The uterine cervix plays a vital role in maintaining pregnancy and an equally important role in allowing parturition to occur. Progesterone, either endogenously produced or supplied exogenously, supports the function of the cervix in sustaining intrauterine pregnancy, and the withdrawal of progesterone, either through natural processes or pharmacologic intervention, leads to delivery which underscores the importance of the progesterone's biological activities manifest in normal gestation and pregnancy that ends prematurely. Research crossing many scientific disciplines has demonstrated that progesterone is a pleotropic compound that affects the cervix through cytoplasmic and membrane receptors with profound effects on cellular and molecular functions that influence inflammatory cascades and extracellular matrix, both of which have consequences for parturition. Beyond the local cell and molecular biology of progesterone, it has systemic effects of relevance to pregnancy as well. This paper examines the biology of the cervix from its gross to cellular structure and biological activities of its cell and molecular processes that may be affected by progesterone. The implications of these processes for preterm birth are explored, and direction of current research is in relation to translational medicine implications for diagnostic, prognostic, and therapeutic approaches to threatened preterm birth. Yellon and coworkers  have aptThe intentional focus on the biology of the cervix in this paper is supported by the recent review by Word et al.  who makeThe gatekeeper function of the cervix is simultaneously structural and biological, and the breadth of its functions and interactions with other anatomic structures and biologic or pharmacologic mediators should not be ignored. However, in this paper, we propose to review what is known about the role of the cervix as a mechanical structure and how progesterone influences this function. We will next consider the cellular and molecular actions that are inherent in maintaining pregnancy and in responding to changing hormonal conditions during gestation. Finally, the concept of inflammation as the final common pathway to parturition will be examined both from the standpoint of term and preterm pregnancy and options for altering the inflammatory processes that play a role in preterm birth.At the gross level, the change of the cervix early in pregnancy from a dense, rigid tissue with a closed os to parturition with a softened consistency, shortened distance from os to membranes, and effacement at the time of labor, is well known and usually understood as a process that predominantly involves changes in collagen. Recent studies have elaborated that concept and suggest a process that is complex and nuanced. Many of the studies related to the precise processes involved in the pregnancy-related changes to the cervix have necessarily involved animal model studies, especially when experimental protocols have been involved. In considering the role of gonadal steroids in cervical biology and in particular the central role of progesterone in maintaining pregnancy, there is support for the concept that rodents provide a reasonable model for cell biology of the cervix, particularly as it applies to the extracellular matrix . A recenAnother gross aspect of the cervical geometry through pregnancy is the shortening of the cervix. This has taken on a very important significance in recent years as the availability of transvagininal ultrasonography has been able to document the length of the cervical canal, and the length of the closed portion of the cervical canal relates to risk of preterm birth as summarized by recent reviews , 9. RemoFusobacterium nucleatum [As we will discuss later, the connection between amniotic infection and inflammatory reactions has been linked to preterm birth, and the role of shortened cervix is likewise associated. For example, Vaisbuch et al. correlated short cervix with amniotic inflammatory reaction, though not necessarily positive amniotic fluid culture, and 40% of those with intra-amniotic inflammation delivered within one week . Even inucleatum . This faucleatum .Thus, cerclage is not uniformly effective in preventing delivery before 35 weeks, and with sufficient understanding of epidemiologic and biochemical markers involved in patients with sonographically documented short cervix, the application of cervical cerclage may be applied on a more individualized basis with improved outcomes. For example, cervical funneling may remain after cerclage, and one study found that when it does, the patient has a higher likelihood of delivering preterm than when funneling is not present . Beyond the geometry, physical strength, pliability of the cervix, and the shape of the cervical canal during pregnancy, the cellular structure and molecular biology of the cervical cells will necessarily contribute to the mechanical attributes. It is recognized that progesterone has a demonstrable effect on the rate of cervical shortening and preterm delivery when administered to women admitted for preterm labor between 25 and 33 + 6 weeks gestation . The celSeveral cellular components of the cervix deserve mention. Importantly, the muscular character of the cervix is in many ways subordinate to the extracellular matrix in which connective tissue is a key to its mechanical strength. In a thorough review of the extracellular matrix of the body of the cervix, House et al.  emphasizThe significance of fibrillar collagen as the key component of the mechanical properties of the cervix is emphasized by its abundance and diminution in cervical insufficiency . The bodMany of the experimental studies on the composition and changes through the cervical remodeling process have been established in rodents in which gene knockout experiments , steroidRegulation of these elements of the body of the cervix involves, among other mediators, progestational agents. The presence and absence of progesterone and progestational agents are both critical at various stages of pregnancy. Maintaining pregnancy at the level of placenta, uterine quiescence, and limiting cervical inflammatory reactions are well-known attributes of progesterone. Progesterone withdrawal is a key element of parturition and is accompanied by a different set of biological cascades. As noted previously, attention is focused on progesterone because of recently concluded research on its potential use in preventing premature birth. Nevertheless, it is important in exploring the biological effects of progesterone to recognize its integration into systems that include multiple steroid and peptide hormones and tissues other than the cervix. As collagen plays an important role in the compliance and tensile strength of the cervix and progression toward a compliant and ultimately ripened cervix, the role of progesterone is of interest. The cervix begins softening through a process of continuously advancing collagen reorganization of the collagen fibrillar structure accompanied by decreasing levels of collagen accessory proteins, thrombospondin 2, and tenascin C as well as lysyl hydroxylase which is important in collagen crosslinking as demonstrated in mouse studies . This reTenascins are extracellular matrix proteins that also contribute to the strength of tissues such as the cervix, and while not all details of its role in the cervix throughout pregnancy are known, in mouse models of endometrial stroma culture, it was found that tenascin C expression was positively controlled indirectly by progesterone, possibly through IL-1 alpha or prostaglandins . TenasciAnother aspect of collagen disorganization is related to enzymatic action by the matrix metalloproteinases (MMPs). The MMP family of enzymes, including collagenases, gelatinases, and elastases, have recognized significance in tissue remodeling events including intrauterine implantation, invasion by tumors, and vascular problems. The source of the MMPs is often inflammatory cells, but these enzymes may also be elaborated by other cell types. Studies of rat cervix during pregnancy found MMP2 to be present in the stroma but not epithelium in term pregnancy, but its role in cervical ripening was unclear as it was also present in nonpregnant rats , and MMPThe role of hyaluronidase and hyaluronon, and versican and an MMP, ADAMTS1, was noted previously . As indiFinally, it should be noted that attention has also been drawn to the peptide hormone relaxin which is highly conserved among various species and has been associated with increased compliance in the pubic symphysis of animals  as well A complex and as yet incomplete picture of how the extracelluar matrix of the cervix and its individual macromolecular components are regulated throughout pregnancy and parturition undoubtedly implies a very key role for progesterone. Some progesterone-regulated processes are the result of direct effects, while others may be mediated though inflammatory mediators or peptide hormones or enzymes from stromal or inflammatory cells. Despite the variety and complexity of coordinated events related to birth, it is clear that the physiologic processes involved in labor and delivery involve the functional withdrawal of progesterone. As reviewed by Mesiano et al. , this maCervical ripening is an element of preterm as well as term birth but raises the question as to the underlying mechanism of premature ripening and the corollary question of whether the mechanisms involved in premature ripening differ or are the same as those involved in term ripening of the cervix. Much of our current understanding has been gained through research completed in the past few years.As mentioned before, the onset of labor has been associated with the presence of elevated cytokines, the influx of neutrophils, and activation of macrophages which has led to the often-repeated statement that inflammation appears to be the final common pathway for parturition. For example, cervical biopsies from uninfected term and preterm laboring women showed upregulation of Il-6, Il-8, and MCP-1 with elevated peripheral white counts and C-reactive protein which was interpreted as a common pathway in preterm as well as term labor . NeverthNew information on the distinctive attributes of term and preterm cervical biology during parturition and differences in initiation of ripening process was published by Holt and coworkers in 2011 , emergedThere is general agreement that some cases of premature cervical ripening and hence preterm birth are related to infection and that infection may account for up to one-third of preterm births. The inflammatory response elicited by infectious agents has also become the accepted mechanism for preterm birth. In contrast, the remaining instances of preterm birth are attributed to less defined causes such as genetic background of the mother or fetus, environmental factors, intercurrent illness, or health conditions. In consideration of the focus on the cervix and the role of progesterone in maintaining and ending pregnancy, several recently discovered genetic associations that may have an impact on cervical ripening are reviewed.Genetic associations with preterm birth imply, in some instances, potential effects on the cervix. Day and coworkers , reasoniThe cervical epithelium is composed of squamous cells on the external portion of the cervix and cuboidal cells within the os. The latter are more exposed during effacement. Because of the abundant microflora of the lower female genital tract the cervical epithelial cells will be exposed to indigenous bacteria throughout pregnancy and to exogenously acquired bacteria on specific occasions such as coitus during pregnancy. Because of the inflammatory events that are associated with preterm delivery, it is appropriate to consider whether the cervical epithelium is strictly a barrier to invasion by microorganisms, and whether the barrier function differs between squamous and columnar epithelium. Further, it is important to understand whether the cervical epithelia are able to sense and respond to exposure to microorganisms.With regard to the barrier function of the epithelia, a recent report elaborates on the intercellular attachments of the squamous and cuboidal cells . The endNeisseria gonorrhea and Chlamydia trachomatis, which will not be reviewed here. Of perhaps greater importance to the topic at hand is the possibility that the cervical epithelial cells can sense and respond to microbial molecules, and this response can elicit or at least contribute to initiation of the inflammatory cascade. Although immortalized tissue culture cells were used, Herbst-Kralovetz et al. demonstrated that endocervical and ectocervical epithelial cells possessed a full complement of toll-like receptors, and