This study sets out to prospectively investigate the incidence of transitional vertebrae and numerical variants of the spine.Over a period of 28 months, MRIs of the whole spine were prospectively evaluated for the presence of transitional lumbosacral vertebrae and numerical variants of the spine.MRI of the whole spine was evaluated in 420 patients, comprising 211 female and 209 male subjects. Two patients had more complex anomalies. Lumbosacral transitional vertebrae were seen in 12 patients: eight sacralised L5  and four lumbarised S1 . The incidence of transitional vertebrae was approximately 3.3. % (14/418). Thirty-two (7.7 %) of 418 patients had numerical variants of mobile vertebrae of the spine without transitional vertebrae. The number of mobile vertebrae was increased by one in 18 patients , and the number was decreased by one in 14 patients .Numerical variants of the spine are common, and were found to be almost 2.5 times as frequent as transitional lumbosacral vertebrae in the study population. Only whole-spine imaging can identify numerical variants and the anatomical nature of transitional vertebrae. The tendency is toward an increased number of mobile vertebrae in men and a decreased number in women.Main messages• Numerical variants of the spine are more common than transitional vertebrae.• Spinal numerical variants can be reliably identified only with whole-spine imaging.• Increased numbers of vertebrae are more common in men than women.• Transitional lumbosacral vertebrae occurred in about 3.3 % of the study population.• The incidence of numerical variants of the spine was about 7.7 %. Transitional lumbosacral vertebrae are a common finding on spinal imaging, with reported incidences of 1–30 %, depending on the definition and imaging modality used . These sA more insidious problem is the case of morphologically normal lumbar vertebrae but an abnormal number of mobile vertebrae of the spine. Counting from the top of the spine, there might be an increased or decreased number of morphologically normal mobile vertebrae. This may be impossible to appreciate on MR imaging of the lumbar spine alone. However, it is important to realise the presence of a numerical variant, as this will result in variation in neural anatomy and may lead to misattribution of clinical symptoms, i.e. clinical findings or symptoms related to an incorrect spinal level, which may lead to inappropriate intervention.Several authors have suggested that the only reliable method for determining the anatomical level is to count down from the atlantoaxial joint. Obviously, this requires imaging of the entire spine , 5, 11.Anecdotally, there is a lack of awareness amongst radiologists regarding anatomical variation, particularly with regard to the frequency of numerical variants of the spine in the absence of morphological transitional vertebrae.This paper sets out to determine the incidence of numerical variants and transitional lumbosacral vertebrae of the spine in consecutive patients in routine MR imaging practice.From 1 January 2013 to 30 April 2015, all MRIs of the whole spine presented to the main author were prospectively assessed for the presence of numerical variants of the spine and the presence of a morphological transitional lumbosacral vertebra.The vertebrae were counted from the C2 vertebra downwards, assuming seven cervical and 12 thoracic vertebrae. Although variation in the number of cervical and thoracic vertebrae has been described, variation in the cervical spine is very uncommon , 11, 13.In this study, vertebrae were considered transitional based on the criteria described by O’Driscoll et al. . The verThe spine was assessed solely on the basis of the MRI appearances and not in conjunction with other imaging modalities.In the case of transitional lumbosacral vertebrae, their nature was determined by counting down from the top, assuming seven cervical and 12 thoracic vertebrae (please see above). In the case of the transitional vertebra, it was called sacralised L5 if it followed after L4, and it was called lumbarised S1 if it followed after L5.The routine MRI protocol consisted of sagittal T1-weighted (T1W), sagittal short tau inversion recovery (STIR) and sagittally acquired 3D SPACE [sampling perfection with application-optimised contrasts using different flip-angle evolution] sequences. The 3D SPACE sequences were reformatted in the axial and coronal planes.In select cases, additional sequences were performed.syngo MR B17; Siemens Healthcare GmbH, Erlangen, Germany).The sagittal images were acquired in two blocks of 38 cm craniocaudal size. For the assessment of the number of vertebrae, the composed view was reviewed using the image composer of the MRI scanner .All MRIs of the whole spine were analysed, regardless of the clinical indication for the examination.From 1 January 2013 to 30 April 2015, MRIs of the whole spine in 420 patients  were performed and reviewed by the main author.Transitional lumbosacral vertebrae affecting either L5 or S1 were seen in 12 patients; in eight, L5 was partially sacralised , the number of free spinal vertebrae was increased by one, and there was also a transitional lumbosacral