Reduction based on four scenarios was implemented: fulfillment of WHO guidelines and EU limits, and an attributable reduction of 15% and 50% in annual PM10 levels. Retrospective study on 288,229 live-born singleton children born between 2009–2010, using data from Spain Birth Registry Statistics database, as well as mean PM10 mass concentrations. Our finding showed that a decrease in annual exposure to PM10 appears to be associated with a decrease in the annual cases of LBW, SGA and PTB, as well as a reduction in hospital cost attributed to been born with LBW. Improving pregnancy outcomes by reducing the number of LBW up to 5% per year, will result in an estimate associated monetary saving of 50,000 to 7,000,000 euros annually. This study agrees with previous literature and highlights the need to implement, and ensure compliance with, stricter policies that regulate the maximum exposure to outdoor PM permitted in Spain, contributing to decreased environmental health risk, especially negative birth outcomes.Air pollution is considered an ongoing major public health and environmental issue around the globe, affecting the most vulnerable, such as pregnant women and fetuses. The aim of this study is to estimate the health impact and economic value on birth outcomes, such as low birthweight (LBW), preterm birth (PTB), small for gestational age (SGA), attributable to a reduction of PM In 2016 effects ,5,6,7,8.Pregnant women and their fetuses are among the most vulnerable groups exposed to air pollution . Some ofThe WHO defines LBW as a newborn that weighed less than 2500 g. It has been estimated that more than 20,000,000 infants around the world are born with this condition . This is3 in PM2.5 levels would produce a decrease of 1720 premature deaths and an increase of 18% in postpone deaths for year 2011 [10 exposure [On the other hand, health impact assessment (HIA) is a methodology that quantify the health effect of implementing public policies . This teear 2011 ,40. Focuexposure . Furthermore, health impacts cannot be separated from economic impact and some previous studies have estimated the economic loss attributable to exposure to air pollutant in places such as in China , Skopje 10 levels in Spain. For this purpose, we have established four scenarios: fulfillment of WHO guidelines [Therefore, this study aimed to estimate the health impact and the economic value on birth outcomes  attributable to a reduction of PMidelines , fulfillidelines , reductiidelines . 10 mass concentrations for every pregnancy. The study population included a total of 288,229 live-born singleton children  born between June 2009 and October 2010, from all Spanish territory except Canary Islands, Ceuta and Melilla.We used the information from the Spain Birth Registry Statistics database available from the National Statistics Institute (INE), as well as the mean PM10 levels were enough to meet the proposed scenarios. Using the information on birth weight (in grams), infant sex, and gestational age (in weeks) compiled in the Spanish birth registry, we calculated the following outcomes: LBW at term , SGA  and PTB . In addition, we defined the term “exit LBW” as the number of infants that could have been born without LBW if the reduction of PM10 were developed with a resolution of 1 km for all Spanish territory except Canary Islands, Ceuta and Melilla. The models combined daily satellite remote sensing data of aerosol optical depth with meteorological parameters  and land use variables  [10 levels at the maternal address at child’s delivery, we used a random forest model including several spatial variables such as traffic, land use, and population. All addresses were geocoded within a buffer of 30 m around the house to ensure anonymization. Considering the gestational age of each child and assuming that women did not change residence during pregnancy, we estimated average levels of the entire pregnancy period of each child. We focused on the pregnancy-average air pollution levels because it is the most relevant exposure metric for investigating the association between long-term exposure to air pollution and birth outcomes.Spatiotemporal land use random-forest models for PMd lakes) . To esti10 level and birth weight showed that a reduction of 10 µg/m3 of PM10 was associated with an increase of 22 g (95%CI = 17.2–28) (linear effect). Logistic models estimated baseline odds ratio (OR) for LBW at term, SGA, and PTB, associated to an increase of 10 µg/m3 of PM10. The results for LBW at term showed an OR of 1.03 (95%CI = 0.96–1.1), for SGA an OR of 1.05 (95%CI = 1–1.09) and for PTB and OR equal to 1.22 (95%CI = 1.16–1.28). All rates were adjusted for following potential confounding variables: sex of the child, age of the mother, age of the father, marital status, parity, mother’s ethnicity, mother’s education, father’s education, deprivation index, mother and father’s occupation, urbanicity, season of conception, average temperature across pregnancy, and autonomous community of mother’s residence.The needed parameters to estimate the health impact came from a parallel analysis within the same project  ,50. A li10 exposure was reduced, using two different approaches. First, we used the estimated linear effect. Second, we used the baseline ORs and applied the following standard methodology:1.10 level of 15 µg/m3 [The WHO air quality guidelines: Recommendation of an annual PM15 µg/m3 10 level of 40 µg/m3 [The air quality standards of EU: Recommendation of an annual PM40 µg/m3 A 15% reductionA 50% reductionAir quality: We computed a baseline scenario and four control scenarios. The baseline scenario was the estimated daily PM levels for 2009–2010 and the four control scenarios were based on:We evaluated the birth outcomes benefits that could be accomplished if PM10 levels above the guidelines and the other two scenarios were implied a constant reduction of PM10 levels across all cases with our birth outcomes based on the NAPCP [The first two control scenarios were applied to the birth outcomes with PMhe NAPCP .2.10 exposure level and outcome incidence.Population data: We computed the number of pregnant women by each PM3.o): We used the association rates of LBW (OR = 1.03), SGA (OR = 1.05) and PTB (OR = 1.22) from the parallel study [Birth outcomes effects : Related to each scenario in µg/m3.Change in PM5.Population attributable fraction (PAF): We estimated PAF attributable to the different scenarios and outcomes using the following formula.In order to estimate the economic expenses, we extracted the economic health cost associated to each birth outcome that was listed in the minimum basic dataset (CMBD). This is the register of activity data from hospitals in the Spanish National Health System in 2020 . The reg10. Other economic expenses such as indirect cost, costs of pain and suffering, financial costs of long-term complications over the course of life, among others, were not included in this analysis.The result represents the annually reduction of costs of preventing cases at national level attributable to the exposure to PMA total of 288,229 births were included, with a mean gestational age of 39 weeks and a mean birth weight of 3246 g. The incidence of LBW at term was 3%, 10% for SGA, and 6% for PTB. 10 across our population during pregnancy was 23.7 µg/m3, with a minimum value of seven µg/m3 and a maximum of 62 µg/m3. This mean value exceeded the 15 µg/m3 target proposed by the WHO Air Quality Guidelines in 2021 (exposed more than 98% of the cases), as well as the previous recommendation  [3 of PM10, and only one woman was exposed to a mean level of more than 60 µg/m3 of PM10 concentration  . We estintration .3 of PM10 level was 8451 infants. The reduction of PM10 levels to meet the WHO recommendation could have prevented an estimated number of 383 neonates with LBW attributable to PM10 exposure, translated to a decrease of 4.5% cases of LBW compared to the baseline scenario   . If the d (0.3%) . 10 concentration, we estimated that 5% of the infants born with LBW could be avoided, translating in the possibility of 424 infants born with healthy birthweight at term , showing that it could be avoided between 1 to 14% of the cases of LBW if this recommendation were fully followed  would provide the higher benefic, presenting a decreased risk of developing LBW up to 14% of the estimated incidence. The estimated value of this economic impact would reach up to 6,500,000. Even if the PM10 levels could only be decreased to the previous recommendation (levels below 20 µg/m3), it would still represent a significant decrease in LBW incidence. In addition, WHO scenario could have avoided 2–25% of the cases of SGA and 10–100% of the cases of PTB, resulting this guideline in an effective recommendation. On the other hand, the laxer scenario recommended, EU standards (40 µg/m3) [In relation to the four different scenarios. The results from the first approach (linear effect) showed that the best scenario would be the overall reduction of PM10 levels by 50%, with a 5% reduction on LBW. The second-best scenario would be compliance with WHO guidelines with a 4.5% reduction. A reduction according to EU guidelines would produce minimum health benefits. The results from the second approach (baseline ORs) showed that the compliance with WHO guidelines (level below 15 µg/m0 µg/m3) , would hThe economic impact was evaluated taking into consideration the total avoided minimal hospital cost among each recommended scenario, based on the health benefits of being born with a healthy weight. The burden of being born with a birth outcome goes beyond hospital expenses, impacting as well on lifelong health, education, social services and on their families . Neonate10 levels and birth outcome and could potentially bias the results. Another limitation is that we estimated PM10 at the home address listed in the birth Registry, without consideration that pregnant women could spent more time of a day in other locations, such as work or could have moved to a different address during any stage of the pregnancy. However, this study contains a large sample of approximately to 288,000 records, over a period of 16 months, from all Spanish territory, except Canary Islands, Ceuta and Melilla, extenuating potential bias that could be present because of the limited information, as well as growing the strength of the estimations of our results.Apart from the constraints on the economic impact estimation already mentioned, this study is not exempt of more potential limitations. A main one is the no inclusion of data on previous maternal health history, substance use, complications or diseases during pregnancy that may affect the newborn’s weight. Moreover, we did not have information about age at pregnancy, maternal lifestyle or data of exposure to other air pollutants, when estimating the OR. Those previous variables could interact with our estimates if they were correlated with both exposure to PM10 levels by 50% would improve pregnancy outcomes, with an estimated reduction close to 5% of LBW cases and an estimated associate monetary saving of between 50,000 and 7,000,000 euros annually. Even a reduction of 15% would have health benefits. Moreover, this assessment highlights the need to implement, and ensure compliance with, stricter policies that regulate the maximum exposure to outdoor fine PM10 levels permitted in Spain, contributing to decreased environmental health risk—especially negative birth outcomes. European Directive guideline is too permissive. Therefore, more restrictive guidelines, aimed at a maximum reduction in air pollution, should be a priority for public health policies in the EU.In conclusion, these results show that complying with the WHO guidelines or an overall reduction of PM