liganding these receptors with appropriate agonists could elicit a cytokine response [Despite the physical barrier, there are of course microorganisms that have the ability to invade through cells including a number of sexually transmitted pathogens, such as response , but somresponse . The toll-like receptors are membrane-associated pattern recognition receptors (PRRs) that are foundational to innate immunity as they bind to commonly expressed microbial components (pathogenicity-associated molecular patterns or PAMPs) and transduce signals that elicit cytokine production. Less well studied are the NOD (nuclear oligomerization domain) receptors which are cytosolic receptors that bind bacterial cell wall components and also transduce signals that result in cytokine expression. The NODs are found in epithelial cells and would be expected to be part of the genital tract epithelium innate defense. Indeed, they have been found in functional form in endometrial epithelium  and in tTogether, these reports confirm the ability of cervical epithelial cells to respond to microbial substances with cytokine reactivity. While it may make little difference whether cytokines generated in the lower female genital tract originate with the cervical stroma or epithelium, the host clearly has the ability to generate typical responses to microbial challenges with resulting cytokine release and subsequent cervical ripening and birth. But the question of how these receptors and responses are regulated remains. Progesterone was associated with decreased TLR-4 and TLR-9 signaling in macrophages , 50. In Current medical literature repeatedly states that inflammation is the final common pathway to parturition. In considering what inflammatory activities are relevant to this concept, however, it is important to note that mechanistic details may differ with the gestational age at which preterm birth occurs, and there may be unique characteristics associated with inflammation that is centered in the placenta versus fetal membranes or the cervix. And current concepts emphasize that inflammatory reactions associated with preterm birth do not have to be focused in the generative tract tissues. For example, the inflammation associated with periodontitis during pregnancy has been linked to the risk of prematurity according to a recent review of more than 100 clinical studies . The assβ, and TNFα as associated with preterm birth, though the review also emphasized inconsistencies that remain in the literature. Thus, cytokines along with other biomolecules may most accurately be portrayed as indicators of the induction of the inflammatory cascade. While the literature on cytokine expression in relationship to preterm birth has grown substantially over the past decade, it is important to point out in relationship to the mechanism of preterm birth that the excursions in cytokine concentration are probably neither the first cause nor the final mechanism for delivery at the level of the cervix, uterus, or placenta. A recitation of the studies measuring cytokines in tissues and fluids at various gestational ages in term and preterm labor and delivery is not needed here. It will suffice to mention that a recent review  identifiIf the cytokines serve as biomarkers, the natural question that follows is how they may support understanding and prediction of the clinical outcomes that may be imminent. One study indicated that IL-6 along with the other inflammatory marker C-reactive protein (CRP) levels predicted that a baby was more likely to be born with sepsis and that the time to delivery was related to these factors as well . ElevateWhile CRP and leukocytosis represent inflammatory markers linked to preterm birth in addition to interleukins, additional factors are also reported as being associated with preterm birth. Thus, macrophage inhibitory factor (MIP) has been associated with preterm birth  as were If early cytokine elevation serves as a biomarker for preterm birth, then cytokine origin deserves consideration. Cellular upregulation of cytokine expression is usually the result of cellular (surface or cytoplasmic receptor) components of the innate immune system that recognize pathogen-associated molecular patterns. These PRRs (pathogen recognition receptors) engage signaling cascades that result in cytokines that recruit leukocytes or activate cells of the immune system. Thus, microorganisms may be the initiating factor for proinflammatory cytokine production, but they are not the only source of cytokine generation. A cognate concept of PAMPs which are microbial-focused recognition systems is the DAMP or damage-associated molecular pattern that may play a role in recognition of endogenous molecules which have undergone alteration through processes such as necrotic damage or oxidation , 64. Theα and infiltrating leukocytes [Since proinflammatory cytokines do not represent the ultimate step in parturition, it is appropriate to note the downstream effects of these molecules. Increases in Il-6 and Il-8 at the cervix are associated with effacement . In addiukocytes , are eleukocytes . The cytukocytes . κB mediated transcription [Evidence has been presented that in the rodent uterus TLR-4 signaling after lipopolysaccharide binding induces MAP kinase signaling resulting in cyclooxygenase 2 (Cox 2) and intracellular phospholipase A(2) induction along with a number of other inflammatory proteins through Nf-cription . Interescription . Also incription . But thecription , 72. α TNFα, Il-6, and Il-8, and the modulation of cytokine-mediated biological activity may occur through the anti-inflammatory cytokines. The current literature has tended to elevate Il-10 as the most significant anti-inflammatory cytokine in relation to preterm birth to date. In mouse pregnancy, preterm birth tended to be characterized by increased levels of several proinflammatory factors, while there was a downregulation of Il-10 [α and β, soluble Il-6 receptor a, TNFα, soluble TNFα and TREM-1 which were also elevated [The majority of the discussion related to cervical inflammatory reactions and term and preterm birth have centered on the proinflammatory cytokines with emphasis primarily focusing on IL-1of Il-10 . Likewisof Il-10 . In the of Il-10  which onelevated .Another approach to examining inflammatory modulation has been to experimentally use substances that antagonize pro-inflammatory cytokines. A study involving 75 women with recurrent spontaneous abortion showed improved live birth rates when etanercept or adlimumab were added to a regimen of anticoagulant and IVIG . Though Recognizing that there are other anti-inflammatory factors, some investigators have established balance sheets that attempt to determine if broad panels of cytokines favor pro- or anti-inflammatory cytokines. One report indicated a 7-fold increase in preterm birth (before 34 weeks) risk when a high inflammatory to anti-inflammatory ration was detected . Other sBefore leaving the topic of the interplay between pro- and anti-inflammatory cytokines, brief mention should be made regarding the genetic background of individuals that could contribute to adverse pregnancy outcomes. Gene polymorphisms have been identified in structural genes of inflammatory factors or their receptors which can lead to defective bioactive molecules or even complete absence of the gene product. In addition, many single-nucleotide polymorphisms located in gene promoter regions of inflammatory cytokines have been identified which can alter the regulation and hence the response to normal stimuli , 82. In At the outset of this paper, two concepts were mentioned. First, inflammation is involved as a common pathway in birth, and second, progesterone (endogenous or exogenous) is one of the most consistently effective compounds in maintaining pregnancy, namely, averting the initiation of the common pathway of labor. The two concepts now come together in the following paragraphs.β showed through microarray-based analysis that 38 inflammation and immunity genes were stimulated [ Progesterone has often been described as having immune-suppressive activity and from a teleological point of view, this makes sense as the mother's immune system needs to be tilted toward tolerance to host the fetal allograft. Recent reviews have noted that the presence of sex steroid receptors in innate immune cells such as macrophages or lymphocytes, is well recognized , but innimulated . Sex steimulated .Progesterone does not act in isolation from other steroid and peptide hormones, and its activities are made more pleotropic as a result of the fact that it has biological activity resulting from traditional gene level activation through steroid response elements on steroid hormone-regulated genes, but also nongenomic activities mediated by membrane receptors which engage in G-coupled signaling cascades. Many of the interactions with the innate immune system, and by extension, term and preterm parturition appear dependent on this non-genomic mode of cellular activation. β-OH steroid dehydrogenase which converts estradiol to the less estrogenic estrone and 20α-OH progesterone to the more active progesterone showed that at parturition, this enzyme was downregulated in endocervical cells allowing for a localized functional progesterone withdrawal [α-hydroxyprogesterone caproate treatment randomly assigned to pregnant women decreased cervical shortening after 21 days and decreased IL-1b but did not affect Il-6, Il-8, TNFα, or nitric oxide [Adding to the complexity and hence the lack of absolute clarity in the precise mechanism of progesterone action on the immune system is the fact that some of the activities of progesterone are systemic and some are local. For example, a study of 17thdrawal . Studiesthdrawal  in humanic oxide . These sα-hydroxyprogesterone caproate, treatment did not affect basal levels, but with stimulation by lipopolysaccharide or lipoteichoic acid, Il-6 was elevated, whereas progesterone-treated subjects did not have elevated cytokine [In a pregnant rat study , normal cytokine .The possibility that some of the effects of progesterone are initiated by effects on inflammatory cells is suggested by the finding that progesterone can modify TLR signaling. Macrophages treated with progesterone had diminished responses to stimuli that act through TLR4 and TLR9 , 50 withProgesterone is responsible for interactions with leukocytes which elaborate progesterone-induced blocking factor  which ha+ CD25+) are increased peripherally and in the uterus of progesterone-treated mice [α, and gamma interferon, while upregulating Il-4 and Il-10 in responder cells.The possibility that progesterone exerts effects on the immune network at a central regulatory level is suggested by studies that indicated T-regulatory cells  have been focused on the potential role of hormones in cancer and metastatic processes. These various other attributes of progesterone have proved important in recognizing that cell surface receptors for progesterone can transduce signals through the MAP kinase pathway including vascular functions , 101. Eve levels .The complexities of progesterone activities biological mechanisms related to pregnancy and parturition have not been exhaustively reviewed here, but it is clear that there are several mechanisms known to be consistent with the forestalling of parturition. However, additional details continue to be uncovered. For example, progesterone affects monocytes at the earliest level of pregnancy through means of glycodelin which has been recently reviewed and has activities that may contribute to the Th2 dominance in pregnancy . While gA substantial body of scientific knowledge has been built around the concept that the uterine cervix serves a physical support function for the gravid uterus changing from a rigid to a pliable structure at the time of delivery. But in the absence of information that brings some practical value to the extensive research reported here, the understanding of the physiology, cellular biology, and environmental effects on cervical function will be strictly academic.The structural role of the cervix, like other structures, is only part of the story. The softening and dilation of the cervix is a biological process timed intricately, coinciding with the uterine contractions that move the fetus into and through the birth canal. This can, and too often does, occur prematurely. Sometimes, the biological characteristics recede into the background as the structural properties of the cervix assume the central focus. In the case of multiple births, cervical dysfunction seems largely a matter of structural support. The same is also true when cervical dysfunction is secondary to previous LEEP procedure. Despite the conceptual potential