flip angle = 8. Two T1-3D scans were acquired for each participant for an increased SNR. FLAIR scans main acquisition parameters were: TR/TE = 10000/120 ms, inversion delay = 2500 ms, in-plane resolution 0.898×0.899 mmThe DTI data were pre-processed using FMRIB's Software Library (FSL) version 5.0 http://www.analyzedirect.com/) by a trained researcher who was blinded to family relationship. Initially, the pre-processed DTI images were adjusted to note the mid-sagittal slice number using volume render and fly tools. The auto-trace tool was used to trace whole CC in the mid-sagittal slice of FA images , whilst RD is calculated from the average of two eigen vectors (λ2 and λ3) whilst λ1 is taken as AD. The two sets of data (scans 1 & 2) were highly correlated (r≥0.85). Here, we report the heritability results based on the averages of the two scans. Additional analyses of the individual scans are presented in Tracing and parcellation were done individually on both images (i.e. scan 1 and 2 for each participant). The two sets of data were significantly correlated . The four DTI metrics were calculated using the three eigen vectors extracted from the DTI images. The mathematical formulae are shown in WMLs were delineated from FLAIR and 3D T1-weighted structural scans using an automated pipeline described in detail previously The twin method was used to study the influence of genetic and environmental factors on a particular trait. Monozygotic (MZ) twins share all genes whereas dizygotic (DZ) twins share only half of their genes. By comparing the similarity between the identical and non-identical twin pairs for a particular trait, the effect of genetic, shared and non-shared factors can be estimated. We calculated heritability of the four DTI measures  across whole CC and its five sub regions as described below.Age and scanner were significantly associated with the four DTI measures of whole CC (p≤0.05). Sex was significantly correlated with MD, AD and RD of whole CC (p≤0.05), but not FA (p>0.05). Handedness was significantly associated with MD and RD of whole CC (p≤0.05) but not with whole CC FA (p>0.05). Previous studies have identified risk factors for the integrity of WM across various regions of brain, which include hypertension, serum cholesterol http://solar.txbiomedgenetics.org/) To estimate heritability and genetic correlations, the SOLAR  software package was used, which is based on the variance components method (Bivariate genetic correlations were assessed between (i) whole CC DTI metrics and (ii) whole CC DTI measures and total WML burden. Analyses were undertaken controlling for the covariates listed above.The demographic details of the sample are shown in 2 = 0.37–0.56). For the region-wise analysis, similar to the entire CC, FA, MD and RD are heritable. However, AD is heritable only in the anterior CC (region A).Intra-class correlations (ICC) estimated for MZ and DZ twin groups (95% CI) for whole CC DTI measures are shown in Significant heritability for women was observed for all four DTI measures ranging from 0.39–0.68 for the whole CC (see S4 Table in g = −0.34) and 51% (ρg = −0.72) common genetic variance with MD and RD respectively. The negative sign of the correlation coefficient indicates opposing effects of the shared genetic factors on the measures, i.e. there are some shared genetic factors that are associated with an increase in FA and a decrease in MD or RD g = 0.92) with RD and 77% of common genetic variance (ρg = 0.88) with AD in the same direction. Similarly RD and AD shared 37% common genetic variance (ρg = 0.61).Bivariate genetic correlation analysis was performed for the whole CC between the four DTI measures  and sepa2 = 0.73, SE = 0.051, p = 3.03×10−15). Bivariate genetic correlation analysis of the four DTI measures of the whole CC with total brain WMLs showed significant correlations for WMLs with all four DTI CC measures  for the four DTI measures for scan 1. S3b Table, Heritability estimates for Whole CC and its five sub-regions [A–E] for the four DTI measures for scan 2. S4 Table, Heritability estimates for the four DTI measures of whole CC in females. S5a Table, Genetic (upper matrix) and environmental correlations (lower matrix) of whole CC DTI measures and total WMLs for scan 1. S5b Table, Genetic (upper matrix) and environmental correlations (lower matrix) of whole CC DTI measures and total WMLs for scan 2.(DOC)Click here for additional data file.