Controversy remains regarding surgical managements of sylvian fissure arachnoid cyst (SFAC). This review presents our experience in the microsurgical fenestration of pediatric patients with SFAC to define surgical indication, and risks and benefits with special emphasis on postoperative subdural fluid collection (SDFC) and cyst size reduction.Thirty-four children with SFAC who underwent microsurgical cyst fenestration at a single institution over a 10-year period were retrospectively reviewed for their clinical presentation, neuroimaging findings, and postsurgical course. The SFACs were classified by a novel grading system based on the degree of arachnoid cyst extension from the sylvian fissure to the insular cistern shown on MR images: grade 0 — little or no prominence of sylvian fissure, grade I — SFAC confined to the sylvian fissure, grade II — SFAC partially extending to the insular cistern, grade III — SFAC extending to the entire insular cistern.p > 0.9). All patients underwent microsurgical cyst fenestration. Postoperative SDFC is common but often resolved overtime in two-thirds of the cases with the mean average of 6 months. However, 3 patients had symptomatic postoperative SDFC and needed reoperation shortly after the first operation. Microsurgical cyst fenestrations for SFAC effectively resolved the presenting symptoms and often showed restorations of intracranial structures on follow-up imaging. Cyst resolution or reduction greater than 75% was noted in 61.8% of the patients postoperatively which was noted in a half of the SFAC of children even with age of 11 years or older. During the follow-up, no cyst recurrence or SDFC was noted. Patients with greater surgical reduction of cyst size tended to occur in younger children, and those with lower MR grade.There were 26 males and 8 females. SFAC was present in the left side in 24. Twelve patients presented with cyst rupturing to the subdural space. Cyst grading did not show significant difference compared with rupture status (Our results showed a high reduction rate of SFAC and brain re-expansion after microsurgical fenestration together with symptomatic improvements regardless the patient’s age. Considering the developing CNS during childhood, reductions of a large space-occupying lesion followed by restorations of the structural integrity of the developing brain are very desirable. However, a multi-center cooperative prospective longitudinal study on long-term comparative data of those treated and untreated of neuro-psychological outcome and cyst rupture incidence is needed. Sylvian fissure arachnoid cyst (SFAC) is the most common type of intracranial arachnoid cyst (IAC), consisting of 47 to 66% of all pediatric IAC –3. PreseMuch controversy remains regarding the management of SFAC, specifically the role of surgical interventions. In particular, when the child presents with a large space-occupying cyst in the middle cranial fossa with relatively insignificant symptoms, it may be challenging for clinicians to determine their recommendations. The reasoning of surgical intervention in such a case may be prophylaxis for future neurological deterioration or hemorrhagic rupture. However, there is no consensus in this regard, and its decision depends on the surgeon’s preference and previous experience, rather than on systematic protocols . IncidenFollowing successful SFAC fenestration, a great majority of children’s preoperative headaches, emesis, decreased vision, cranial nerve palsy, and papilledema improve. On the other hand, the improvement of chronic symptoms, such as bone bulging, macrocephaly, developmental delay, and seizures, are much less , 8. CunyWith regard to the natural history of arachnoid cysts, the stability of cyst size without intervention has been documented at 3–4 years follow-up , 2. AsymRupture, either spontaneous or post-traumatic, is a well-recognized complication of SFAC leading to subdural effusion or hematoma. Cress et al. reported that SFAC is the most common cause of subdural hygroma, or hematoma related to rupture of IAC, comprising 87% of cases, and the rupture is more common among children, with mean age 5.9 years during childhood . Among aCyst size reduction has been noted in most of the cases following cyst fenestration by either microsurgery or endoscopy . The cysSurgical intervention is accepted when patients present with evidence of increased ICP, such as headaches, papilledema, abducens palsy, or lethargy, or with acute presentation due to rupture of the cyst to the subdural space. On the other hand, for the cases presenting with incidental SFAC or ambiguous symptoms, surgical management remains controversial regardless of the size of SFAC and is often not recommended because of stable in size of SFAC over extended time and the potential surgical complications , 13.Surgical procedures for SFAC include microsurgical or endoscopic cyst fenestration while cystoperitoneal (CP) shunts are not widely recommended because of shunt dependency. Cyst fenestration can be complicated by subdural effusion or hematoma, CSF leak from the surgical site, cranial nerve palsy, and failure of size reduction or recurrence of the cyst , 2, 16. This review of our surgical series of operative SFAC focuses on clinical outcome following microsurgical cyst fenestration, with particular emphasis on cyst size reduction, postoperative SDFC, and clinical outcome.A retrospective study was conducted of all patients who had microsurgical cyst fenestration of SFAC diagnosed and treated at a single neurosurgical center from 2010 through 2019. We included in this study only children who were treated with a temporal craniotomy and microsurgical cyst fenestration to the suprasellar cistern. Patients who underwent endoscopic cyst fenestration or primary CP shunt were excluded. Also, patients who underwent only outer membrane excision without fenestration were excluded. All patients underwent a keyhole temporal craniotomy under neuronavigational guidance for fenestrations by creating a cystocisternostomy. Presenting signs and symptoms, radiographic imaging studies, operative reports, and postoperative and ambulatory records were reviewed. Cyst location and size were reviewed by preoperative, postoperative, and subsequent follow-up magnetic resonance (MR) images. This investigation was approved by the Lurie Institutional Review Board (IRB #2020–3252).Based upon the MR characteristics of arachnoid cyst extension from the sylvian fissure to the insular cistern, we developed our own classifications for SFACs into 4 grades as follows: Grade 0 — no or little enlargement of the sylvian fissure; grade I — cyst localized in the proximal sylvian fissure Fig. ; grade IDependent on the presence and absence of SDFC over the cerebral convexity at presentation prior to craniotomy, SFACs were divided into “rupture” group and “non-rupture” group. Postoperative follow-up evaluations and MR images were done regularly, within 48 h after the surgery, 3 months, 6 months, 1 year, and subsequently annually for 5–6 years after the cyst fenestration. Cyst volume size was measured in the transverse, anteroposterior, and craniocaudal dimensions, at their largest diameter to compare preoperative measurements with subsequent ones. The final comparison of the changes of the cyst size was based on preoperative and the latest MR findings.t-test. Kaplan–Meier curve analysis was done to assess time to subdural collection resolution. Statistical analysis was performed using SPSS Statistics software .Demographic, clinical, and imaging characteristics were analyzed using summary statistics. Further univariate analysis to identify factors associated with cyst and subdural collection resolution were completed using chi-square analysis and independent samples There were thirty-four patients with SFAC who underwent a temporal craniotomy for microsurgical cyst fenestration. They were 26 (76.5%) male and 8 (23.5%) female. At the time of surgery, the average mean age was 9.4 years ± 4.8. Follow-up information was available from 4 months to 9 years (average 3.68 years) after the SFAC fenestration. Three patients had follow-up less than 6 months, while follow-up visits were a minimum of 1 year for the remainder.Four patients (11.8%) were diagnosed incidentally with no or little symptoms referable to the cyst in spite of large cyst size and mass effect on the surrounding tissue. The remaining thirty patients presented symptomatically (88.2%): primary symptoms included 21 with headache ± nausea (61.8%), 3 with neurologic deficits (8.8%), 2 with cognitive dysfunction (5.9%), 4 with seizure or abnormal EEG (11.8%). Of those with neurologic deficit at presentation, one had abducens nerve palsy, another had ipsilateral visual disturbance, and the other presented with acute vision loss and stroke. Papilledema was documented in 6 patients, five of which occurred among the “rupture” group. Two patients were noted to have macrocephaly.p = 0.384).There were twelve (35.3%) patients that presented with a preoperative cyst rupture and SDFC over the cerebral convexity (“rupture” group). Within the “rupture” group, 4 (33.3%) had documented head trauma prior to presentation; a minor trauma in 3, and a football-related head concussion in one. Of the 22 patients with unruptured SFAC, 4 (18.2%) experienced minor trauma prior to presentation. The mean age was 8.4 years ± 4.8 among the “rupture” group and 7.9 years ± 5.3 among the “non-rupture” group without statistical difference (p = 0.598). The location of subdural collection was ipsilateral in 5 and bilateral in 7 at initial evaluation. But four