value of cerclage in support of the structural function, the role of cerclage has not proved uniformly successful, and in evidence-based medicine studies, its use has limited endorsement . The fact that cerclage is not uniformly successful in preventing premature cervical ripening and delivery attests to the fact that biological processes are also at work. The process of parturition engages many of the mediators and consequences of inflammation, and these have profound effects on the uterus and the cervix. We emphasized that within the cervix the inflammatory cascade is highly active during cervical ripening and involves inflammatory cells and mediators which lead to remodeling of the tissue. The process leads to increased tissue compliance through alterations in extracellular matrix coupled with proteolytic action in the tissue and finally with the production of prostaglandins and nitric oxide which are the final steps in a cascade process. Since we recognize the final pathway to birth as a cascade process, it may not matter what specific event triggered the final stages of cervical ripening, labor, and delivery as the process is likely to proceed despite tocolytic drugs although delivery might be delayed slightly to allow for antenatal steroid use. The ability to determine the presence of a shortening of the cervical canal has created a new means of predicting the likelihood of engaging the inflammatory process prematurely. This finding of a physical change in the geometry of the cervix can be related to the mechanism of prematurely engaging the inflammatory process at least theoretically because of the partial disruption of cervical mucus and the movement of the bacterial flora into closer proximity to the endocervical epithelium and its unique display of bacterial recognition receptors and to the fetal membranes where infection and inflammatory processes may arise. The significance of the shortened cervix has its translational application in the duality represented by structural compromise coupled with physiologic changes. Therefore, clinicians have considered both structural and pharmacologic approaches to the short cervix. Cerclage addresses the advancing compliance of the tissue, and progesterone has been introduced because of its demonstrated utility at least in a percentage of cases of impending preterm labor. The most recent compilation of the evidence for use of progesterone  concludeWe have attempted to document the multiple levels at which progesterone affects the cervical biology in a variety of ways that promote the prolongation of pregnancy. Unfortunately, the scientific explanation of all of the effects of progesterone at the level of the cervix has not been established, but sufficient understanding is available to appreciate how this intervention may reduce the likelihood of adverse outcomes, although as many structured reviews have stated, the literature does not yet contain studies that adequately address all the practice questions related to the use of progesterone including adverse metabolic effects on mother and fetus.  Microorganisms may be the genesis of inflammatory reactions leading to preterm birth, and several investigators in large and small studies have sought the translational application of this fact in the hypothesis that antibiotics should prevent prematurity. However, evidence reviewed in 2007 did not show that antibiotic treatment of at risk women prevented preterm birth . A diffeAnother lesson implied by the concept of inflammation-related cascades as the trigger for initiation of parturition is that we need to develop a better understanding of how to manage the trigger. Antibiotics in general terms represents a blunt instrument, and simply introducing antibiotics broadly into obstetric care cannot be expected to be effective as the literature has demonstrated. Every pregnant woman carries an abundant flora, and the flora differs among individuals. Some of the organisms found commonly in the flora have a reputation as harmful, and yet eliminating these organisms has not had an effect on prematurity . IndividIn this paper, we have also noted that recent research suggests that there are differences in some of the mechanistic details between birth that is related to progesterone withdrawal versus birth precipitated by bacterial triggering of virulence pattern recognition receptors such as TLR or NOD molecules. Continued research may identify useful targets in these pathways, but interestingly, information suggesting that progesterone may modulate the terminal steps in the delivery cascade (prostaglandin and nitric oxide) suggests that the role of progesterone may increase in the future, depending on the outcome of well-designed and appropriately powered studies to investigate efficacy, closely defined populations for study, and investigation of adverse effects in mothers and their infants after administration of pharmacologic interventions. Translational research will continue as an outgrowth of the science that identifies novel targets for interdicting preterm birth, but devising safe and meaningful research that provides useful evidence that truly informs clinical practice will be a challenge as investigators, clinicians, and funding agencies wrestle with deciding which approaches are most appropriate and promising for clinical trials.


Preterm birth rates have increased substantially in the recent years mostly due to obstetric intervention. We studied the effects of increasing iatrogenic preterm birth on temporal trends in perinatal mortality and serious neonatal morbidity in the United States.We used data on singleton and twin births in the United States, 1995-2005 , to examine trends in stillbirths, neonatal deaths, and serious neonatal morbidity . Preterm birth subtypes were identified using an algorithm that categorized live births <37 weeks into iatrogenic preterm births, births following premature rupture of membranes and spontaneous preterm births. Temporal changes were quantified using odds ratios (OR) and 95% confidence intervals (CI).Among singletons, preterm birth increased from 7.3 to 8.8 per 100 live births from 1995 to 2005, while iatrogenic preterm birth increased from 2.2 to 3.7 per 100 live births. Stillbirth rates declined from 3.4 to 3.0 per 1,000 total births from 1995-96 to 2004-05, and neonatal mortality rates declined from 2.4 to 2.1 per 1,000 live births. Temporal declines in neonatal mortality/morbidity were most pronounced at 34-36 weeks gestation and larger among iatrogenic preterm births  than among spontaneous preterm births ; P < 0.001. Similar patterns were observed among twins, with some notable differences.Increases in iatrogenic preterm birth have been accompanied by declines in perinatal mortality. The temporal decline in neonatal mortality/serious neonatal morbidity has been larger among iatrogenic preterm births as compared with spontaneous preterm births. Preterm birth is the leading cause of neonatal mortality and morbidity and preterm infants are more likely to experience neurodevelopmental delay and childhood disability. Thus, the recent increase in preterm birth that has been observed in many industrialized countries is a cause for concern. For instance, in the United States, the rate of preterm birth increased by 20% from 10.6% in 1990 to 12.7% in 2007 ,4.Preterm birth can result from many maternal and fetal causes. Three major clinical subtypes of preterm birth can be identified, namely, iatrogenic  preterm birth, spontaneous preterm birth, and preterm birth following premature rupture of membranes. In North America, the recent increases in preterm birth occurred predominantly due to increases in iatrogenic preterm birth at late preterm gestation 34-36 weeks) ,6. Other weeks ,6Infants born following medically indicated preterm birth are at a two-fold higher risk of neonatal mortality as compared with infants born following spontaneous preterm birth -15. If tOur goal was to estimate temporal trends in iatrogenic and spontaneous preterm birth and to quantify trends in stillbirth, neonatal mortality and serious neonatal morbidity among the different preterm birth subtypes. We hypothesized that, over the past decade, there have been larger declines in neonatal mortality and serious neonatal morbidity among preterm infants born following obstetric intervention, as compared with infants born following spontaneous preterm labour.We used population-based data on singleton and twin births in the United States, 1995-2005, from the National Centre for Health Statistics (NCHS). Information in the NCHS period linked birth and death files, and fetal death files was abstracted from birth certificates of liveborn infants and from fetal and infant death certificates ,17. ThesPreterm birth was defined as live birth before 37 completed weeks of gestation, and classified into 3 subtypes using a previously published algorithm ,15. SincNeonatal death was defined as death of an infant that occurred within the first 28 days after birth and serious neonatal morbidity was defined as any of the following conditions: a 5-minute Apgar score ≤3, assisted ventilation ≥30 minutes and neonatal seizures. A composite measure including neonatal death or any of the serious neonatal morbidity listed above was used to estimate the overall rate of adverse neonatal outcomes.We examined potential differences in maternal characteristics between 1995-96 and 2004-05, with respect to age, race , marital status (married or common-law vs. other), education (<12 years vs. 12 years or more), smoking during pregnancy (yes/no) and prior live births (yes/no). We also examined infants' gender, gestational age distributions among stillbirths and neonatal deaths, and the birth prevalence of congenital anomalies.Temporal trends were quantified by contrasting neonatal mortality and neonatal mortality/serious neonatal morbidity between 1995-96 and 2004-05 using odds ratios and 95% confidence intervals (CI). Temporal changes were further examined within gestational age categories 24-27, 28-31, 32-33, and 34-36 weeks. Odds ratios were reported separately for singletons and twins. Differences in the magnitude of the temporal decline in neonatal mortality or neonatal mortality/serious neonatal morbidity between subtypes of preterm birth  were assessed using a test for heterogeneity of the odds ratios . We alsoMaternal characteristics changed during the study period: women who delivered in 2004-05 were older, more educated and smoked less during pregnancy compared with women who delivered in 1995-96 , which increased from 5.3 per 100 live births in 1995 to 6.7 per 100 live births in 2005, were responsible for most of the increase. Preterm birth rates increased from 7.3 in 1995 to 8.8 per 100 live births in 2005 among singletons  and from 52.3 to 62.0 per 100 live births among twins .The increase in the singleton preterm birth rate was predominantly due to an increase in iatrogenic preterm birth from 2.2 in 1995 to 3.7 per 100 live births in 2005 . There was no significant change in neonatal mortality rates among live births following preterm rupture of membranes between 1995-96 and 2004-05 . The difference in temporal trends in neonatal mortality between infants born after PROM and those born following iatrogenic and spontaneous preterm birth was significant . In general, larger reductions in neonatal mortality were observed at late preterm gestation (34-36 weeks) compared to earlier gestational ages   was not significantly greater than the decline following spontaneous preterm birth . The observed declines in neonatal mortality within each preterm birth subtype were largest among live births at 34-36 weeks gestation . Neonatal mortality/serious neonatal morbidity rates among preterm live births following PROM increased significantly from 1995-96 to 2004-05 and this change was significantly different from the temporal changes in the 2 other subtypes of preterm birth . Significant reductions in neonatal mortality/morbidity among twin live births following iatrogenic preterm birth were observed at 24-27, 28-31 and 34-36 weeks but not among those born at 32-33 weeks. Among twins born following spontaneous preterm birth, neonatal mortality/serious neonatal morbidity was significantly reduced at 24-27 and 28-31 weeks but not at 32-33 and 34-36 weeks, while among twins born following PROM, neonatal mortality/morbidity was not significantly reduced in any gestational age group . Similar results were also obtained when analysis was restricted to the US states that did not introduce the new birth certificate form in 2004 or 2005. Preterm birth rates were similar between states that did and did not introduce a new birth certificate . Supplementary analyses carried out among older mothers (≥35 