vertebra. Therefore, there were altogether 14 patients with transitional lumbosacral vertebrae.In a further two patients , two balanced hemivertebrae were noted in the thoracic spine. These were in addition to a normal complement of mobile vertebrae, and might be seen as one additional vertebra. However, these two cases will be excluded from the further analysis, as the numbering of vertebrae is not straightforward, nor is it universally agreed upon in these circumstances. Also, the assumption of 12 thoracic vertebrae is no longer valid in these cases.This results in an incidence of an increased or decreased number of vertebrae of 34/418, or 8.1 %. In 32 of 418 patients, or 7.7 % of cases, there was no morphological anomaly at the lumbosacral junction despite an anomalous number of mobile vertebrae.As mentioned earlier, in two cases there were transitional lumbosacral vertebrae in addition to an increased number of mobile vertebrae.Transitional lumbosacral vertebrae were seen in 14 of 418 or 3.3 % of patients.There were four patients with known developmental anomalies. One was known to have Goldenhar syndrome, and this patient had one more mobile vertebra than normal and an additional transitional vertebra. One patient with known Langer-Giedion syndrome had one more mobile vertebra than normal. A patient with known Klippel–Feil syndrome and a patient with Arnold–Chiari malformation had a normal number of vertebrae.The indications for the MRI examinations were quite varied, and included pain with suspected spinal origin, neurological symptoms with suspected spinal origin, inflammatory or infectious lesions of the spine, assessment of neoplastic disease of the spine, osteoporosis, spinal injury follow-up, and abnormal posture and alignment, including scoliosis.The most striking finding of this study is the low number of morphological transitional lumbosacral vertebrae in the study population. Only 3.3 % of our patients demonstrated a transitional lumbosacral vertebra on MRI, using the criteria described by O’Driscoll et al. . This isThe presence of a transitional lumbosacral vertebra does alert to the presence of anatomical variants in the neural anatomy and should trigger extra care when undertaking interventional procedures.Anatomical variants without transitional morphology are more problematic because they can easily be missed. They were much more prevalent than morphologically transitional vertebrae in our study population, which showed a rate of 7.7 %. These patients will typically not be identified as having a numerical variant when only MR imaging of the lumbar spine is performed. Numerical variants of mobile vertebrae are associated with variation in the neural anatomy and can lead to inappropriate spinal intervention , 7, 14.In men, there is a clear tendency toward an increased number of mobile vertebrae, either as true mobile vertebra or lumbarisation of a sacral vertebra, with a male-to-female ratio of 2:1.The reverse is true in the case of a decreased number of mobile vertebrae or sacralisation of a lumbar vertebra, with a male-to-female ratio of roughly 1:2. The absolute combined numbers of increased or decreased mobile vertebra + transitional vertebra were very similar. However, for lumbarisation, there is a tendency to be complete—i.e. not transitional but fully mobile—while the opposite is true for sacralisation.This study is the first to prospectively evaluate the presence of transitional lumbosacral vertebrae and or numerical variants on whole-spine MRI.Hahn et al.  used a cHanson and coworkers  reviewedAkbar et al.  used a wCoronal reformats of the 3D SPACE sequence were useful in identifying transitional vertebrae, as has been described elsewhere .Intra- and interobserver variation was not assessed in this work. It stands to reason that there is some variability in the assessment of transitional vertebrae. While coronal reformats can provide some help, they are not always available, and radiographs remain the gold standard. The fundamental problem that remains, however, is that numerical variants are relatively common and cannot be appreciated unless whole-spine imaging is performed.In our institution, the imaging protocol of MRI of the lumbar spine was modified in light of these findings. All patients now undergo imaging using a sagittal half-Fourier acquisition single-shot turbo spin-echo (HASTE) localiser of the spine in two sagittal blocks, which allows imaging of the whole spine in about 30 s, ensuring adequate determination of anatomical levels in all examinations.Numerical variants of the spine are common, and were almost 2.5 times as frequent as transitional lumbosacral vertebrae in the study population. While MRI of the lumbar spine can usually identify transitional lumbosacral vertebrae (though not as reliably as radiographs), it cannot identify numerical variants of the spine, which is possible only by imaging of the whole spine. In men, the tendency is toward an increased number of mobile vertebrae, whereas the number tends to decrease in women. An accurate determination of anatomical levels is a prerequisite for accurate assessment of pathological findings and for any image-guided spinal intervention.