of bilateral subdural collections became ipsilateral before the surgical intervention  patients had left-sided arachnoid cysts; 10 29.4%) were located on the right side. Preoperative MR showed grade I in 11 (32.4%), grade II in 9 (26.5%), and grade III in 14 (41.2%). There was no significant difference between cyst grading and rupture status  placed as an initial treatment. One of them experienced increased subdural effusion despite ESD for 3 days, and he subsequently underwent cyst fenestration. The other patient had 6 days of ESD, which was removed after symptomatic improvement; however, 2 months later, due to recurrent headaches and increasing subdural collection on a follow-up imaging, he underwent craniotomy for cyst fenestration.The third patient, a 12-year-old male, had a non-ruptured SFAC and presented with acute headaches and homonymous hemianopia with evidence of ipsilateral posterior cerebral artery infarct on MR Fig. . He undeA keyhole temporal craniotomy of size ranging from 2.5 to 3.0 cm in diameter was placed over the cyst dome using a neuronavigational system. Exposed dura uniformly showed bluish discoloration indicative of underlying fluid collection. The ICP was not measured, but it deemed elevated in all because the cyst wall bulged out upon the opening of the dura, or cyst fluid or subdural fluid gushed out under pressure. All non-rupture cysts contained crystal clear fluid. Among the “rupture group,” 10 patients showed clear xanthochromic subdural fluid while the remaining two had grossly hemorrhagic fluid but without clot formation. Only one patient showed the presence of an organized subdural membrane over the parietal cyst membrane.For the cyst fenestration, the outer cyst membrane was partially excised, and the cyst space was entered. Then, the medial cyst wall next to the edge of the tentorium was approached under a surgical microscope. The medial cyst membrane adjacent to the suprasellar cistern at the tentorial edge was often thick, multilayered, and fibrous. It was sharply dissected and then partially excised to establish the maximum cystocisternostomy. Upon opening the medial cyst membrane, para-sellar structures, such as the ipsilateral carotid artery and its branches, the oculomotor nerve and the optic nerve, chiasm, and tract were exposed Fig. . In someFollowing the craniotomy, three patients (8.8%) had an unplanned return to the operating room due to postoperative symptomatic SDFC: two from the “non-rupture” group and one from the “rupture” group. One was a 4-year-old boy of the “non-rupture” group who developed acute headaches, lethargy, and bradycardia 3 days postoperatively due to an expanding ipsilateral hemorrhagic subdural effusion. He was treated with ESD for 7 days and his symptoms resolved. The ESD was removed and 2 years following the cyst fenestration, not only the subdural collection but the SFAC had resolved.Another patient, a 7-year-old with a ruptured grade III arachnoid cyst, presented with headaches when MR showed a ruptured subdural collection over bilateral convexity. His symptoms improved and he was observed. However, 6 weeks later, he acutely developed severe headaches and MR showed increased midline shift with increased left convexity subdural collection and mild reduction of the left SFAC. He had a subdural membrane noted at craniotomy for fenestration. A cyst fenestration was done following the evacuation of the hemorrhagic subdural collection (no clot). Postoperatively, overnight he developed lethargy and left oculomotor nerve palsy, needing a re-craniotomy with ESD. He improved and hemorrhagic subdural fluid becomes clearer and the ESD was removed 14 days postop. SDFC resolved on 3-month postoperative imaging and his group III SFAC was reduced to group II.The third patient was an 18-month-old girl, “non-rupture” group III SFAC, with macrocephaly and developmental delay, developed symptomatic bilateral subdural collection 4 weeks after the fenestration. She underwent burr hole and drainage of subdural collection with a placement of ESD. However, 2 weeks after removal of the ESD, she developed symptomatic SDFC, and had placement of a subdural peritoneal shunt. This was the only patient who was treated with shunting after cyst fenestration in our series.Neurological complications included transient cranial nerve III palsy in 2 (5.9%) patients, which were transient and resolved in 2 months. Another patient had vertical diplopia, likely due to trochlear nerve manipulation, which resolved in 6 weeks.Of 26 patients with preoperative headaches, 20 (77%) had resolved. Headaches improved and only intermittent or migraine-like headaches in 3 (2 grade I and 1 grade II), while headaches were persistent in 3 (2 grade I and 1 grade II). In all of grade III patients, preoperative headaches resolved. Three patients who presented with seizures showed no seizures during the 2.5 to 10 years follow-up, and only one remained on antiepileptic drugs. Macrocephaly stabilized in 2 patients. One patient who presented with cranial nerve six palsy preoperatively had resolution of the palsy postoperatively. However, all 3 patients with psychomotor delay/behavioral disturbance showed no or little improvement.All 4 incidentally found SFAC remained asymptomatic, and their cyst size decreased by 90% or greater in 2 patients, 75% in 1 patient, and 50% in 1 patient.Post-operatively, 30 patients developed cerebral convexity SDFCs (18 “non-rupture” group and 12 “rupture” group), while 4 patients, “non-rupture” group, showed little or no SDFC on postoperative imaging.The SDFCs were present on immediate postoperative imaging while two patients developed a delayed SDFC after 7 and 10 days, respectively, both of which resolved without intervention. Six patients had persistent but decreased asymptomatic SDFCs, 4 of which were persistent for more than 5 years .The remaining 24 (70.6%) of 30 SDFCs were resolved at various times during follow-up; 8 resolved in less than 3 months, 6 resolved between 4 and 6 months, and 5 resolved between 7 and 12 months; thus, 19 (79.2%) of the resolutions of subdural collection occurred within 1 year. The remainders, 2 were resolved between 13 and 24 months and 2 others were resolved 6 years after the cyst fenestration. Follow-up of a child with SDFC was too short. Figure The changes in cyst volume were evaluated before and after the cyst fenestration. SFAC collapsed or resolved in 8 (23.5%), reduced more than 75% in 13 (38.2%), reduced to between 50 and 75% in 3 (8.8%), less than 50% reduction in 7 (20.6%), and remained unchanged in the 3 (8.8%). Thus, 21 (61.8%) patients showed quite significant cyst volume reduction greater than 75% of the preoperative size following microscopic cyst fenestration. The extent of the cyst reduction was compared with the MR grades, “rupture” vs. “non-rupture” status and the patient’s age, respectively (Table p > 0.1). Comparing the cyst rupture status at presentation, “non-rupture” groups had a significant cyst reduction (p < 0.01): 17 of 22 “non-rupture” group vs. 4 of 12 “rupture” group had the cyst collapse or a greater than 75% cyst reduction. The patient’s age was classified into 1–5 years (9 patients), 6–10 years (9 patients), and 11–17 years (16 patients), and compared with the cyst size outcome. Six (66.7%) of the 1–5 year group, 7 (77.8%) of the 6–10 year group, and 8 (50%) of 11–17 year old group had the cyst collapse or a greater than 75% reduction. Although the younger patients appear to have greater cyst size reduction, the difference is not statistically significant (p > 0.1).A cyst collapse or a greater reduction more than 75% was noted in 9 of 11 grade I, 5 of 9 grade II, and 7 of 14 grade III. Although the lesser grade cysts appear to have greater cyst size reduction, the difference is not statistically significant  , 38. ForHowever, Chen et al. compared endoscopic, microsurgery, and CP shunt by meta-analysis, and noted clinical improvement and cyst reduction were better after CP shunt. Also noted was that short-term complications were worse among the microsurgery group while long-term complications were worse after CP shunt . In spitBoth endoscopic cyst fenestration and microsurgical cyst fenestration have been extensively described in the literature , 43–46. Comparisons between microsurgical and endoscopic techniques are beyond the scope of this communication. We have used microsurgical cyst fenestration to establish a sufficient stoma between the cyst and basal cistern. Cyst wall resection without cyst fenestration tends to cause symptomatic SDFC , 32. CysRuptured SFAC often present with severe symptoms. The recommended procedure of choice is burr hole/drainage or placement of a temporary ESD. Wu et al. stated that fenestration or resection of the arachnoid cyst membrane is not a requisite in patients with previous asymptomatic arachnoid cyst . HoweverCreation or expansion of subdural space is naturally common after decompression of a large space-occupying lesion such as SFAC, resulting in iatrogenic subdural effusion, which is one of the reasons against surgical treatment of asymptomatic SFAC. Tamburrini et al.  attributThe literature indicates various rates of the cyst reduction after cyst fenestration of SFAC. Spacca et al. reported SFAC disappeared in 5 patients, was reduced in 24, was unchanged in 9, and increased in 2 among 40 patients who underwent an endoscopic fenestration . Schultzp > 0.2); dividing the age 10 years or younger vs. older, greater than 75% reduction was noted in 72.2% and 50%, respectively. The reduction of the cyst is significantly greater among the “non-rupture” group; a greater than 75% of the cyst reduction was noted in 72.7% of the “non-rupture” group while only 33.3% among the “rupture” group (p < 0.01).Our current study showed several factors influence the post-fenestration cyst reduction. They are SFAC grades, “rupture” vs. “non-rupture,” and patient’s age. The cohort of lower grade showed more cyst size reduction postoperatively; cyst disappearance or more than 75% reduction were noted in 81.8% among grade I, in 55.6% among grade II, and in 50% among grade III. Also, we noted a younger age tends to show better cyst reduction, albeit no statistical significance  based on the cyst size, and presenting symptoms of the patient. Although our patients did not experience cyst recurrence and SDFC in long-term follow-up, the follow-up period may be too short to conclude the efficacy of the treatment provided.Controversy remains regarding the management and treatment of SFACs, specifically regarding the role of surgical intervention for patients with relatively minor presentation. Although it remains controversial, several authors recommend cyst fenestration for asymptomatic SFAC because of improved cyst size reduction and low risk of complications , 32 and