The purpose of this study was to assess the visiting restrictions placed on families visiting adult patients on critical care units within trauma hospitals in England. Whilst it is well recognised that high-quality care for patients is of paramount importance, we should also be aware that supporting patients' families offers long-term benefits for patient, family and hospital. In our own unit we are reviewing whether we could adopt a more flexible attitude to visiting times and assessing how to provide a more welcoming environment to relatives. To inform our own review and in order to develop a best practise approach, we surveyed all of the major trauma centres in England.A telephone survey on visiting times was conducted in 53 adult critical care units in trauma centres in England. A list of trauma centres was obtained from the NHS England website. All critical care units  within each hospital were surveyed. Each respondent was asked about the visiting hours, whether children were allowed to visit and how many visitors to a bed space.Fifty-three units with between four and 75 beds and covering the whole of England were surveyed: there was a 100% response rate. Visiting hours varied between hospitals and between units within the same hospital. Nine units (17%) had open visiting hours, although most gave advice on times to avoid such as nursing handover. The majority of units (44.83%) operated restricted visiting with a median (range) of 6 (2 to 9) hours. All units allowed a maximum of two visitors to the bedspace. Children were allowed in nine units without restriction, the remaining units advised that it may not be appropriate for children to visit and it was at the discretion of the parents and medical staff.The majority of adult critical care units in England, including our own, have restricted visiting policies. Visiting policies are a source of debate amongst staff in intensive care with concerns about open visiting including increased workload and interruptions to normal routine . This is


Cesarean birth is associated with altered composition of the neonate's microbiota and with increased risk for obesity and other diseases later in life. The mechanisms of these associations, and whether cesarean birth is associated with an altered adult microbiota, are unknown.In 1097 adult volunteers without diabetes, inflammatory bowel disease, or recent antibiotic use, fecal microbiome metrics were compared by history of cesarean birth (N = 92) or appendectomy (N = 115). Associations with potential confounders, microbiome alpha diversity, and individual microbial taxa were estimated by logistic regression. Permutation tests assessed differences in microbial composition (beta diversity) based on Jensen–Shannon divergence.Cesarean birth history was associated with younger age; appendectomy with older age and higher body mass index. Neither was associated with fecal microbiome alpha diversity. Microbial composition at all taxonomic levels differed significantly with cesarean birth (P ≤ 0.008) but not with appendectomy (P ≥ 0.29). Relative abundance differed nominally for 17 taxa with cesarean birth and for 22 taxa with appendectomy, none of which was significant with adjustment for multiple comparisons.Adults born by cesarean section appear to have a distinctly different composition of their fecal microbial population. Whether this distinction was acquired during birth, and whether it affects risk of disease during adulthood, are unknown.Intramural Research Program, National Cancer Institute, National Institutes of Health (Z01-CP-010214).Supported by the  •Fecal microbiome differed in composition for adults who had been born by cesarean section versus vaginal delivery.•No difference was found for adults with a history of appendectomy.•Source of the cesarean-associated microbiome distinction, and possible effects on disease during adulthood, is unknown. In a reIf cesarean delivery has a prolonged effect on the microbiota, this could contribute to the risk for metabolic diseases later in life. Herein, we explored whether the fecal microbiota differs between adults who reported that they were born by cesarean versus vaginal delivery. For comparison, in the same population we looked for differences in the fecal microbiota with history of appendectomy . The app2https://github.com/biocore/American-Gut/tree/master/data/AG). A current summary is available at http://microbio.me/AmericanGut/static/img/mod1_main.pdf, and details of the OTU picking and taxonomy assignment are available at http://nbviewer.ipython.org/github/biocore/American-Gut/blob/master/ipynb/module2_v1.0.ipynb. Alpha diversity , UniFrac distance matrix and relative abundance of different taxa were calculated in the Quantitative Insights Into Microbial Ecology (QIIME) pipeline.The 16S rRNA V4 region was sequenced by the American Gut Project. The operational taxonomic unit (OTU) table rarefied to 10,000 sequence reads per sample, as well as metadata, was downloaded from the American Gut Project website , sex missing (196), race missing (19), specimen not feces (393), used antibiotic in the past month (131), has diabetes (107) or inflammatory bowel disease (170)]. After that, 37 duplicated samples were also removed. The remaining 1097 samples were used for statistical analysis .2.2We