Despite the World Health Organization’s (WHO) recommendation that caesarean section (c-section) rates should not exceed 15%  with greMany birth complications today can be attributed to modern lifestyles and technology, but challenging birth can be traced to the origin of bipedalism 5–7 million years ago .Fear of birth or tocophobia is a common reason for electing to give birth by c-section. The evolutionary perspective argues that fear and the deeply rooted need for assistance during birth can often be alleviated with emotional support such as provided by doulas, thus avoiding unnecessary risky and costly c-section.


Dear Sir,An 8-day old girl, born via vaginal delivery and healthy otherwise, was admitted with the antenatal diagnosis of an intra-abdominal cyst, 5mm in diameter at 30th gestational week. Abdominal ultrasonography (USG) was performed on first postnatal day showed a 10mm cyst originating from right ovary. She remained asymptomatic for a week when she developed bilious vomiting. Her physical examination was normal except for a palpable mass on the right side of the abdomen. X-ray abdomen showed bowel loops displaced to left half of the abdomen. Repeat USG showed an increase in size of cyst to 49mm. Six hours later another USG was performed owing to further increase in abdominal distension. The size of cyst increased to 80x70x40mm moreover debris was also noted in it. The baby however remained vitally stable. Next day another USG showed cyst size of 100x80x45mm. Because of increase in the diameter of cyst and bilious drainage from nasogastric tube, laparoscopy was performed. This showed normal looking ovaries. The procedure was then converted to laparotomy. At exploration a communicating ileal duplication cyst was found . Meckel’s diverticulum was also present 50cm away from the cecum. Resection of the cyst and anastomosis was performed. Appendectomy was also done but Meckel’s diverticulum was left as such. Postoperative course was uneventful. Histopathology was reported as ileal duplication cyst. She is asymptomatic for the last one year.Alimentary tract duplications are very rare congenital malformations with reported incidence of 1 in 18000 live births. Ileum is most common location of these cysts. In our case patient had prenatal diagnosis of intra-abdominal cyst suspected of ovarian origin. The unusual postnatal feature was continuous and rapid increase in the size of the cyst with bilious vomiting. This was due to the communication of cyst with the adjacent ileum the contents of which pooled in the cyst. This coupled with mucoid secretions of the cyst resulted in rapid increase in the size.Source of Support: NilConflict of Interest: None declared


Recent reports have shown a decrease in birth weight, a change from prior steady increases. Therefore we sought to describe the demographic and anthropometric changes in singleton term fetal growth.This was a retrospective cohort analysis of term singleton deliveries (37–42 weeks) from January 1, 1995 to January 1, 2010 at a single tertiary obstetric unit. We included all 43,217 neonates from term, singleton, non-anomalous pregnancies. Data were grouped into five 3-year intervals. Mean and median birth weight (BW), birth length (BL), and Ponderal Index (PI) were estimated by year, race and gestational age. Our primary outcome was change in BW over time. The secondary outcomes were changes in BL and PI over time.p < 0.0001) over the 15 year period while BL also significantly decreased by 1.0 cm (P < 0.001). This contributed to an increase in the neonatal PI by 0.11 kg/m3 (P < 0.001). Mean gestational age at delivery decreased while maternal BMI at delivery, hypertension, diabetes, and African American race increased. Adjusting for gestational age, race, infant sex, maternal BMI, smoking, diabetes, hypertension, and parity, year of birth contributed 0.1 % to the variance  of BW, 1.8 %  of BL, and 0.7 %  of PI. These findings were independent of the proportional change in race or gestational age.Mean and median BW decreased by 72 and 70 g respectively  contains supplementary material, which is available to authorized users. For decades, newborn birth weight has been a focus of clinical investigation as an assessment of fetal growth. During the 1990s several investigators reported a steady increase in newborn birth weight. –12 or a The intrauterine environment, genetics, and gestational age all contribute to newborn weight. Maternal factors including hypertensive disorders –18, diabTherefore, the primary aim of this study was to evaluate the change in term singleton newborn birth weight over 15 years at a tertiary inner city hospital, while adjusting for relevant factors that contribute to fetal growth. As a secondary aim, we evaluated the changes in Ponderal Index  during this time period to better estimate the changes in weight for length as a measure of neonatal adiposity.A contemporaneously maintained database was used to examine the impact of maternal demographic characteristics and co-morbid conditions upon fetal growth among term singleton deliveries. In brief, delivery records from the Department of Obstetrics and Gynecology, MetroHealth Medical Center, Cleveland, Ohio, are entered prospectively into a computerized database for research purposes. The data collection began in October 1974, and data such as maternal history, pregnancy complications, and delivery details are ascertained for each patient. Each entry is independently compared with the patient’s medical record by an independent reviewer . Only daOf the 49,550 singleton non-anomalous live born births recorded between January 1, 1995 and January 1, 2010, 43,217 were included in the analysis. We excluded births with gestational age less than 37 weeks (6287) or greater than 42 completed weeks (38) and records with a birth weight that was inconsistent