MMc was present in most infants across infancy, with levels ranging from 0 to 1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal and infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc level in HIV-exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence the level of MMc, which may subsequently affect infant T cell responses.Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors that influence MMc detection and level across infancy and the effect of MMc on T cell responses to bacillus Calmette-Guérin (BCG) vaccination in a cohort of HIV-exposed, uninfected and HIV-unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day 1, and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4  During pregnancy maternal cells are transferred to the fetus and persist in small quantities postnatally, a phenomenon known as maternal microchimerism (MMc). The impact of these maternal cells on the development of the fetal and infant immune system is largely unknown. MMc is acquired as early as the second trimester , 2, is f+ T cell infiltration . The mean maternal age at delivery was 27 years (standard deviation [SD] 5.1)  . This waP = 0.033; P = 0.028), as did the association with increased HLA compatibility , while the impact of infant female sex remained significant   analyzed in whole blood samples collected at day 1 of life (henceforth referred to as birth) was 148,187  per sample. Two outcomes were considered for each analysis: (a) the detection of any MMc (no or yes) and (b) the level of MMc. At birth, MMc was detectable in 23 of 58 (39.7%) infants, with levels ranging from 0 to 24/100,000 gEq . In orde= 0.037) .In addition to the birth time point, we also evaluated MMc at week 7, 15, and 36 of life. Across infancy, MMc was detectable at any time point in 44 of 58 (75.9%) infants, with a range of detection of 1 to 3 time points and levels ranging from 0 to 1,193/100,000 gEq . Within P = 0.012; P = 0.036; P < 0.001; P = 0.013; P = 0.080; P < 0.001) and nonsignificantly higher levels in the adjusted model  of MMc among early- versus late-ART iHEUs across infancy. Collectively, these data indicate that longer duration of maternal ART (from preconception) may partially restore MMc levels in iHEU.We next assessed whether the timing of ART initiation (preconception or during gestation) altered the effect of maternal HIV on MMc by considering the iHEUs by timing of maternal ART initiation (early or late ART) and repeated the analyses. While both of the HIV-exposed groups had lower levels of MMc compared with the iHUs at birth, this was only significant for infants born to mothers with late ART initiation . Similar+ T cell responses in 33 infants across 48 samples and adjusted for BCG strain (Danish versus Russian), HIV exposure, and infant age in our analyses. Both detection . Infant PBMCs from these time points were stimulated with BCG culture filtrate proteins, followed by intracellular cytokine staining. T cells were sorted into polyfunctional, monofunctional, or nonresponding populations, and we measured MMc level in each population by qPCR. While we were able to detect an enrichment of maternal T cells in the polyfunctional population from 1 iHU, they remained the minority of the responding population, and no MMc was detected in the polyfunctional cells in the other 3 infants  for functional evaluation  compared with sons  , 54, in + T cell responses to BCG in the infant. Polyfunctional T cells may be indicative of the quality of immune responses to vaccines and have been associated with better clinical prognosis during tuberculosis (TB), HIV, and other infections as compared with the absolute magnitude of T cell responses  cohort, and very few in the Western Cape in South Africa, precluding our ability to study this group. Furthermore, HIV infection and ART exposure is associated with higher rates of preterm birth  and informative typing for a maternal allele with an assay available (n = 58).Data and samples were utilized from the InFANT study, a prospective birth cohort study conducted in Khayelitsha, Cape Town, South Africa, funded by the Canadian Institute for Health Research (co-PIs CM Gray and HB Jaspan). Mother-infant pairs were recruited at the Midwifery Obstetric Unit at Site B in Khayelitsha, Cape Town, South Africa, from March 2014 to March 2018. Infants were followed from birth, at day 4 to 7, and at weeks 7, 15, and 36 of life. Voluntary counseling and HIV testing was done at the time of antenatal care registration. Both pregnant women living with HIV (WLHIV) and women not living with HIV were eligible for the study. Pregnant WLWH and their infants were provided with ART according to the current country-specific guidelines . ExclusiWhole blood samples were collected on day 1 (birth) and weeks 7, 15, and 36 of life into sodium-heparin tubes. A 200-μL aliquot of the whole blood was lysed using FACS lysis buffer and subsequently fixed and stored at –80°C until genomic DNA (gDNA) extraction. The gDNA was extracted from fixed whole blood (WBF) samples from infants and mothers using QiaAMP DNA Mini Kits (Qiagen), with slight modifications to the manufacturer’s protocol. In brief, WBF samples were thawed and centrifuged for 2 minutes to pellet cells. The supernatant was discarded and the pellet resuspended in 180 μL Qiagen Buffer ATL and 20 μL proteinase K followed by incubation at 56°C for 1 hour. This was followed by addition of 200 μL Buffer AL and 200 μL 100% ethanol and the entire sample lysate was transferred onto the QIAamp MinElute column. The gDNA was eluted using 200 μL molecular grade water, which was allowed to incubate in the column for 10 minutes at room temperature to increase DNA yield.GSTT1, ATIII, TG, and TNN, targeting insertion/deletion polymorphisms . Noninherited, nonshared HLA polymorphisms were identified that could be used to evaluate MMc . Mother-orphisms . The matorphisms , 70, 71.orphisms . DNA froTo analyze the degree of HLA class II relatedness for each mother-infant pair, we generated a scoring system based on whether the infant’s paternal allele at each locus  was a match to self from the mother’s perspective. A score of 0 at a single locus signified no match between the infant’s paternally inherited allele and either of the mother’s 2 alleles; a score of 1 signified a match between the infant’s paternally inherited allele and at least one of the mother’s alleles at that locus. For each pair, we summed the score at each locus to give an HLA compatibility score from 0 to 5 .A 12-hour whole blood assay was used to evaluate vaccine responses as previously described . Briefly+ events were collected using BD FACSDiva v6 software. Postacquisition compensation and analysis was performed in FlowJo version 9 . +CD4+ T cell response assessed by analyzing permutations of TNF-α, IL-2, and IFN-γ expression after stimulation using combinatorial polyfunctionality analysis of antigen-specific T cell subsets (COMPASS) (Staining and flow cytometry were conducted as previously described . In brieCOMPASS) . PFS andCOMPASS) .2 for 6 hours, upon which the reaction was stopped with the addition of EDTA (2 mM). Cells were treated with human Fc block  and then stained with LIVE/DEAD Fixable Aqua (Thermo Fisher Scientific) and the following extracellular monoclonal antibody–fluorochrome conjugates: CD3–PE-Cy7 , CD4-BV421 , CD8–PerCP-Cy5.5 , CCR7-BV785 , and CD45RO–PE-CF594  or CD45RO-APC . Cells were washed and then resuspended in Cyto-Fast Fix/Perm Buffer (BioLegend), followed by washing in Cyto-Fast Perm Wash solution (BioLegend). Cells were then stained with intracellular monoclonal antibody–fluorochrome conjugates IL-2–PE , TNF-α–FITC , and IFN-γ–BV605 . Cells were washed, resuspended in cell staining buffer, and run on a BD FACSAria II cell sorter with single-stained AbC Total Antibody or ArC Amine Reactive Compensation Beads as compensation controls. To sort BCG-stimulated T cells into a polyfunctional population , a monofunctional population (positive for 1 cytokine), and a nonresponsive population (negative for the 3 cytokines), cells were gated according to the scheme in PBMCs were isolated via density gradient centrifugation from infant whole blood. Available PBMCs from infants who had detectible MMc at birth (in whole blood) and a COMPASS PFS of greater than 0.6 at the concurrent time point were selected for stimulation with BCG culture filtrate proteins. PBMCs were thawed and treated with BD FastTimmune anti-CD28/anti-CD49d costimulatory antibodies , brefeldin A , and BD GolgiStop (1:1500). PBMCs were then stimulated with BCG culture filtrate proteins , media, or PMA  and ionomycin  and incubated at 37°C, 5% COP value of less than 0.1 .Statistical analysis was performed using Stata 14 software (StataCorp LP) and R (version 4.0.3). Detection of MMc at birth was evaluated by logistic regression with adjustment for the total number of gEq tested for each subject. Level of MMc at birth was evaluated with negative binomial regression, accounting for the number of microchimeric gEq detected as well as the total number of gEq assessed in each sample , 74, 75.Detection of MMc across infancy was assessed using generalized estimating equation (GEE) models clustered by individual, a binomial outcome structure, and an independent correlation matrix. Level of MMc across infancy was assessed using GEE models clustered by individual, a negative binomial outcome structure, and an independent correlation matrix. In addition to the covariates mentioned above, mode of feeding and infant age in weeks were considered for inclusion in the adjusted models.The effect of MMc on the polyfunctionality of BCG vaccine responses (PFS) were assessed using GEE models clustered by individual, a gaussian outcome structure, and an independent correlation matrix. We have previously shown that iHEU infants have altered T cell functionality in response to BCG  and thatThe study was approved by the University of Cape Town Human Research Ethics Committee (Rec ref 285/2012) and the Institutional Review Board of Seattle Children’s Hospital (Protocol 15690). All mothers in the study were of consenting age and provided written informed consent for their and their infant’s participation.CB, BA, HBJ, SBK, CMG, JLN, and WEH conceived and designed the experiments. HBJ and CMG designed and recruited the InFANT cohort. CB, BA, AK, AAH, and AUH processed samples and performed wet lab experiments. CB, WEH, XS, and AK analyzed the data. CB, HBJ, and WEH wrote the original draft of the manuscript. All authors reviewed and edited the manuscript.