years) showed that between 1995-96 and 2004-05, neonatal mortality/serious neonatal morbidity among singletons born preterm following iatrogenic delivery, declined from 10.3 to 7.4 per 100 live births, odds ratio = 0.69 (95%CI: 0.64-0.75); among preterm infants born spontaneously the composite outcome increased from 6.5 to 7.1 per 100 live births, odds ratio = 1.10 (95%CI: 1.03-1.18). Neonatal mortality/serious neonatal morbidity rates remained relatively stable among infants born following PROM (12.7 and 13.2 per 100 live births), odds ratio = 1.05 (95%CI: 0.95-1.16).Supplementary analyses showed that trends in neonatal mortality/serious neonatal morbidity remained unchanged even after the exclusion of infants with congenital anomalies from the analysis. There was a significantly larger temporal decline in neonatal mortality/serious neonatal morbidity following iatrogenic preterm birth  than following spontaneous preterm birth , this difference was not statistically significant. One possible reason for this may be the lesser frequency of neonatal mortality i.e., the lack of a significant difference could have arisen due to a lesser study power.The limitations of our study include a potential misclassification of preterm birth subtypes. Some cases of spontaneous preterm labour or PROM who were delivered by caesarean for indications such as fetal compromise may have been misclassified as iatrogenic in our study. This problem arose because our data source did not include details regarding the onset of labour. However, the misclassification introduced because of this is likely small as studies from other more clinically focussed databases (which include information on labour onset) have shown similar proportions of iatrogenic and spontaneous preterm births. For instance, a study from British Columbia, Canada , showed Another limitation arises because we were not able to utilize data on neonatal morbidity from those states that introduced the new birth certificate forms in 2004 and 2005 due to the incompatibility of definitions for assisted ventilation. However, sensitivity analyses showed that this had a minor impact on our findings. In addition, newborns from states that introduced the new birth certificate during 2004-05 had similar characteristics as compared with infants born in the other states (data not shown). Disease specific information, such as occurrence of intraventricular hemorrhage, necrotizing entrerocolitis or respiratory distress syndrome, was not available in the US data. Instead, we used a composite outcome including neonatal mortality or severe neonatal morbidity, the latter being approximated by Apgar score at 5 minutes < = 3, prolonged ventilation, and neonatal seizures. This composite outcome was chosen to identify neonates who died or those at a high risk of infant death or disability. This composite outcome has been used in previous studies  and is sIn summary, our study shows that recent increases in obstetric intervention in the United States have resulted in larger declines in rates of neonatal mortality and serious neonatal morbidity among infants born following iatrogenic preterm birth as compared with infants born following spontaneous preterm birth. On the other hand, neonatal mortality/serious neonatal morbidity rates among infants born following PROM showed a temporal increase among singletons and no significant change among twins. Whereas our findings on iatrogenic preterm birth are encouraging, they highlight the need for improving outcomes among preterm infants born following preterm premature rupture of membranes. More research is needed to identify the underlying maternal and fetal conditions that lead to preterm delivery in order to develop targeted interventions to prevent adverse neonatal outcomes resulting from preterm birth.OR: odds ratio; CI: confidence interval; PROM: premature rupture of membranes; NCHS: National Centre for Health Statistics.The authors declare that they have no competing interests.All authors contributed to the conception and design of the study and in the preparation of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/11/39/prepub


Objective: Intrauterine growth references are primarily useful indicators in the assessment of the general health status of newborn infants. Although Lubchenco’s references are still used in many neonatal care units, we believe that there is a need for up-to-date intrauterine growth references specific for different populations. To develop gestational age-and gender-specific national references for birth weight, birth length and head circumference.Methods: Data were collected from neonatal records of perinatology services of eleven hospitals from January to December 2009. The anthropometry of a total of 4750 singleton live births born between 28 and 41 weeks of gestation were recorded. Means and standard deviations were calculated, and percentiles for each gender and gestational week were produced using the LMS program. The results were compared with US infants and also with local data.Results: Gestational age- and gender-specific 3rd, 5th, 10th, 15th, 25th, 50th, 75th, 85th, 90th, 95th and 97th percentile values were produced. Comparison of the 10th, 50th and 90th percentile values showed that the boys were heavier and longer than the girls. Head circumference values were also higher in the boys. Proportions of small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants in the sample were 10.1%, 79.1% and 10.8%, respectively. Conclusion: These gender- and gestational age-specific references will be of use in clinical practice and also for research purposes until more comprehensive, reliable and accessible national data pertaining to the intrauterine growth of Turkish infants are produced. Conflict of interest:None declared. Body weight, length and head circumference at birth are measurements used in the assessment of peri- and postnatal growth and health. However, for evaluation of fetal growth, it is essential to know the gestational age-adjusted birth weight, length and head circumference . It is kProducing gestational age-specific percentiles provides the opportunity to determine SGA and LGA infants. Another application of intrauterine percentiles is in predicting whether a preterm infant will be able to maintain his/her growth velocity or achieve catch-up growth in postnatal life . In 1966It is known that fetal, maternal, placental and environmental factors may all influence fetal growth . GeograpIn Turkey, there are a few studies on intrauterine growth, which were conducted in single centers or with small sample sizes. Another limitation of these studies is that either they are based on a single parameter like birth weight or they are not detailed enough to get gestational age-specific percentiles ,15,16,17This study was designed to produce gestational age- and gender-adjusted percentile charts in a cohort of Turkish newborns born in a city in the Central Anatolian Region of Turkey. These references will also serve to determine the prevalence of appropriate, SGA and LGA newborns in the community.rd percentiles or higher than the 97th percentiles. Finally, we used the data from 4750 infants to produce our charts.This is a cross-sectional and retrospective study in which data were collected from the medical records of infants born between January and December 2009 in 11 hospitals in Kayseri, a Central Anatolian city in Turkey. 65% of the deliveries had taken place in private, 26% in state and 9% in University hospitals. Gestational ages were recorded by the obstetricians or trained nurses in labor wards. A total of 5421 infants born at gestational ages between 28-42 weeks were recruited. Since the numbers of infants between 28-33 and 41-42 weeks of gestation were too small, we combined these age groups as 28-29, 30-31, 32-33 and 41-42 weeks. We excluded infants whose mothers had chronic diseases, who were smokers or who had undergone multiple deliveries. Infants who had fetal health problems, congenital malformations and those with missing data for measurements of weight, length or head circumference were also excluded. To get a smooth distribution for weight, length and head circumference percentiles, we also removed the original data less than 3th percentile and 90th percentile cut-off values were used to define SGA and LGA. Preterm delivery was defined as birth before completion of 38 weeks of gestation. SGA was defined as a low measurement than normal according to gestational age and gender. The 10Statistical AnalysisDescriptive statistics for each gestational age within sex were performed using the SPSS version 15.0 . rd, 10th, 15th, 25th, 50th, 75th, 85th, 90th and 97th percentile curves for birth weight, length and head circumference, we used the LMS Chart Maker Pro version 2.3 software program , which fits smooth centile curves to reference data. This method summarizes percentiles at each gestational age based on the power of age-specific Box-Cox power transformations that are used to normalize data. These three quantities depend on gestational age. The final curves of percentiles are produced by three smooth curves representing L , M  and S . The calculated 10th, 50th, and 90th percentiles were compared with the available data on USA infants since both studies were conducted in similar periods. To make local comparisons, we used the most recent study in which 3rd, 10th, 50th, 90th, 97th percentiles for term infants of both genders were reported. To construct the gestational age- and gender-specific 3rd, 5th, 10th, 15th, 25th, 50th, 75th, 85th, 90th, 95th and 97th percentile values for all parameters are shown in There were 2493 52.5%) male and 2257 (47.5%) female infants included in the study. 39.4% of the infants were preterm and 60.6% were term newborns. Gestational age- and gender-specific descriptive values including birth weight, length and head circumference are shown in 2.5% maleth, 50th and 90th percentiles between genders showed that boys were heavier and longer than girls. Head circumference measurements were also higher in the boys. The largest differences between male and female infants at birth were less than 200 g for weight, 0.8 cm for length and 0.6 cm for head circumference  and LGA was 10.1%, 79.1% and 10.8%, respectively. th, 50th and 90th percentile values reported for USA infants in a recent study conducted on infants born after 32 weeks of gestation. USA percentiles were all higher than our data  in their clinical practice as well as by parents who desire to assess and follow the actual and future growth pattern of their siblings. Gestational age- and gender-specific anthropometric references also provide a basis for estimation of SGA and LGA prevalences and data for comparison with other studies. SGA infants have adverse outcomes other than growth problems such as neurodevelopmental delay ,20. LGA rd, 5th, and 10th birth weight percentiles have been used as cut-off values to identify clinically important fetal growth restriction . Our data also revealed that percentile values were higher in the males than in the females after the 35th week of gestation. The gender difference significantly increased in the 90th percentile range for all anthropometric measurements.There are several previous studies reporting gender difference for birth weight and length throughout pregnancy or at a certain gestational week (Data from a global survey showed variations in birth weight among several countries. In this report, birth weight in term infants varied from 2790 g in India to 3511 g in Algeria ,31. Comparing our data with those of USA newborns, we found that the percentile values of the neonates in our sample were somewhat higher before 32 weeks of gestation. After the first 32-35 weeks of gestation, USA percentiles were strikingly higher than the percentile values in our study  and 3. TComparing our results with data from other national studies, such as the Kartal Hospital data , we founThe potential limitations of this present study can be listed as the possibility of measurement errors in preterm neonates, the use of a cross-sectional method which limits the monitoring of the actual growth pattern, collection of data from different hospitals, the relatively small sample size, and the potential errors due to the reporting of the last menstrual period. However, this study provides a quite large sample size and detailed information. Both the percentile and the mean and standard deviation values we report can be used in comparisons with national or international data. We believe that these data will be of use both in clinical practice and for research purposes until more comprehensive, reliable and accessible national data pertaining to the intrauterine growth of Turkish infants are produced.


Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth.Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics.We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone.In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives. ANN NEUROL 2013;73:714–720 Case–control studies are frequently employed as a means of testing for association between a disease of interest and candidate etiological risk factors. However, despite the apparent simplicity of this approach, spurious results are not uncommon4In the analysis of month of birth, researchers have invariably assumed homogeneity within individual countries and have therefore felt justified in using averaged population statistics as controls. Here, we review the evidence that month of birth varies significantly with geographical locationdf). The chi-square test was also used to compare data sets within and between countries. In comparisons between consecutive years from the same country, the number of births in February was reduced by 1/29 for leap years, so that all such comparisons were based on data for 365 days. In these chi-square tests, we took p < 0.05 as evidence for a statistically significant difference, unless otherwise stated. To explore these complex data more formally, we used a multinomial logit model,Using publically available national statistics, we established year-specific month of birth data sets  for multiple years from 17 countries , 51 North American regions (50 states and the District of Columbia), and 10 UK Government Office Regions (Supplementary Information). Data sets were tested for evidence of seasonality by comparison with the expected distribution of births in each month under the assumption of a uniform birth rate using a chi-square test .p < 0.05/12 = 0.0042). Using the expected month of birth distribution in cases and controls, we determined the noncentrality parameter for each of these tests,p < 0.05) excess of births in March, April, or May and/or a nominally significant (p < 0.05) deficit in November, December, or January. In all analyses, the numbers of cases and controls were equal.To investigate the type I error rate of a typical month of birth analysis, we estimated the expected month of birth distribution in cases and controls using the UK Government Office Region data. For the cases, the distribution was weighted according to the regional prevalence of multiple sclerosis (see Structure and Risk Factors) and the observed year of birth, whereas the simple unweighted average was used for the controls. Because this analysis assumes homogeneity within each region, it is expected to underestimate the type I error rate. Two types of analyses were considered. First, we mirrored a discovery study, consisting of twelve 2 × 2 contingency tables, each comparing the number of case and control births in 1 month with the number in the other 11, and with significance declared if the Pearson chi-square test was significant after Bonferroni correction p < 0.05/ = 0.0042p < 10−6). Considering the variation in birth rates seen for individual months and applying a Bonferroni correction (so that p < 0.0042 is considered significant), we found statistically significant evidence for seasonality, with excess births in either March, April, or May and/or reduced births in November, December, or January, mirroring the pattern described for multiple sclerosis,Given the large number of cultural and biological factors that influence the timing of birth,To assess correlations within the month of birth data sets more rigorously, we used a multinomial logit model, including country as a factor, together with year of birth and whether that year was a leap year as covariates. Although this model explained only a small proportion of the variance in month of birth, the parameters representing the effect for each country were all highly significant, confirming that the distribution of month of birth differs significantly between countries. Fitting a second model that included latitude as an additional factor confirmed that the relationship between month of birth and latitude is statistically highly significant.To test for the presence of regional heterogeneity in birth rates within individual populations, we considered 440 UK Government Office Region month of birth data sets (see Supplementary Information). More than 99% showed statistically significant evidence for seasonality, with 66% reproducing the pattern described for multiple sclerosis ; the most marked differences were seen in March and October. Comparing each Government Office Region month of birth data set with the set of UK controls employed in 1 influential studyp = 0.06) and the greatest deficit in December  and a less significant deficit in November  showed that the greatest excess in births was seen in March  have reminded researchers that seemingly homogeneous populations often turn out to be structured, and have also shown just how easily such effects are able to generate false-positive associations even in population-specific case–control studies (see the example from genetics below). Testing and making compensation for structure has become an indispensable part of complex genetics but seems to have been largely ignored in efforts to explore the possible role of environmental factors in complex traits. In our analysis of publicly available birth records, we confirm that birth rate is heterogeneous in the general population, where it is characterized by substantial and significant differences both between and within populations. It follows that birth rates calculated by the unweighted averaging of available population statistics are unlikely to provide appropriate controls for studies of specific diseases, where case collections are invariably heterogeneous with respect to year of birth and regional origin. Although it seems logical to average over many observations to generate more reliable control estimates, the mean birth rates obtained by such a process are a weighted average of the seasonality present in the population and not an estimate of some fundamental underlying rate. This weighted mean can only safely be compared with cases that have the same structure. Self-evidently, spurious differences will arise if birth rates are calculated for cases having a different distribution across subgroups that make up the normal population. Three groupsThe confounding effects described here are a consequence of the substantial geographical and temporal variation in birth rate that is present in the general population; they are not specific to multiple sclerosis and have the potential to generate false-positive association with month of birth in any study where cases are inadequately matched, regardless of the phenotype. To date there are >500 reports relating month of birth to the etiology of a complex trait. The list includes various autoimmune diseases  birth rate is subject to highly significant variation with respect to place and time; and (2) the probability of being born in the spring  is positively correlated with latitude, whereas the probability of being born in the winter  is negatively correlated.Because typical multiple sclerosis case collections are unlikely to be uniform with respect to region of origin or year of birth: (1) studies using national statistics as controls are predisposed to generate false-positive associations with month of birth; and (2) the associations generated by such studies are inherently biased in favor of showing a false-positive apparent excess of births in spring and/or reduced births in winter.http://www.ons.gov.uk), together with corresponding multiple sclerosis prevalence estimates and the approximate region-specific frequency of the C allele of the rs1042712 single nucleotide polymorphism (SNP) from the lactase gene  that C_rs1042712 is a risk factor for multiple sclerosis, with >99.9% certainty, and would generate a genome-wide significant result (p < 5 × 10−8) >40% of the time. If the study were then repeated using a similar design but with 2,000 patients from the East of England Government Office Region, the apparent association would be replicated with 1-tailed nominal significance on the majority of occasions (>90%). Conversely, if replication were attempted in Wales, researchers would most likely (>95%) find nominally significant evidence that C_rs1042712 appears protective. The ease with which apparently significant results can be generated despite the relatively modest absolute difference in allele frequency illustrates how sensitive case–control analysis is to unrecognized, and therefore uncompensated, population structure.If controls are randomly selected from across the United Kingdom , the expected allele frequency is 11.6%, less than is seen in London (14.5%) and more than in Wales (9.5%). If an association study were performed in London using 10,000 such controls and 2,000 local patients, it would find nominally significant evidence  would be observed on >95% of occasions. This bias arises because a disproportionate number of the cases will come from northern  parts of the country, which generally have a lower than average allele frequency for this particular SNP; as a result the estimated allele frequency in cases will tend to be lower (11.3%) than in the general population (11.6%). This illustrates why, even if all cases and all controls from a country are included in an analysis, structure can still generate false-positive associations unless there is compensation for the confounding effects of their unequal distribution. Whether a study that only employs cases and controls from a single Government Office Region would be free from bias cannot be judged from the figures provided in the Table. Given the highly significant difference in both disease and allele frequency between regions, it seems probable that structure will also occur within, although to a lesser extent than between, regions.Genetic analyses are uniquely well placed with respect to the assessment and compensation of structure. First, although the above analysis has considered matters from a geographical perspective, the primary confounding variable in genetic studies is ancestry, not geography. The probability that individuals carry a particular allele of interest primarily depends upon who their ancestors were and not where they were born or domiciled when recruited to a study. Because ancestry does not change over time, and can be accurately inferred using genetic markers, in principle little if any geographical precision is necessary to assess and correct for structure in allele frequency distribution within a population. Conversely, for social and mobility reasons, there is an inevitable correlation between geography and ancestry,


Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics.This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy.Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length  and a smaller birth length [difference −2.61 mm (95%CI −5.32 to 0.11)]. The maternal T-allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference −33 grams (95%CI −55 to −10)], and tended to be associated with birth weight [difference −38 grams (95%CI −89 to 13)]. This association persisted after adjustment for smoking quantity.Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large-scale genome wide association studies focusing on gene – fetal smoke exposure interactions. CHRNA5-CHRNA3-CHRNB4), to be associated with smoking quantity Maternal smoking during pregnancy is strongly associated with increased risks of preterm birth or a small size for gestational age at birth Therefore, we explored in a population-based prospective cohort study among 3,563 European mothers, whether maternal rs1051730 modifies the associations of maternal smoking during pregnancy with fetal growth characteristics in different trimesters.In our population, 610 (17.1%) mothers continued smoking during pregnancy . Mean mainteractionP<0.05]. Among mothers who smoked during pregnancy, the T-allele was associated with a lower third trimester estimated fetal weight [difference −32.7 grams (95%CI −55.4 to −10.0)], and tended to be associated with lower birth weight [difference −38.1 grams (95%CI −89.2 to 12.9)]. Among the mothers who smoked during pregnancy, those who had a T/T genotype gave birth to children with a birth weight that was 117 grams lower (95% CI −229 to −4 grams), as compared to children whose mothers had a G/G genotype. We found a significant interaction between maternal smoking status and maternal genotype of rs1051730 for fetal weight at all time points [interactionP<0.05].In the total population, we did not observe associations of the maternal T-allele of rs1051730 with fetal growth characteristics . Among mIn We performed several sensitivity analyses. First, results of the analyses with a dominant genetic model are shown in CHRNA5-CHRNA3-CHRNB4), influences the susceptibility of impaired fetal growth by maternal smoking. Among mothers who smoked during pregnancy, the T-allele resulted in smaller femur length and lower estimated fetal weight from second trimester onwards.Results from this prospective population-based cohort study suggest that maternal genotype of the common genetic variant, rs1051730, located within the 15q25 nicotinic acetylcholine receptor gene cluster  were considered as non-smokers in our analyses. This could have resulted in biased effect estimates if fetal growth would be different between quitted smokers and non-smokers. However, we have previously reported that first trimester smoking only does not affect second and third trimester fetal growth We established gestational age by ultrasound. By using this method, growth variation of the fetal characteristics used for pregnancy dating is assumed to be zero. In our study, first trimester crown-rump length and biparietal diameter were used for pregnancy dating but not for assessing fetal growth. Since pregnancy dating characteristics and growth characteristics are correlated throughout pregnancy, growth variation in head circumference, abdominal circumference, and femur length may be reduced by dating the pregnancy on the other fetal characteristics. This may have led to underestimation of our effect estimates. However, we expect this effect to be small in our results. This underestimation will consequently be lowest in women included in the first trimester . We performed a sensitivity analysis using only these women, but results did not change (data not shown).The effects of maternal smoking status during pregnancy on fetal growth have been studied previously, showing that among mothers who continued smoking during pregnancy, children had smaller femur length from second trimester onwards and smaller head circumferences from third trimester onwards, as compared to children from mothers who did not smoke during pregnancy The effects of maternal smoking on fetal growth are known to differ between individuals. We have previously demonstrated that maternal first trimester folic acid supplementation use reduces the adverse effects of maternal smoking during pregnancy on fetal growth CHRNA5-CHRNA3-CHRNB4) on chromosome 15q25. This locus has been investigated previously and common genetic variants in high linkage disequilibrium with rs1051730 (HapMap r2>0.8) were associated with higher circulating cotinine levels, but not with number of cigarettes smoked per day The mechanism through which rs1051730 modifies the associations between maternal smoking and fetal growth is yet unknown. Rs1051730 is located in the nicotinic acetylcholine receptor gene cluster  were included during pregnancy, of whom 3,862 mothers had a singleton live birth and had genotype of rs1051730 available. We had smoking status during pregnancy and fetal ultrasounds available in 3,563 (92.3%) of these mothers. A participant flow chart is given in Information about maternal smoking status during pregnancy was obtained by postal questionnaires sent in first, second and third trimester. Response rates for these questionnaires were 91%, 80% and 77%, respectively P-value = 0.78). Distribution of fetal genotype was similar .Maternal DNA was extracted from whole blood samples. Genotyping of the G>T substitution of rs1051730 in mothers was performed using TaqMan allelic discrimination assay . Child DNA was isolated from cord blood. Genotyping was carried out using the Illumina 610 k Quad arrays. The frequency distribution of maternal rs1051730 genotype did not deviate from the Hardy-Weinberg equilibrium in subjects with European ancestry .Fetal ultrasound examinations were carried out in two dedicated research centers in each trimester of pregnancy. Reliability and reproducibility of these ultrasound examinations was tested in early pregnancy and was very good  2 [kg/m2]) at enrollment Maternal age and information about maternal educational level and parity was obtained by a questionnaire at enrollment in the study. Maternal alcohol consumption habits were assessed by questionnaires in each trimester. Maternal anthropometrics, including height and weight, were measured without shoes and heavy clothing and body mass index (BMI) was calculated  with fetal growth characteristics in second and third trimester  and at birth . Based on previous studies, we considered an additive model, but performed a sensitivity analysis using a T-dominant model. All other analyses were based on an additive model and the effect estimates reflect the effect for each additional copy of the risk allele. Analyses were performed in the total group, and in strata of mothers who did not smoke during pregnancy and mothers who smoked during pregnancy. We tested the interaction between maternal smoking and maternal genotype, to assess whether the associations of maternal smoking with fetal growth were modified by the T-allele of rs1051730. All models were adjusted for sex and gestational age at visit. Analyses in the total population were adjusted for smoking status. To assess possible confounding effects, we additionally adjusted for first trimester smoking quantity as a covariate. Next, a fully adjusted model was explored, with further adjustment for maternal age, body mass index at enrollment, parity, educational level and alcohol consumption. The regression models with neonatal head circumference and length as outcome were additionally adjusted for postconceptional age  and for the source of the measurement . We repeated the analyses for fetal genotype.The associations of smoke status, rs1051730 genotype and longitudinally measured fetal growth were analyzed using unbalanced repeated measurement regression models. The repeatedly measured outcome data for this analysis were the gender and gestational age adjusted SD scores. These models take the correlation between repeated measurements of the same participant into account and allow for incomplete outcome data Table S11.Subject characteristics of the mothers per maternal genotype (continued smokers n = 610)1Values are means (SD) or percentages. 2Median (95% range). Differences in distributions between groups were evaluated using a Student T-test for continuous variables and Chi-square tests for categorical variables *P-value<0.05.(DOC)Click here for additional data file.Table S21.Associations of maternal rs1051730 genotype and maternal smoking with longitudinally measured growth measures1Values are based on repeated linear regression models and reflect the differences in growth in gender and gestational age specific standard deviation scores (SDS) between the number of risk alleles and smoking status compared to the reference group (SDS = 0). *P-value<0.05; **P-value<0.01.(DOC)Click here for additional data file.Table S31 .Cross-sectional associations of maternal rs1051730 genotype with fetal growth characteristics in different trimesters (assuming a T-dominant model)1Effect estimates  reflect the differences in phenotype of women with one or two copies of the T-allele of rs1051730, compared to women without risk alleles (assuming a dominant model). 2Interaction term = maternal genotype×smoking status. *P-value<0.05; **P-value<0.01. All analyses were adjusted for gestational age at visit, sex and smoking quantity. Analyses in the total group were additionally adjusted for smoking status . Birth length and head circumference at birth were additionally adjusted for source of the birth measurements.(DOC)Click here for additional data file.Table S41 .Cross-sectional associations of fetal rs1051730 genotype with fetal growth characteristics in different trimesters 1Effect estimates  reflect the differences in phenotype for each additional copy of the T-allele of rs1051730 (assuming an additive model). 2Interaction term = fetal genotype×smoking status. *P-value<0.05; **P-value<0.01. All analyses were adjusted for maternal rs1051730 genotype, gestational age at visit and sex. Analyses in the total group were additionally adjusted for smoking status . Birth length and head circumference at birth were additionally adjusted for source of the birth measurements.(DOC)Click here for additional data file.Table S51 .Cross-sectional associations of maternal rs1051730 genotype with fetal growth characteristics in different trimesters1Effect estimates  reflect the differences in phenotype for each additional copy of the T-allele of rs1051730 (assuming an additive model). 2Interaction term = maternal genotype×smoking status. *P-value<0.05; **P-value<0.01. All analyses were adjusted for gestational age at visit, sex and smoking quantity. Analyses in the total group were additionally adjusted for smoking status . Birth length and head circumference at birth were additionally adjusted for source of the birth measurements.(DOC)Click here for additional data file.Table S61 .Cross-sectional associations of maternal rs1051730 genotype with fetal growth characteristics in different trimesters1Effect estimates  reflect the differences in phenotype for each additional copy of the T-allele of rs1051730 (assuming an additive model). 2Interaction term = maternal genotype×smoking status. *P-value<0.05; **P-value<0.01. All analyses were adjusted for gestational age at visit, sex, maternal age, BMI at enrollment, parity, educational level, alcohol use and smoking quantity. Analyses in the total group were additionally adjusted for smoking status . Birth length and head circumference at birth were additionally adjusted for source of the birth measurements.(DOC)Click here for additional data file.