with gestational age (greater than 2.5 standard deviations) based on the data for United States term birth weight by Alexander et al. .3) over time as a marker of fetal weight for length an estimate of adiposity [Gestational age was defined by best obstetrical estimate, normally including the patient’s last menstrual period with ultrasound confirmation usually less than 20 weeks gestation. In cases where there was a discrepancy, we used the estimated gestational age calculated by ultrasound dating. We queried data on variables relevant to newborn birth weight including maternal age, parity, self-identified race , smoking, illicit drug use, prenatal care, weight at delivery, height, complications of pregnancies , and mode of delivery. To assess fetal growth, infant birth weight, birth length, weight for length as an estimate of adiposity, and sex were abstracted. Birth weight (BW) was measured at delivery on a scale that is calibrated monthly. Birth length (BL) is measured from the crown of the newborn’s head in a neutral position to the heel of the fully extended leg using a disposable tape measure. These methods have been used consistently over the time of our review by our nursing staff. Additionally, we estimated the change in newborn Ponderal Index . We also described the total change from 1995 to 2010 of each of these variables. Additionally, the changes in mean and median BW were estimated by year, race and gestational age.We initially evaluated if the changes in BW, BL and PI (dependent variables) over time were correlated with the changes in all available independent variables  in univariate correlation analyses  and SAS Version 9.2 . Due to the large sample size in our study, we particularly evaluated the effect size as an indicator of magnitude of each relationship.A 3  factors were included in the multiple regression model , in examining the actual magnitude of estimates in the models, they are very similar  which did not significantly change over time.Our study has several strengths. We used a large number of patients from a well-established, prospectively collected database. The patient population is similar to many inner-city hospitals, thus the results could be generalized to similar populations, but may not be applicable to others. This is one of the first studies of an entire population to report on changes in birth length. The multiple regression controlled for common confounding variables. The methods of measuring neonatal weight and length at birth did not change over the study period. To explore the accuracy of the clinical birth lengths, we analyzed the clinical measure of neonatal length in 450 infants who were also subjects in an anthropomorphic study that included length at birth by a trained research nurse using a measuring board. The measurements correlated well with an r = 0.67 . Thus, while the variables entered into our model, including year, were significantly correlated, many other factors as described above may also affect the changes seen in BW over time.This analysis also has limitations. It was retrospective and limited by what data was available and confined to a single site. The patient population is not representative of the overall population in the United States. Some potential confounders, such as maternal pregravid BMI, gestational weight gain, glycemic control, degree of hypertension, gestational age at first ultrasound, socio-economic status, and paternal height and weight could not be evaluated. As birth weight is dependent on these and other, unaccounted for factors, the rSeveral previous studies have reported the change in BW over time in large populations. In 2010 Donahue et al. reported a 52 g decrease in mean newborn BW amongst 36,827,828 deliveries over 15 years in a national birth certificate database . SimilarThe majority of the decrease in birth weight over time was related to concomitant changes in maternal demographics, especially race and comorbidities, and gestational age. This suggests that the single parameter of birth weight alone may be an insufficient assessment of intrauterine growth. Our study is among the first to consider neonatal length and the Ponderal Index in our evaluating trends in fetal growth. The trend of a decrease in birth weight and length is clinically important insomuch as it represents a change in intrauterine growth which has potential long-term implications for both child and adult health, relative to fetal programming and increasing adiposity.The concept of decreased neonatal length has also been referred to as stunting or decreased crown-heel length for gestational age . Stuntin3) is the definition of density used in many formulations of body composition. In a sample of 215 Caucasian, African American and Hispanic neonates, there was a significant correlation between Ponderal Index and percent body fat using air densitometry or Pea Pod (R =0.40, P = <0.001, see Additional file How useful is the concept of Ponderal Index in assessing fetal growth? Rohrer first proposed the term in 1921 as the “corpulence index” used to evaluate growth in neonates and children after World War I in Germany (33The term is useful because mass/volume (lengthIn summary, consistent with recent reports we found a decrease in mean birth weight over time. The majority of this change can be attributed to variations in demographic factors and obstetrical practice affecting fetal growth. We also noted a significant decrease in length at birth and increase in Ponderal Index over time. These data stress the importance of considering factors beyond birth weight alone in the assessment of fetal growth. The increases in maternal BMI coupled with the increased Ponderal Index as an estimate of neonatal adiposity are consistent with the concept of developmental programming relating to the increase in the worldwide obesity epidemic.