Marsupialisation of odontogenic cysts is a minimally invasive treatment method used in human dentistry. Marsupialisation decompresses the cyst and promotes remodeling of alveolar bone and shrinkage of the cyst. In this retrospective study we look at the effectiveness of marsupialisation at reducing the size of odontogenic cysts in dogs. The case series consists of six Boxer dogs with 12 odontogenic cysts. Each case underwent a high resolution CT scan prior to treatment and at follow-up. Each CT scan was reviewed, the volume of each cyst calculated using manual segmentation and the reduction in cyst volume calculated. There was a marked reduction in cystic volume of 66.6% over a mean of 138 days. This shows that the use of marsupialisation effective method of reducing cyst volume. An odontogenic cyst is a pathological, epithelium lined cavity which is derived from the odontogenic epithelium and contains either fluid or semisolid material , 2. OdonIn veterinary dentistry, the current treatment method of choice for odontogenic cysts is the surgical exposure of the cyst and complete extirpation of the cyst lining through the use of curettage . This teMarsupialisation was first described in human dentistry by Partsch . The proTo the authors' knowledge, there has only been one report in the veterinary literature of the use of marsupialisation in the treatment of an odontogenic cyst. In that study, this technique was used alongside extirpation in the treatment of an extensive periapical cyst in order to avoid excessive iatrogenic trauma to the maxilla of the patient . There iThe objective of this retrospective study was to review a case series of Boxer dogs which had odontogenic cysts marsupialised as a first stage treatment and to evaluate the effectiveness of the technique at reducing the cystic volume. Volume reduction was calculated by comparing cyst volumes on computed tomography before marsupialisation and at follow-up.We hypothesized that marsupialisation is an effective first stage treatment of odontogenic cysts and results in significant reduction in volume of the cyst through decompression, allowing safe enucleation at a later stage if required.Clinical records were searched for Boxer dogs that had undergone treatment of odontogenic cysts at Eastcott Referrals, Swindon, UK, part of Linnaeus Veterinary Limited between 2019 and 2022. To meet the inclusion criteria, a case must have had at least one odontogenic cyst originating from the mandible or maxilla treated with the use of marsupialisation. Each case was required to have had a preoperative and follow-up high resolution CT scan as well as a histopathological diagnosis. The clinical notes for cases that met these criteria were reviewed, and the following were recorded: the signalment , presenting clinical signs, findings of clinical examination at presentation and follow-up, histopathological diagnosis and the interval between marsupialisation and follow-up CT.Since 2019 a standard protocol has been used at Eastcott Referrals, Swindon for the management of odontogenic cysts using marsupialisation. This protocol is described below.A transverse collimated CT scan was obtained for each case prior to surgery using the following acquisition parameters . A bone and soft tissue window is acquired which allows us to locate the cyst, identify any teeth involved and a point of access to the cyst. Following this, the patient was positioned in lateral recumbency, and a detailed oral examination and dental charting was performed. The oral cavity was rinsed with a 0.12% chlorhexidine solution and appropriate locoregional anesthesia was performed.®, Ethicon, Somerville, NJ, USA) creating a marsupialisation  and acetaminophen/codeine  10 mg/kg TID. The owners were instructed to feed soft food only and lavage the stoma sites with 0.12% chlorhexidine solution twice daily after meals for 2 weeks. Hard chews and toys were also restricted for this period. Each owner was advised to book a follow-up appointment with the referring vet 10–14 days post-operatively. Following this, regular monthly check-ups were advised to monitor the stoma sites for signs of premature closure.Each case is re-examined at the clinic 3 months post-operatively and a follow-up CT scan is performed using the same acquisition parameters. A detailed oral examination including dental charting is performed and the patency of the stoma is assessed using a periodontal probe. Appropriate local anesthesia is performed and the remaining cyst lining extirpated. In some cases where there is sufficient infilling of bone so that no cavity remains, the stoma was left open and the patient was re-examined in a further 3 months.TM, Geneva, Switzerland). For each cystic structure identified, the location was recorded as either mandibular or maxillary. The cyst was then categorized based on the surrounding tissue into either a cyst completely surrounded by bone (B), a cyst surrounded by bone with soft tissue involvement (B + ST), or a cyst surrounded by bone with extension into the nasal cavity (B + NC).Each CT scan was reviewed in DICOM format by both a board-certified radiologist and a resident in dentistry and oromaxillofacial surgery using viewing software  was then calculated with the ROI compute volume function in the viewing software which uses a combination of the slice width, slice spacing and individual ROI volumes. The volume for each cyst was recorded at time of marsupialisation and at follow-up. The reduction in volume (cm3) between marsupialisation and follow-up was calculated for each cyst  which represented the outline of the cyst in that selected slice . This waach cyst . Each ROp < 0.20 were combined in an overall model, with nonsignificant terms then removed by backwards elimination. Residuals from this model met normality assumptions . Residuals from this model met normality assumptions . Tukey post-hoc tests were used to compare any significant factors with more than two levels. Significance was taken as p < 0.05, all analysis was undertaken in Minitab 19.Statistical analysis focused on the analysis of percentage reduction in cyst volume. Because several dogs had more than one cyst, generalized linear mixed effects models were used with dog as a random effect. The first steps of analysis were to consider whether the mean reduction differed from zero and to test separately the influence of each of five potential influencing factors . Any of these factors that achieved This case series consisted of six male Boxer dogs with a mean age of 6 years 3 months (range 2 years 4 months to 9 years 8 months). A total of 12 cysts were marsupialised. Fifty percentage (6/12) of the cysts were incidental findings with no evident clinical signs, with others presenting as facial swelling  and upper respiratory signs such as stertor and nasal discharge . The reason for pursuing marsupialisation was the presence of a cyst associated with teeth of strategical importance such as the canine, maxillary 4th premolar and mandibular 1st molar teeth . These teeth had no evidence of external inflammatory resorption, excellent periodontal health and the apical 1/3 of the root was encased in bone. The other three cysts were located intranasally where a complete enucleation would have required an advanced maxillofacial surgical approach such as a rhinotomy.3 (0.45–19.50cm3) and 1.32 cm3 (0.00–4.46cm3) at follow-up (Seven cysts (58.3%) were in the mandible and five cysts (41.7%) were in the maxilla. Evaluation of the histopathology results and clinical findings provided a diagnosis of dentigerous cyst in 9/12 (75%). The remaining 3/12 (25%), were classified as odontogenic cysts with further classification not possible. An unerupted 1st premolar tooth was involved in 9/9 dentigerous cysts with 7/9 (77.8%) located in the mandible. Five of the cysts (41.7%) were completely surrounded by bone (B), 4 (33.3%) had extension into the surrounding soft tissue (B + ST), and 3 (25.0%) extended into the nasal cavity (B + NC). The mean volume of the cysts prior to marsupialisation was 6.13 cmollow-up . The meap < 0.20 (p = 0.018) and cyst category . The only significant difference identified by a Tukey test was that the estimated volume reduction adjusted for age was significantly higher for cysts with extension into the surrounding soft tissue (B + ST) than cysts that were completely surrounded by bone (B).The reduction in cyst volume between pre-operative CT and follow-up CT was significantly different from zero . An examp < 0.20  and wereThe size of the initial stoma ranged from 7 to 25 mm in diameter. All cases showed reduction in the size of the stoma site and there was no evidence of food impaction or infection of the stomas. There was no premature closure of any of the marsupialisation sites. At follow-up, all the cysts were enucleated.Dentigerous cysts are the most common odontogenic cyst in dogs, occurring in 71% of cases . In comparison, B cysts had a mean volume of 3.5 cm3 (0.6–5.3 cm3) and B + NC cysts had a mean volume of 5.0 cm3 (1.6–7.7 cm3). This finding supports that of previous human studies which found that the larger the cyst, the greater the rate of volume reduction post-marsupialisation (The rate of reduction of the cysts when adjusted for age was found to be significantly higher in cysts with extension into surrounding soft tissue (B + ST), compared to cysts that were completely surrounded by bone (B) and those which extended into the nasal cavity (B + NC). B + ST cysts were the largest in the case series with a mean volume of 10.8 cmlisation , 15.Follow-up CT and radiographs at least indicated new alveolar bone formation around the teeth left in place and that the teeth were vital, however, the presence of periodontal ligament regeneration could not be confirmed. Histopathology would be required to determine whether there is periodontal ligament regeneration as a result of decompression and bone regrowth. It is uncertain whether that these teeth retain their periodontal ligament or whether it is destroyed as a result of cystic expansion.Seventy-five percentage of the identified odontogenic cysts were dentigerous and were a result of an unerupted 1st premolar tooth. Given that brachycephalic dogs are predisposed to unerupted teeth and 86% of unerupted teeth in Boxer dogs progress to the formation of dentigerous cysts , a detaiOral home care and frequent follow-up examination were very important in the post-operative management of the stoma. Therefore, good owner and dog compliance is a key component in the decision process when considering performing a marsupialisation. Prior to treatment, all clients were given information on the marsupialisation technique, aftercare and the follow-up required. Appropriate oral home care was then demonstrated at discharge. The post-operative protocol used for each of the cases in this study was a 2 week duration of twice-daily lavage of the marsupialisation sites with 0.12% chlorhexidine solution, which was based on previous reports in humans , 19, 20.In human patients, marsupialisation sites are reported to be uncomfortable, especially in the early stages . For thiRegular follow-up was advised to monitor the stoma site and the effectiveness of the oral home care performed by the owner. If premature closure did occur, reopening of the stoma under general anesthetic would be required. Communication was crucial and clear instructions on follow-up examination and treatment were supplied to the referring vet to avoid confusion and complications during initial follow-up. Causes of premature closure may include the size and location of the stoma, as well as the characteristics of the surrounding tissues incorporated into the stoma.Neoplastic transformation of cyst lining to an ameloblastoma and a squamous cell carcinoma have previously been reported in odontogenic cysts. Histopathological examination of the cyst lining was performed to confirm the diagnosis of a cyst and identification of any neoplastic transformation of the cyst lining , 27. HowTM, Geneva, Switzerland) was chosen to measure preoperatively and at follow-up for each of the cases in this series. The method used to determine the volume is known as manual segmentation. In a recent study, manual segmentation using Horos was compared against alternative techniques and software in the assessment of pre- and post-operative tumor volumes of high-grade gliomas in humans. It was found that the manual and semi-automated software showed high agreement in preoperative volumetric assessment and were adequate for post-operative volumetric assessment (The open source imaging software (Horus, OsiriXsessment . From thA major difficulty encountered during this study was determining the region of interest at the location of the marsupialisation site. At this point the cyst lining is continuous with the oral cavity and not self-contained. For this study, it was agreed that the region of interest should extend to the level of the stoma. The level of the stoma was determined by creating a straight line across the point where the cyst lumen is exposed to the oral cavity between the two outermost points on the surrounding bone. This method was used for each slice in which the marsupialisation site was present for every follow-up CT scan.The main limitation of this case series is that it is a retrospective case series and therefore factors such as period between initial surgery and follow-up CT scan could not be controlled. We found that using contrast computed tomography allowed clearer delineation between the cyst and the surrounding structures. However, only two of CT scans in this case series made use of contrast enhancement. Therefore, all of the cysts were analyzed and measured using the soft tissue window without contrast enhancement to reduce variability and give a more consistent result. Contrast enhancement may have allowed more precise measurement of the cyst volume. However, in the authors opinion, the use of contrast may not have contributed to the overall result given the significance of the volume reduction determined from the current data.Since only Boxer dogs were included in the study, there may be variations in the response to marsupialisation between different breeds, meaning that the results of this study should be applied with caution to the treatment of dogs of other breeds. Another limitation of this study was the small number of cases included in this case series. A larger study would allow further cross comparison between the location of the cysts and the volume reduction post-marsupialisation as well as a direct comparison between types of cysts. The effect of age, sex and breed could also be investigated in detail in a larger sample.This case series shows that marsupialisation is an effective, non-invasive 1st stage treatment of odontogenic cysts. The effect of decompression through the use of marsupialisation of the cysts causes a reduction in the volume of the cysts. Extirpation can be performed as a second stage treatment, once the cyst is smaller, with reduced risk of iatrogenic damage to vital structures.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the animal study because retrospective case series on a surgical technique already used routinely by the authors. Written informed consent for participation was not obtained from the owners because this is a retrospective case series where the procedure had been performed prior to the study's conception.JH wrote the manuscript, conceived and designed the study, performed the manual segmentation on all CT scans, and contributed to the statistical analysis. IT and PS contributed to conception and design of the study. All authors read the manuscript, contributed to manuscript revision, and approved the submitted version.