Background: The use of cancer-related biomarkers in newborns has been very limited.Objective: We investigated the formation of micronuclei (MN) in full-term and preterm newborns and their mothers from the Rhea cohort (Crete), applying for the first time in cord blood a validated semiautomated analysis system, in both mono- and binucleated T lymphocytes.Methods: We assessed MN frequencies in peripheral blood samples from the mothers and in umbilical cord blood samples. We calculated MN in mononucleated (MNMONO) and binucleated (MNBN) T lymphocytes and the cytokinesis block proliferation index (CBPI) in 251 newborns (224 full term) and 223 mothers, including 182 mother–child pairs. Demographic and lifestyle characteristics were collected.r = 0.35, p < 0.001), and we found a moderate correlation between MNMONO in mothers and newborns . MNMONO frequencies in newborns were positively associated with the mother’s body mass index and inversely associated with gestational age and mother’s age, but we found no significant predictors of MNBN or CBPI in newborns.Results: We observed significantly higher MNBN and CBPI levels in mothers than in newborns. In newborns, MNMONO and MNBN were correlated (in vivo cell division and accumulated in utero, and the latter includes additional damage expressed as MN during the in vitro culture step.Conclusions: Although confirmation is needed by a larger study population, the results indicate the importance of taking into account both mono- and binucleated T lymphocytes for biomonitoring of newborns, because the first reflects damage expressed during  The incidence of childhood cancer in Europe is estimated to increase around 1% per year, with the strongest increase of 2.1% seen in children < 1 year of age for the period 1978–1997. Better diagnostic tools and recent evolution of our genetic background can only partly explain this increase; therefore, changes in our environment are the most probable causes of the observed increase ] or more times (polynucleated cells)  . MN freq who are residents of the prefecture of Heraklion in Crete, Greece  immediately after the delivery. To prevent clotting, 0.5 mL extra heparin  was added to the tubes used to collect umbilical cord blood. After collection, the samples were kept at 4°C and processed within 24 hr  at the National Cancer Institute .CBMN assay. The CBMN assay was carried out according to the standardized protocol developed by us for the semiautomated image analysis system , which was filtered twice through Whatman 41 filters .Slides scoring and interactive validation. The automated scoring procedure followed by visual validation of selected MN cells was carried out by the same researcher (K.V.L.), using the PathFinder platform installed by Imstar  at the Laboratory of Cell Genetics from Vrije Universiteit Brussel, consisting of a PathFinder CELLSCAN capture station and two PathFinder MN analysis workstations. At the end of the processing step, the cells containing detected MN are presented one by one on the computer screen for visual confirmation or rejection by the scorer, according to Human MicroNucleus project (HUMN) scoring criteria (x number binucleate cells + 3x number polynucleate cells) ÷ total number of cells.criteria . After vStatistics. Consistent with Organisation for Economic Co-operation and Development (OECD) guideline T487 (OECD 2010), data were included only for subjects with at least 1,000 BN lymphocytes counted . Normality was evaluated by the Kolmogorov–Smirnov goodness-of-fit test, and because not all data were normally distributed, differences between groups were tested using the nonparametric Mann–Whitney U-test. Associations between genotoxicity parameters and demographic characteristics were tested using Spearman’s rho correlation analysis. Multivariable linear regression analysis with backward selection was used to identify maternal and child factors that were significant predictors of the different genotoxicity parameters . The backward selection was done by eliminating variables that were not significantly associated with the outcome (p < 0.05). Each initial model included maternal age, birth weight, sex of the child , prepregnancy BMI, GA, delivery type , smoking at the 30th week of pregnancy , and the use of antioxidant supplements during pregnancy . The models were restricted to observations with complete data for all variables. For the analysis of all newborns, preterm status  was added as an independent variable. Additional models of newborn data from mother–child pairs included maternal genotoxicity parameters as initial predictors. Twin births  were modeled as individual observations, without accounting for correlated observations. To reduce the number of independent variables and limit multiple testing, highly intercorrelated (Spearman’s rho correlation) independent variables (vitamin B12 and folate concentrations) were excluded from the regression model. The level of significance was set at p < 0.05 for all statistical analyses. We used SPSS  to analyze the data.Study population. Demographic data were available for most of the subjects  and 3,616 , respectively. In the total population . Median values were similar when restricted to data from participants in mother–child pairs (p < 0.001). Median MNMONO frequencies were not significantly different between maternal and child samples . Genotoxicity parameters did not differ significantly between preterm and full-term newborns (data not shown). In newborns, MNMONO and MNBN frequencies were positively correlated with MNBN (r = 0.346) (data not shown). Within the pairs (data not shown), we found a significant positive correlation between the number of MNMONO/1,000 MONO from newborns and mothers (r = 0.263).pulation , median ld pairs . Median Multivariable analysis. None of the variables included in the initial model  were significant predictors of MNBN and CBPI among the 173 children with complete data for all potential predictors (edictors . Howevern = 156). As for all births combined, no variables significantly predicted MNBN frequency or CBPI  in addition to the variables evaluated previously (data not shown). As for previous models, we found no significant predictors of MNBN, including maternal genotoxicity parameters. In addition, maternal genotoxicity parameters did not predict child’s MNMONO frequency. However, we found a significant positive association between maternal CBPI and child’s CBPI (data not shown).n = 163), mothers delivering a girl had significantly fewer MNBN than did those delivering a boy. MNMONO frequencies increased significantly with maternal age. Mothers who delivered by cesarean section had significantly higher CBPI values compared with those who delivered naturally, and higher prepregnancy BMI also was associated with higher CBPI values.We also evaluated predictors for maternal genotoxicity parameters . In the The present study investigated factors that predict the frequency of MN in blood samples from newborns (full term and preterm) and mothers in the Rhea cohort (Crete), conducted within the European Union project NewGeneris. Detailed questionnaires provided information concerning gestational factors, demographic data, medical status, smoking, alcohol consumption, and other factors.12 concentration.The CBMN assay is a well-validated reference biomarker for early genetic effects, and the present study is, to the best of our knowledge, the first to analyze MN frequencies in peripheral and umbilical cord blood from mothers and newborns using a semiautomated image analysis system. This system has several advantages, including a well-defined detection algorithm; applicability to human T lymphocytes; discrimination among MONO, BN, and polynucleated cells; scoring MN according to HUMN scoring criteria; thorough validation with false-positive and false-negative rates as low as possible; and determination of cell proliferation  in the total population  compared with term births at ≥ 37 weeks. To reduce bias due to pregnancy complications, we performed subsequent multivariate regression analysis using data from full-term infants only. We identified no significant predictors of MNBN levels in full-term newborns, but MNMONO frequency was inversely correlated with GA. in utero exposure only). In contrast, MN in BN cells may originate from preexisting MN plus DNA or protein lesions that are expressed as chromosome breaks/loss during in vitro replication. MNBN levels may therefore reflect genetic damage induced by stress during delivery. The different  response we detected in MNBN levels between preterm and full-term children can result from differences in DNA repair or apoptotic capacity. A possible explanation for the higher MNBN frequencies in preterm children might be the maturation of DNA repair enzymes during the last weeks of gestation and increased transfer of antioxidants such as vitamin B, vitamin C, and beta-carotene during the final days of gestation (estation .Predictivity of MNMONO in newborns. Up to now, MNMONO frequencies have been rarely taken into account in biomonitoring studies (in vivo before the start of the CBMN assay culture. MNBN cells, in addition to in vivo accumulated MN, reflect damage present on DNA or key proteins and expressed as MN during in vitro cell division. studies . The valin utero exposure time of up to 6 months (in utero exposure, we observed a significantly positive correlation between MNMONO frequencies in mothers and newborns. This suggests that maternal exposure is reflected in their newborns, and one has to consider inherited similarities in DNA repair capacity.Whether MN frequencies in newborns can be interpreted in the same way as in adults, and whether they are predictive for cancer, is not known at this time. Three major facts need to be considered regarding their biological significance in newborns compared with adults. In adults, circulating T lymphocytes may accumulate MN over several years, in contrast to newborns, where damage accumulates during a short 6 months . Second,6 months . Therefo6 months , and in in vivo cell division and accumulated in utero, and the latter includes additional damage expressed as MN during the in vitro culture step. Because of physiological differences and the age of circulating T lymphocytes, it is not yet clear whether MN frequencies in newborns can be interpreted in the same way as in adults—that is, whether they are predictive for cancer and childhood cancer in particular.Although confirmation in a larger study population is needed, multivariable analysis revealed the importance of taking into account GA when studying MN frequencies in newborns. In addition, our results indicate the importance of assessing both MNMONO and MNBN for biomonitoring of newborns, because the first reflects damage expressed during