To examine the rates of obstetric intervention and associated perinatal mortality and morbidity in the first 28 days among low-risk women giving birth in private and public hospitals in NSW (2000–2008).Linked data population-based retrospective cohort study involving five data sets.New South Wales, Australia.691 738 women giving birth to a singleton baby during the period 2000–2008.Rates of neonatal resuscitation, perinatal mortality, neonatal admission following birth and readmission to hospital in the first 28 days of life in public and private obstetric units.Rates of obstetric intervention among low-risk women were higher in private hospitals, with primiparous women 20% less likely to have a normal vaginal birth compared to the public sector. Neonates born in private hospitals were more likely to be less than 40 weeks; more likely to have some form of resuscitation; less likely to have an Apgar <7 at 5 min. Neonates born in private hospitals to low-risk mothers were more likely to have a morbidity attached to the birth admission and to be readmitted to hospital in the first 28 days for birth trauma (5% vs 3.6%); hypoxia (1.7% vs 1.2%); jaundice (4.8% vs 3%); feeding difficulties (4% vs 2.4%) ; sleep/behavioural issues (0.2% vs 0.1%); respiratory conditions (1.2% vs 0.8%) and circumcision (5.6 vs 0.3%) but they were less likely to be admitted for prophylactic antibiotics (0.2% vs 0.6%) and for socioeconomic circumstances (0.1% vs 0.7%). Rates of perinatal mortality were not statistically different between the two groups.For low-risk women, care in a private hospital, which includes higher rates of intervention, appears to be associated with higher rates of morbidity seen in the neonate and no evidence of a reduction in perinatal mortality. The strength of this study lies in the large sample size of linked birth data admissions associated with these births.The use of data from five population-based datasets which have been linked to enhance validity and ascertainment.Limitations are the restricted number of variables that are included and the scarcity of specific information on potential confounders.Body mass index and key sociodemographic risk factors could not be controlled for and this would have added risk to women giving birth in public hospitals.In Australia, the national statistics reveal that 29% n=83 573) of women who gave birth in hospital gave birth in private hospitals directly under private obstetric care. 573 of wWhat is not disputed are the much higher rates of obstetric intervention that occur in private hospitals in Australia. At a national level, the intervention rates in childbirth, such as caesarean section, are significantly higher in the private sector (43.1% vs 28.4%) and the rates of normal vaginal birth significantly lower 42.7% vs 61%).1%.6 The 8A recent study in New South Wales, AustraliaThe New South Wales Centre for Health Record Linkage conducted linkage of several datasets via the Health Record Linkage (CHeReL). Pregnancy and birth data for the time period 1 July 2000 until 2 June 2008 of all singleton births were provided by New South Wales (NSW), Ministry of Health as recorded in the NSW midwives data collection (MDC), now the perinatal data collection (PDC). This population-based surveillance system contains maternal and infant data on all births of greater than 400 g birth weight and/or 20 completed weeks gestation. Hospitals are coded either as private or public in the data set. However, the data identifying women who received care in public hospitals under private accommodation status is no longer collected as it had been in the years 1996–1997 and for this reason patients who are under private obstetric care in public hospitals are not able to be differentiated from their public counterparts, so for this study we analysed the data by hospital (private/public). A previous study published in 2000The NSW PDC contains statistics on all births in New South Wales—which amounts to one-third of all births which occur in Australia annually. Data is provided for maternal age, maternal hypertension, maternal diabetes, parity, private/public patient status, fetal presentation, onset of labour, gestation at birth, delivery type, Apgar scores and admission to neonatal intensive care and resuscitation details for the neonate. This dataset (NSW PDC) was linked to the Admitted Patient Data Collection (APDC) for the time period 1 July 2000 to 30 June 2008. The APDC records all admitted patient services provided by NSW Public Hospitals, Public Psychiatric Hospitals, Public Multi-Purpose Services, Private Hospitals and Private Day Procedures Centres. The APDC provided additional information, such as data on maternal medical conditions, which was used to exclude further maternal cases and was used to calculate admission and readmission details for neonates. Further linkage occurred in the NSW Registry of Births, Deaths and Marriages (RBDM) and the Australian Bureau of Statistics Death Data, which provided mortality data. The NSW Register of congenital conditions provided cases of congenital conditions, as did the coding in the APDC. Any neonate (and mother pair) with a recorded congenital condition (ICD-10-AM codes Q0.0-Q99.9) on