To examine cross-national differences in gestational age over time in the U.S. and across three wealthy countries in 2020 as well as examine patterns of birth timing by hour of the day in home and spontaneous vaginal hospital births in the three countries.We did a comparative cohort analysis with data on gestational age and the timing of birth from the United States, England and the Netherlands, comparing hospital and home births. For overall gestational age comparisons, we drew on national birth cohorts from the U.S. , the Netherlands (2014 & 2020) and England (2020). Birth timing data was drawn from national data from the U.S. (2014 & 2020), the Netherlands (2014) and from a large representative sample from England (2008–10). We compared timing of births by hour of the day in hospital and home births in all three countries.The U.S. overall mean gestational age distribution, based on last menstrual period, decreased by more than half a week between 1990 (39.1 weeks) and 2020 (38.5 weeks). The 2020 U.S. gestational age distribution (76% births prior to 40 weeks) was distinct from England (60%) and the Netherlands (56%). The gestational age distribution and timing of home births was comparable in the three countries. Home births peaked in early morning between 2:00 am and 5:00 am. In England and the Netherlands, hospital spontaneous vaginal births showed a generally similar timing pattern to home births. In the U.S., the pattern was reversed with a prolonged peak of spontaneous vaginal hospital births between 8:00 am to 5:00 pm.The findings suggest organizational priorities can potentially disturb natural patterns of gestation and birth timing with a potential to improve U.S. perinatal outcomes with organizational models that more closely resemble those of England and the Netherlands. Some industrial countries, most notably the United States, have reportedly experienced a significant shift in the distribution of births by gestational age . Some poStudies of the timing of birth date back almost 200 years. As birth registration became more widespread in the twentieth century, studies of birth timing became more feasible, be it by season –10, day We use data on gestational age and timing of births in home and hospital births in three high income countries with different maternity care systems–the United States, the Netherlands and England–allowing identification of what may be considered natural birth patterns and to speculate on the role that the organization of care might have on the birthing process. While the United States maternity care system primarily relies on obstetricians, the Netherlands and England rely primarily on midwives with obstetric consultants for back-up in higher risk cases . S1 Tab. NotablyThe data for these analyses are drawn from population-based birth data from all three countries, and from studies of birth timing and place of birth done in England  and the https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm). These data come from the National Standard Certificate of a Live Birth, an agreement between individual U.S. states that collect the data, and the National Center for Health Statistics, where agreed upon variables are compiled into a national datafile. A revision of the Standard Certificate in 2003 added hour of birth to the dataset, but the revised certificate was not uniformly adopted; it was not until 2016 that all states included hour of birth in their data collection [The U.S. data are based on approximately 3.7 million annual births drawn from national vital statistics files available through public sources, specifically the public website, CDC Wonder , and thellection . The birData from the Netherlands on gestational age were drawn from the 2020 public use datafile of births registered by Perined which includes perinatal data from nearly all of the approximately 165,000 births in that year . Data onst April 2008 and 30th April 2010, and include 32,257 births planned to occur in one of 36 hospital obstetric units that were part of a stratified random sample, 11,666 births planned in 53 freestanding midwifery units , 17,582 births planned in 43 alongside midwifery units  and 18,269 planned home births from 142 National Health Service (NHS) trusts (organizations providing maternity care). Births were eligible for inclusion if a vaginal birth was planned and some labor care was received from an NHS midwife in her planned birth setting. Those who had an elective caesarean section or caesarean section before the onset of labor, presented in preterm labor (<37 weeks’ gestation), had a multiple pregnancy, an unplanned home birth, or who were “unbooked”  were excluded, as were those who had a stillbirth before the start of care in labor. All data were collected on study-specific forms, extracted from the medical records, by midwives attending that labor [Data for gestational age of all births in England in 2019 came from the UK Office for National Statistics . Data onat labor .Data from the three countries were tabulated by completed weeks of gestation for the gestational age comparisons. Births by hour of day were recorded in 24 hourly increments beginning at midnight and presented as the annual average of these figures. To examine gestational age distributions in the United States from 1990 to 2020, gestational age was determined using last menstrual period, because the currently recommended method, obstetrical estimate related to ultrasound readings, was not available in 1990 . For theWe compared gestational age distributions for births in the U.S.,  England We examined birth timing by hour of day in home and hospital births occurring between 37 and 42 completed weeks in the three countries and repeated this analysis for vaginal births in hospitals without induction or augmentation of labour.The Medical Ethics Review Committee of VU University Medical Center confirmed that the Medical Research Involving Human Subjects (WMO) did not apply for the Dutch data and therefore an official approval of the study by this committee was not required (reference number 2020.476). The United States data are publicly available and de-identified. The IRB reviewed the research and made the determination that it was not human subjects research and therefore had no requirement to obtain consent. The study from which the English data were drawn was given approval by the Berkshire Research Ethics Committee in October 2007 (reference number: 07/H0505/151), with an amendment to the original protocol approved by a sub-committee in April 2008. All the data collected were routinely recorded in the maternity, postnatal or neonatal notes and did not include personally identifiable data.There was a notable shift in the U.S. distribution of gestational age at birth, based on last menstrual period, over the 30-year period between 1990 and 2020 . In 1990We found that over the course of 30 years, average gestational age in the U.S. was reduced by more than one half week. To examine the possible impact of the organization of maternity care on gestational age at birth, we compared home and hospital births in the U.S. with comparable births in two countries with different organizational models of maternity care: the Netherlands and England. We found that overall, the U.S. obstetrics-centered model had a distinctly larger proportion of all births at ≤39 weeks compared with the midwifery-centered models of England and the Netherlands. Gestational age distributions for home births in the U.S., the Netherlands and England, however, were very similar, with a modal category of 40 weeks.We next examined the pattern of births by time of day. In all three countries we found that home births had strikingly similar diurnal patterns in the timing of birth, with a clear peak in the hours from 1:00am to 5:59am.Limiting the hospital births to vaginal births without interventions that could alter the timing patterns (inductions or augmentation) brought the U.S. differences into sharp relief. In this restricted sample, the timing of births at home and in hospital in England and the Netherlands was largely the same. In the U.S., however, a decidedly different pattern emerged. Vaginal births without induction or augmentation in U.S. hospitals were far more likely to occur during standard working hours.A full explanation of the reasons for this difference is beyond the scope of this study and merits future research. The undercounting of induction  and augmThe consistency of the data on the timing of home births strongly suggests a natural pattern whereby birth without intervention is more likely to occur in the early hours of the morning. That this is the natural pattern of the timing of ‘undisturbed’ birth is consistent with studies of the timing of births dating from earlier in the twentieth century when there was less medical intervention in the management of labor –44.For the purposes of hospital organization, the allocation of human resources, and provider and support staff convenience, the timing of birth, at least in the United States, appears to have evolved into a pattern that is easier for the maternity care system to manage. A variety of studies of birth outcomes reference an “evening effect” and “weekend effect.” Some of these studies document poorer outcomes during evening and late night hours for both infants –48 and bThe organization and culture of maternity care practice in a given hospital can have a profound impact on the nature of care provided, including the likelihood and timing of a cesarean section , 51–54. To our knowledge, this is the first international study using large datasets to compare gestational age and timing of birth between three high income countries. Nevertheless, this study is not without limitations. Any study drawing on data from different time periods and different countries will face limitations based on comparability of measures , 57. WheAnother limitation of comparing home and hospital births is the difference in pregnancy risk factors and complications, although it is unlikely that these may influence the average timing of spontaneous onset of labor . StudiesFuture research on this topic can help resolve some of the questions raised in this paper. Specifically, comparative, prospective studies that simultaneously explored not only birth timing in home and hospital births, but also hospital maternity care practices could better identify differences that might impact timing and outcomes. The recent concern in England that an emphasis on “normal birth” is negatively impacting outcomes at a time when the cesarean rate in England is rapidly rising  suggest If there is a medical reason for offering an intervention, it may be beneficial to consider the natural pattern of labour in planning that intervention. More intentional examination of the organizational model of maternity care in the United States may benefit from lessons in other industries  where resources and operations were adjusted to correspond to need rather than organizational convenience , 65.England and the Netherlands, both of which have better infant and maternal outcomes than the U.S., rely heavily on midwives to provide maternity care, which may reflect both a difference in the allocation of resources and a preference for spontaneous labor over intervention . The facThe positive outcomes associated with births in freestanding birthing centers–where, unlike lower risk hospital births in the U.S., the timing pattern is similar to home births –and, likS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.