South Asian babies born in developed countries are generally lighter than babies from other ethnic groups born in the same country. While the mean birth weight of Caucasian babies in the Netherlands has increased the past decades, it is unknown if the mean birth weight of South Asian babies born in the Netherlands has increased or if the prevalence of low birth weight (LBW) or small-for-gestational-age (SGA) has decreased.The aims of this study are: 1. to investigate secular changes in mean birth weight and the prevalence of LBW and SGA in Surinamese South Asian babies, and 2. to assess differences between Surinamese South Asian and Dutch Caucasian neonates born 2006–2009.A population based study for which neonatal characteristics of 2014 Surinamese South Asian babies, born between 1974 and 2009 in the Netherlands, and 3104 Dutch Caucasian babies born 2006–2009 were obtained from well-baby clinic records. LBW was defined as a birth weight <2500 g. SGA was based on a universal population standard (the Netherlands) and three ethnic specific standards .In Surinamese South Asian babies from 1974 to 2009 no secular trend in mean birth weight and prevalence of LBW was found, whereas SGA prevalence decreased significantly.Surinamese South Asian babies born in 2006–2009  were 450 g lighter than Dutch Caucasian babies , while LBW and SGA prevalences, based on universal standards, were three times higher. Application of ethnic specific standards from the Netherlands and the UK yielded SGA rates in Surinamese South Asian babies that were similar to Dutch. There were considerable differences between the standards used.Since 1974, although the mean birth weight of Surinamese South Asian babies remained unchanged, they gained a healthier weight for their gestational age. In developing regions with lower socioeconomic status and poorer nutrition, babies are lighter and more frequently have adverse birth outcomes compared to developed regions . South An origin -8. Consen origin ,9,10.In the Netherlands, perinatal mortality generally declined between 2000 and 2006 , but theThe objectives of our study were firstly to determine if there are secular trends in birth weight and prevalence of LBW and SGA  in Surinamese South Asian babies born in the Netherlands, and secondly, to assess the differences in neonatal characteristics between Surinamese South Asian and Dutch babies born in 2006–2009, particularly the distributions of birth weight in both populations.th birthday.In the Netherlands, the health of all infants is periodically assessed by physicians and nurses of Youth Health Care at well-baby clinics. The results of these check-ups are registered in health records which are kept at least 10 years after the child’s 19The records of all Surinamese South Asian children born in the periods 1974–1976 and 1991–1993 were analysed in a previous study . For thiAs this study encompassed routinely collected data from medical records, under Dutch law approval by an ethical review committee was not needed . ApprovaMost South Asian people in the Netherlands are descendants of Asian Indians who migrated from 1873 to 1916 to the former Dutch colony Suriname. At around the time of Suriname’s independence in 1975 many Surinamese South Asians moved to the Netherlands, to the city of The Hague in particular [Surinamese South Asian ethnicity was then determined by a typical Surinamese South Asian family name of both parents (by matching the names with a list of common Surinamese South Asian family names), and Suriname or the Netherlands as country of birth for respectively first generation and second generation parents in the Netherlands. Parents with a typical Dutch family name who were also born in the Netherlands were considered Dutch Caucasian. Only children of whom both parents were Surinamese South Asian or Dutch Caucasian were included in the study. In cases with one or both parental family names missing (4.3%), ethnicity was determined by the child’s family name and the available parental family name, together with the parent’s country of birth.Based on these selection criteria, 2858 records of Surinamese South Asian children born in 1974–1976, 1991–1993 or 2006–2009, and 3256 records of Dutch children born 2006–2009 were retrieved. For the final selection, children born outside the Netherlands (n = 635) were excluded, as in these cases gestational age and birth weight were self-reported and therefore considered less reliable. Additionally, children of multiple birth (n = 92), or with a missing record of birth weight (n = 174) or gestational age (n = 95) were excluded. A total of 2014 records of Surinamese South Asian children and 3104 records of Dutch children remained for the analyses.th percentile for gestational age was defined as SGA. Children of unknown parity were defined as primiparous.In all time periods a midwife or an obstetrician calculated the gestational age based on the first day of the last menstrual period. In cases with unknown or dubious last menstrual period, gestational age was determined from an ultrasound dating scan. The gestational age, together with other details regarding pregnancy and birth, were added to the child’s health record after a home visit by a Youth Health Care nurse in the second week postpartum. In 92% of cases of cohort 1974–1976 gestational age was recorded in completed weeks, and in the remainder in weeks and days. In 1991–1993 and 2006–2009 gestational age was registered in weeks and days. A gestational age of <37 weeks was considered a preterm birth. LBW was defined as a birth weight <2500 g. To estimate the prevalence of SGA in Dutch Caucasian and Surinamese South Asian babies, the most recent universal Dutch standard for birth weight by gestational age   was applAs this study had two objectives, the data were analysed accordingly. Firstly, the data of Surinamese South Asian babies were analysed to assess the differences between the time periods, and secondly, differences between Dutch and Surinamese South Asian babies born in 2006–2009 were analysed.Furthermore, we used a stepwise approach. In the first step we compared neonatal and maternal characteristics using Pearson’s Chi-square tests  and analysis of variance . In the second step, birth weight characteristics were examined. To test for differences between birth weights, a general linear model (GLM) was used with birth weight as the dependent variable and sex, parity, and gestational age as adjusting factors. Differences in the prevalence of LBW (LBW vs. not LBW) and SGA (SGA vs. not SGA) were assessed with logistic regression analyses, firstly with time period as the independent variable to test for differences between Surinamese South Asian time periods and secondly with ethnic group as the independent variable to test for differences between Surinamese South Asian and Dutch babies born in 2006–2009. Analyses of LBW were adjusted for sex, parity, and gestational age. Analyses of SGA based on the South Asian standard from the Netherlands were adjusted for sex and parity, as this standard isn’t sex or parity specific. Analyses based on the sex-specific Canadian and British standard were adjusted for parity.All analyses were conducted using IBM SPSS Statistics 20.We found differences in neonatal and maternal characteristics between Surinamese South Asian cohorts, and between the Dutch and Surinamese South Asian population Table . Within We found no secular changes in mean birth weight of Surinamese South Asian neonates Table . LBW preSurinamese South Asian neonates born in 2006–2009 differed from Dutch babies in almost all birth weight characteristics Table . The meaWhile the shape and spread of both distributions were similar Figure , the SurThis study shows that the mean birth weight of Surinamese South Asian neonates did not significantly change over a period of 35 years. As the mean birth weight of Dutch babies was previously shown to have increased by almost 100 grams since the late 1980′s , this fiHowever, mean birth weight alone does not tell the whole story. The decrease in SGA rates in our population showed that Surinamese South Asian neonates have actually gained weight, but this effect was not reflected in higher mean birth weights, most likely due to a considerable increase in the prevalence of preterm delivered babies. Contrary to reports from other countries which found increasing trends in the proportion of preterm delivered babies , pretermThe strengths of this study are the large sample size, and the availability of some important confounding factors. However, not all known confounders such as maternal age, socio-economic status, maternal height and pre-pregnancy weight, and information on smoking during pregnancy were available to enable adjustment. Another limitation is that a change in pregnancy dating methods, from menstrual dating in the early years to menstrual and ultrasound dating in the more recent years, could have influenced the temporal trends among the Surinamese South Asian infants. Lastly, children with congenital or chromosomal anomalies could not be excluded, as this information was unavailable. Nevertheless, as most of these children receive specialised care and do not usually attend the standard check-ups at well-baby clinics, it is expected that only a small proportion of these children were included in our study.Compared with the birth weights of South Asian babies in other countries, the mean birth weight of Surinamese South Asian babies born in 2006–2009 3032 g) was lower than the birth weights of South Asian babies in the United States (3170 g) 032 g was, Norway In addition, there may also be differences between the populations of South Asians in these countries. For example, the Norwegian study  only incWhile the large left shift of the birth weight distribution of Surinamese South Asian babies compared with that of Dutch Caucasian babies was remarkable, similar differences in birth weight between South Asian and Caucasian neonates have been observed in other developed countries ,6,7. TheIn conclusion, this study found no secular changes in mean birth weight and LBW prevalence in Surinamese South Asian babies since 1974. While not expressed in the mean birth weight, SGA prevalence decreased significantly, indicating that Surinamese South Asian babies have actually gained a healthier weight for their gestational age. Surinamese South Asian babies were approximately 450 grams lighter than Dutch Caucasian neonates, and LBW and SGA was highly prevalent when based on a single standard. When applying ethnic specific criteria to determine SGA, the rates were concordant with those found in Dutch Caucasian babies.The authors declare that they have no competing interests.JAdW designed the study, extracted, analysed and interpreted the data and wrote the first draft of the manuscript. SvB participated in the analyses, interpretation of the results and revision of the manuscript. BJCM contributed to the design of the study, helped with the interpretation of the results and revising the manuscript. All authors read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/931/prepub