used logistic regression to test the association between history of cesarean birth (CSECTION in the data set) and the following variables: age, race/ethnicity, sex, geographic region, BMI, weight change, diet type, gluten sensitivity (GLUTEN), lactose intolerance (LACTOSE), asthma, and frequencies of smoking and alcohol consumption. The logistic regression was repeated with history of appendectomy (APPENDIX_REMOVED) as the dependent variable and the same dependent variables.2.3We used logistic regression to test associations of case status (cesarean birth or appendectomy) with richness, standard estimates of alpha diversity  and each of the 1949 taxa in the 1097 samples, adjusting for age, sex and race/ethnicity. The Wald test was used to calculate P values as the primary test. Significance after false discovery rate (FDR) adjustment for multiple comparisons was also considered.2.4Pi =  denote the relative abundances for subject i. The Kullback–Leibler (K–L) divergence between subject i and j is defined as DKL(Pj|Pi) = ∑k = 1Kpki log(pki/pkj) with respect to the distribution of subject i. Since the K–L divergence is not symmetric, we calculated the J–S divergence as the distance between the pair , defined as JSD = (DKL(Pi|Qij) + DKL(Pj|Qij))/2, where the vector Qij = (Pi + Pj)/2 represents the average distribution of microbiome community i and j. Based on the J–S divergence matrix, we also performed hierarchical clustering. Based on the distance matrix, we performed permutation tests to investigate whether the case group (cesarean birth or appendectomy) was significantly clustered relative to the whole set of samples.As used previously to define and test associations with clusters of the microbiome in the vagina , our pri2.5The funding source had no direct role in study design, data collection, data analysis, interpretation, or writing the report.3Of the 1097 participants, cesarean birth was reported as “yes” by 92, “no” by 948, and missing or uncertain by 57. Likewise, appendectomy was reported as “yes” by 155, “no” by 961, and missing or uncertain by 21. Selected characteristics of the participants and associations with cesarean birth and appendectomy history are presented in In the 1097 fecal specimens, taxa were mapped to 261 bacterial families, 626 genera, and 844 species. Microbiome richness and alpha diversity estimates were not associated with cesarean birth or appendectomy history . In contCoprobacillus and Holdemania (phylum Firmicutes) and of Neisseria (Proteobacteria), as well as nominally increased abundance of five genera in the Lachnospiraceae, Peptococcaceae, and Ruminococcaceae families of Clostridia (Firmicutes), Dysgonomonas  and Salmonella and Haemophilus . 4Prevotella and especially Lactobacillus taxa. In contrast, cesarean-delivered neonates had a diverse array of taxa resembling the skin microbial community, including Staphylococcus, Streptococcus, Propionibacterineae, Haemophilus, and Acinetobacter  was reported to generally resemble the healthy oral microbiome. Placenta microbial composition differed for two types of women — those who reported a first-trimester urinary tract infection, with enrichment of several genera including r genera . No overr genera . The plar genera .Our study had several strengths, including relatively large size; high quality, unbiased profiles of the microbiome; restriction to individual adults; careful exclusion of recent antibiotic use and medical conditions that might have altered the microbiota; state-of-the-art statistical methods; and comparison of two conditions postulated to alter the gut microbiota. Although widely dispersed across the USA, the participants were not representative of the American adult population, being overwhelmingly non-Hispanic Caucasian (93%) and non-smokers (96%). Nonetheless, the prevalence of cesarean birth in our population, which was born on average in 1967, was 8.8%, comparable to the estimated cesarean rates of 5.5% and 10.4% for births throughout the USA in 1970 and 1975, respectively . The preOur study also had important limitations, of which our lack of data on clinical indication for cesarean section may be the most important, given the fetal distress and antibiotic exposures associated with emergency cesarean. All of the covariate data (metadata) that we did have were self-reported, including birth and appendectomy history. We lacked data to confirm the Human Microbiome Project's finding that fecal microbial composition differed with self-reported history of having been breastfed . The valIn summary, we found a distinct difference in the composition of the fecal microbiota of adult volunteers who were born by cesarean section. History of appendectomy had no such distinction. The cesarean-birth distinction was independent of age and robust across all levels of bacterial taxonomy, but insufficient to define a cesarean-associated microbiome signature. The weaker association with hierarchical clusters , suggestAssociations of microbiome richness and alpha diversity with cesarean birth or appendectomy history.Associations of mean relative abundances for all 1949 taxa with cesarean birth or appendectomy history.The following are the supplementary data related to this article.The authors wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.