Catch-up growth was rapid over the first year and plateaued around the population mean by early childhood. Shared environmental factors accounted for the majority of individual differences in initial physical size (57.7%−65.5%), whereas additive genetic factors accounted for the majority of individual differences in the upper asymptotes of height, weight, and head circumference (73.4%−92.6%). Both additive genetic and shared environmental factors were associated with variance in how quickly twins caught up. Gestational age and family SES emerged as important environmental correlates of physical catch-up growth.Owing to high rates of prenatal complications, twins are, on average, substantially smaller than population norms on physical measurements including height, weight, and head circumference at birth. By early childhood, twins are physically average. This study is the first to explore the process of catch-up growth by fitting asymptotic growth models to age-standardized height, weight, and head circumference measurements in a community sample of twins ( As early as 24 weeks gestation, twins display a dampened rate of physical growth relative to singletons . Discrep2) is a risk factor for all-cause mortality .The present study seeks to describe the process by which twins catch-up to the population mean in terms of height, weight, and head circumference. Specifically, we fit nonlinear growth models to height for age, weight for age, and head circumference for age z-scores from birth to 15 years (birth to three years for head circumference) to model the magnitude, rate, and shape of catch-up growth of physical size in twins. We then conducted biometric analyses on the best fitting growth models to determine relative additive genetic, shared environmental, and nonshared environmental contributions to catch-up growth. Finally, we examined measured prenatal and postnatal correlates to trajectories of catch-up growth across childhood. The study design and hypotheses were preregistered and all R and Mplus scripts are available on the Open Science Framework (n = 120). Of those remaining, 1,637 had at least one physical measurement. As is typical in twin studies, we restricted analyses to monozygotic and same-sex dizygotic twins . Finally, provided my focus on typical physical development, we removed all individuals with height, weight, or head circumference measurements greater than 4 SD above or below the population mean (n = 6). Thus, the final sample is 1,281 .Participants were 1,281 individual twins recruited as a part of the LTS, an ongoing longitudinal study of temperament and intellectual development in twins . All twiData were collected between 1957 and 1993. Physical measurements were collected by trained examiners during laboratory visits at the University of Louisville at 16 time points between 3 months and 15 years . Most individuals in the study did not have data at all 16 points, but 88.2% had four or more weight measurements, 84.7% had four or more height measurements, and 87.3% had four or more head circumference measurements. All study procedures were approved by the University of Louisville Institutional Review Board. Informed consent was obtained from all participants included in this study.Physical measurement procedures are described in detail elsewhere . Birth lBaseline household SES was measured based on the Hollingshead Four Factor Index of Socioeconomic Status, which is based on parental occupation, education, sex, and income . HollingWe considered a variety of growth models to describe typical trajectories of height and head circumference including polynomial , exponential, and sigmoid-shaped  growth models. Because models were not nested, the best fitting model was determined by comparing Bayesian Information Criterion (BIC) values across models with lower values indicating better overall model fit. We review the characteristics of the Weibull and Morgan-Mercer-Flodin growth models as these models fit the physical growth data best.t is estimated using the following equation.Weibull Growth Model. The Weibull growth model is a nonlinear, asymptotic curve derived from the Weibull distribution . Using tb0 corresponds to the intercept, or estimated weight when time equals zero . b1 corresponds to the upper asymptote, or an individual’s maximum estimated weight. b2 reflects the average rate at which an individual approaches their upper asymptote. Finally, b3 is a shaping parameter that controls the inflection point of the curve or the point at which growth is the fastest. In cases where b3 is less than 1, the Weibull curve approximates an exponential shape, and when b3 is greater than 1, the Weibull curve takes a sigmoid shape. Using the b3 parameter, the age of most rapid growth can be calculated using the following equation:In this model, In cases where the inflection scaling parameter is less than 1, the age of inflection is not defined as it is negative in cases where 1 t can be estimated using the following equation  can be used to calculate the age at which growth is the fastest using the following equation:In the Morgan-Mercer-Flodin model, b0 – b3). All growth models were fit using Mplus version 8.4  was used to decompose the variance estimates of the growth parameters into additive genetic, shared environmental, and nonshared environmental components . FollowiConstrained growth models were fit by regressing the height, weight, and head circumference growth parameters onto the study covariates. Because all study covariates were consistent across twin pair, the covariates were included at the between-pair level of the model.Due to the longitudinal nature of the study, there were missing physical growth measurements at each age (see Supplementary Table I). Missing data were handled using full information maximum likelihood estimation (FIML) in Mplus. FIML assumes that data are missing at random (MAR). When data are MAR, missingness may be related to other observed variables , but not to the missing value itself . To explore patterns of missingness, we fit a series of logistic regression models using study covariates, birth year, zygosity, and observed physical measurements at the previous age to predict the likelihood of missing height or head circumference measurements at a given age. As height, weight, and head circumference measurements across childhood are relatively stable over time , using the previous measurement to predict missingness at the subsequent assessment  allowed us to approximate if missingness was related to the missing value. There was evidence that height and head circumference measurements were MAR (see supplementary Tables 2–4). Missingness did not appear consistently biased by smaller or larger children and birth year emerged as a consistent significant predictor of missing height, weight, and head circumference measurements. In general, children born later were more likely to be missing all physical growth measurements, which may reflect a change in the focus of the LTS from physical development in the 1950s to cognitive development in later decades or a loss of study funding in the 1990s . Birth year was included in all models as a predictor of measured height and head circumference at each age to avoid generating biased parameter estimates .SD = 2.6 weeks; mediation gestation = 38 weeks). About a third of the infants (33.6%) were born prematurely (less than 37 weeks gestation) and 3.4% were born very prematurely (less than 32 weeks gestation). At birth, the average twin was 1.59 SD lighter, 0.78 SD shorter, and had head circumference measurements that were 1.35 SD below the population mean. By 15 years, the average height-for-age z-score was 0.03 (SD = 0.98) and the average weight-for-age z-score was 0.19 (SD = 0.95). Average head circumference z-scores at 36 months (the last head circumference measurement) were 0.43 (0.89). Sequential height, weight, and head circumference measurements were highly correlated, suggesting strong stability of physical measurements over time .Means and standard deviations of height, weight, head circumference, and study covariates are presented in Supplementary Tables 5–8, respectively. The LTS sample was of average SES, and family SES was approximately evenly distributed across quintiles . The average length of gestation was 37.2 weeks . The estimated intercept of −0.66 indicates that the average twin was approximately two thirds of a standard deviation below the population mean in terms of birth length. The upper asymptote was estimated to be −0.11, indicating that the average twin caught up to within approximately a tenth of a standard deviation of the population mean. The inflection point was calculated to be 1.75 , indicating that height catch-up was most rapid in early toddlerhood. Estimates for all growth parameters are presented in Predicted Height Catch-Up Based on the Weibull FunctionBiometric contributions to individual differences in height catch-up are presented in Relative to females, males had lower initial lengths, had a slower average rate of growth, and demonstrated an earlier inflection point. Thus, males started off farther behind than females and caught up by growing slower and for a longer period of time see . ImportaEnvironmental Correlates of Height Catch-Up GrowthAs an approximation of effect size, we calculated the proportion of the shared environmental variance explained by measured shared environmental constructs . This was calculated by subtracting the unstandardized shared environment variance in the constrained model from the shared environmental variance in the unconstrained model and dividing the difference by the shared environmental variance in the unconstrained model . Study cModel fit information for the growth curve models fit to weight can be found in Supplementary Table X. Based on the BIC values, the Weibull growth model fit the data best. Although the Weibull model fit the data best relative to the other growth models, the RMSEA value (.10) and TLI value (.88) indicated that the Weibull curve did not fit the data well. Growth curve models were initially fit following a traditional approach to modeling the residual structure: residual variances were freely estimated and covariances between residuals were omitted. Modeling the structure of the residuals by including different variance constraints or autocorrelations can improve model fit . There aX2 = 815.94, df = 17, p < .001). The final Weibull growth model fit the data acceptably . Parameter estimates for the final Weibull model are presented in A Satorra-Bentler chi-square difference test  revealedUnstandardized and standardized biometric components are presented in Males had a significantly higher intercept than females, suggesting that male twins were born closer to the population mean. However, males and females were statistically indistinguishable at the upper asymptote. Females had a faster rate of catch-up growth and an earlier inflection point than males see . The quaStudy covariates accounted for 54.6% of the shared environmental variance in the intercept, 24.7% of the variance in the upper asymptote, 14.7% of the variance in the rate of growth, and 6.7% of the variance in the inflection point.Fit statistics for the growth curves fit to the head circumference data are presented in Supplementary Table XI. The Morgan-Mercer-Flodin growth curve fit the data best based on BIC values and fit the data well . The average twin had a intercept of −1.53 and grew to an upper asymptote of 0.40  and nonshared environmental factors (24.0% of the variance), but were not significantly related to additive genetic factors. As with height, additive genetic factors accounted for the majority of the variance in the upper asymptote of head circumference (92.6% of the variance). Additive genetic factors also accounted for the majority of the variance in the rate of head circumference catch-up (69.3% of the variance). Additive genetic factors associated with individual differences in the inflection point of head circumference catch-up were constrained to be 0 as this parameter was initially estimated to be (non-significantly) negative. Individual differences in the inflection point of head circumference catch-up were primarily associated with shared environmental factors (65.1% of the variance). See Relative to females, males had higher head circumference measurements at birth. However, sex was not significantly related to the upper asymptote of head circumference. Females had a significantly faster rate of head circumference growth than males see . GestatiEnvironmental Correlates of Head Circumference Catch-Up GrowthStudy covariates accounted for 66.1% of the shared environmental variance in the intercept, 83.3% of the shared environmental variance in the upper asymptote, and 14.4% of the shared environmental variance in the inflection point. Shared environmental contributions to the upper asymptote of head circumference were nonsignificant and estimates were extremely small. Thus, the percent of variance in the upper asymptote of head circumference accounted for by study covariates should be interpreted with caution. Nonlinear growth models fit to age-standardized measurements of height, weight, and head circumference from birth to adolescence revealed a pattern of development characterized by large Deficits in physical size at birth and rapid physical catch-up growth across infancy. Deficits in height, weight, and head circumference were comparable to observations in previous studies . AlthougThe rate of catch-up growth for each growth metric was most rapid in infancy, highlighting the importance of catch-up growth over the first few months of life. For example, the rate of head circumference catch-up growth was most rapid at approximately 7.5 months and, on average, twins had recovered half of their initial weight Deficits by 12 months. Therefore, children born with significant Deficits in their physical size would be expected to make rapid progress toward the population mean across the first year of life. Children who do not make progress toward the population mean over the first year of life may be at an increased risk for severe health problems related to physical size including stunting, wasting, microcephalia, or failure to thrive. Temporally, twins reached their upper asymptote of head circumference first , suggesting that neurological catch-up begins rapidly following birth and precedes catch-up growth of other structures  in infancy.Biometric analyses of height, weight, and head circumference catch-up growth revealed a consistent pattern across measurement. Aspects of the shared environment accounted for the majority of the variance in the intercept of physical size, additive genetics accounted for the majority of the variance in the upper asymptote, and the rate and shape of catch-up growth was associated with a combination of additive genetic and shared environmental factors. The large association of shared environmental factors and nonsignificant association of genetic factors with variance in physical size at birth suggests that exposure to early bioenvironmental stress  may override genetic contributions to early physical size. Interestingly, nonshared environmental factors explained a small but statistically significant portion of the variance in the intercepts of height, weight, and head circumference. Significant nonshared environmental contributions to early physical size may reflect differences in placental placement which lead to better nutritional access for one twin  or in moOn the other hand, that additive genetics accounted for the majority of the variance in the upper asymptotes of height, weight, and head circumference whereas shared environmental factors did not account for a significant portion of the variance. As children age and early environmental stressors  become more distal experiences, genetic influences on physical size may have more room to operate. Findings that additive genetics contribute to the majority of the variance in the upper asymptote of physical size are consistent with previous research that has found physical size to be highly heritable in samples above the age of 3 years . The nonThe present study made unique contributions to the literature by demonstrating that a combination of additive genetic, shared environmental, and nonshared environmental factors are associated with individual differences in the latent rate and shape of physical catch-up from early bioenvironmental adversity. Therefore, a combination of genetic factors  and shared environmental factors  are related to how quickly infant twins catch-up physically.The intercepts of weight and head circumference were higher for males than females, suggesting that males may be more resilient to the perinatal stressors associated with twinning. However, females demonstrated a faster rate of growth of height, weight, and head circumference than males. The upper asymptotes for height, weight, and head circumference were statistically indistinguishable between males and females. Therefore, early discrepancies in relative physical size between males and females do not persist into childhood, and early discrepancies are overcome by a faster rate of catch-up growth among females. A similar pattern of height and weight catch-up growth was observed among a sample of male and female singletons born at very low birthweight  followed from birth to 20 years . At birtAlthough gestational age emerged as an important environmental correlate of early weight, gestational age did not explain all of the variance in early physical size as birth weights and head circumference measurements for full-term infants were nearly 1SD below the population mean. Regarding birth length, full term infants were only slightly below the population mean (0.2 SD), whereas premature twins were nearly three quarters of a SD below the population mean. It is possible that factors associated with birth length  benefit more from full gestation. However, measurements at birth are known to be unreliable  and may Infants born earlier had a faster rate of height and weight catch-up growth and an earlier inflection point of height and head circumference growth, providing insight into the process by which children recover physically following premature birth. That is, premature infants caught up by growing more rapidly in early infancy than full-term infants (as opposed to more slowly but for a longer period of time). A variety of prenatal stressors associated with premature birth are also associated with restricted prenatal growth  . Once prAccounting for gestational age, sex, and maternal age, children in wealthier families were born heavier and with larger heads, indicating more complete prenatal development. However, even children born in the highest-SES households displayed physical Deficits in early infancy. Children born in very wealthy and very poor homes had birth weights closest to the population mean at birth. Families at the highest end of the SES spectrum may have better access to high quality prenatal care and nutrition to support healthy prenatal development. Poverty may be related to higher birth weights through higher rates of gestational diabetes , a prenaFamily SES was also quadratically related to the upper asymptote of height and weight. At the upper asymptote, children in the poorest homes weighted approximately 0.4 SD above the population mean and were approximately 0.2 SD taller than average. Family SES was unrelated to the rate of height or weight catch-up, indicating that children in the poorest homes grew relative to the population mean at the same rate as their average SES peers, but grew for a longer period of time. In the case of weight, the extended weight growth may highlight the developmental course of child- or adolescent-onset obesity among low birthweight children reared in poverty especially as upper asymptotes of weight were higher than upper asymptotes of height . The extAlthough there is socioeconomic variability in the LTS, it is an almost entirely White sample. Therefore, findings reflect the process of catch-up growth in White twins born in the United States and do not necessarily generalize to populations outside of the United States or nonwhite populations within the United States. For example, rates of malnutrition are extremely low in the United States  and sociRates of very premature birth and very low birth weight were low in this sample (~ 2%), and, therefore, findings reflect patterns of catch-up growth in a relatively low risk sample. Moreover, because the primary goal was to model typical trajectories of physical catch-up among twins, we did not distinguish small-for-gestational age twins from appropriate-for-gestational age twins. Examining physical developmental differences in small-for-gestational age versus appropriate-for-gestational age twins represents an important step for future research as children born small-for-gestational age status may experience greater prenatal stressors  and diffWe were limited to broad measures of the shared environment, which prohibited the exploration of more specific environmental correlates of physical catch-up. Gestational age was included as a crude indicator of prenatal health, and family SES at birth as a general indicator of the postnatal environment. Future work including more specific environmental experiences  would provide further insight into environmental correlates of weight development in twins.Finally, we are unable to make any causal claims regarding “effects” of genetics or environmental factors on catch-up growth in twins. Although the upper asymptotes of height, weight, and head circumference were highly heritable, it is not necessarily the case that one’s upper asymptote of physical size is caused by their genetics. Active or evocative gene-environment or phenotype-environment correlations may inflate the proportion of variance attributed to additive genetics . For example, infant appetite, a highly heritable characteristic , may conCatch-up growth in twins begins immediately after birth as evidence by the preferred fit of exponential-shaped functions over polynomial and S-shaped functions. Temporally, head circumference catch-up preceded height and weight catch-up. However, on average, substantial catch-up of all physical measures occurred within the first year of life. Consistent with previous research, gestational age was an important early environmental correlate of height, weight, and physical size. However, with the exception of birth length, twins born at full term continued to display substantial deficits in their physical size at birth. Therefore, additional prenatal factors associated with twinning  likely also contribute to the relatively small physical size of twins at birth. Importantly, there were no differences in childhood physical size between premature and full-term twins. Family SES also emerged as an important environmental correlate to physical catch-up growth in twins. Children in the wealthiest and poorest homes were closer to the population mean at birth in terms of weight and length. However, children in the poorest homes grew to be both heavier and taller than the population mean by adolescence. The relatively larger estimated weight among very poor children in adolescence (z-score = 0.4) compared to the estimated height (z-score = 0.2) suggests a possible like between poverty and later obesity among children born at low birth weight through extended weight gain across childhood.Although the present study focused on a sample of twins, findings likely generalize to singletons who experience early bioenvironmental risk. As with twins, most singletons who are born at low birth weight, short birth length, or with a small head circumference at birth catch up to population norms , and sub