either dataset was removed from the dataset due to their high-risk status. Probabilistic data linkage techniques were utilised for data linkage and de-identified datasets were provided for analysis. Probabilistic record linkage software assigns a ‘linkage weight’ to pairs of records. For example, records that match perfectly or nearly perfectly on first name, surname, date of birth and address have a high linkage weight and records that match only on date of birth have a low-linkage weight. If the linkage weight is high it is likely that the records truly match, and if the linkage weight is low it is likely that the records are not truly a match. This technique has been shown to have a false-positive rate of 0.3% of records.12Gestation is recorded at birth and is also recorded in the database according to the woman’s menstrual history, usually combined with a routine scan at 12–13 weeks.Admission to neonatal intensive care refers to admission to special care nursery (SCN) or neonatal intensive care unit (NICU).Any resuscitation includes suction of the mouth or nostrils at birth; oxygen administered by mask; intermittent positive pressure respiration (IPPR) by bag and mask or by intubation; external cardiac massage and ventilation.We classified the low-risk primipara as a first time mother aged 20–34 years, who had no pre-existing or pregnancy-related hypertension or diabetes, was a non-smoker and gave birth at 37–41 completed weeks gestation to a singleton baby in a cephalic presentation within the 10th and 90th centiles for gestation and birth weight. The low-risk multipara was a woman aged 20–34 years having her second or subsequent baby, who had no pre-existing or pregnancy-related hypertension or diabetes, was a non-smoker, gave birth at 37–41 completed weeks gestation to a singleton baby in a cephalic presentation within the 10th and 90th centiles for gestation and birth weight. We excluded women with a previous caesarean section or who were induced for a medical indication, or who underwent a caesarean section for a pre-existing medical indication or gave birth without a trained birth attendant . If a caesarean section was undertaken during labour however for non-reassuring heart rate, dystocia, etc these women were included in the study. These characteristics were defined first from the PDC with additional medical conditions identified in the APDC being used to exclude cases.Any neonatal admission including the ICD-10-AM codes Z37.0 (single live birth), Z37.1 (single stillbirth) or Z38.0  was deemed the birth admission and any ICD-10-AM codes referring to conditions which arise in the perinatal period (P00-P96) and those referring to factors influencing health status and contact with health services (Z00-Z99) which were included in this admission were deemed morbidities associated with the birth admission. Any other admission following this discharge from the initial birth admission to home or another hospital was deemed a readmission and included transfers to a hospital other than that where the birth occurred. When examining readmission data, all ICD-10-AM codes recorded were reviewed and those where ≥10 events occurred in either private or public hospitals were marked for analysis. Events were grouped in body systems where appropriate or under headings such as infection for ease of analysis and interpretation.Morbidity was recorded with the birth admission and rates of events were calculated using the number of babies who had any morbidity recorded with their birth.et alStillbirth and neonatal deaths were calculated from multiple sources but were limited to those that occurred within 28 days of birth and they were only counted once. Death may have been detected on any one of the following four datasets. The PDC ‘Discharge status’ variable or admissions in the APDC where the case mode separation was coded as ‘Died’ or the NSW RBDM or ABS Death Data where a death had been recorded. The maternal admission data for any admission that occurred during the pregnancy, as well as the birth admission for all cases of stillbirth or neonatal death were examined to determine any maternal medical or pregnancy-related condition. This methodology of utilising multiple data sources to identify cases has been shown by Lain Obstetric intervention was defined to include induction, epidural use, episiotomy, instrumental delivery (requiring the use of forceps or vacuum) and delivery via caesarean section.2 statistics were calculated for observed events. The total number of babies born in a public or a private hospital were used as the denominator when calculating the percentage of babies born with a morbidity code attached to their birth record or the number of babies readmitted with a designated morbidity code. This methodology provides for comparison between place of birth taking into consideration the fact that up to 55 morbidity codes can be attached to any one birth or readmission record. Taking into account the size of the cohort and the number of analyses undertaken, results were considered significant at the level p<0.01. Analysis was undertaken with IBM SPSS V.20.The cohort was divided into primiparous and multiparous women for the primary analysis of birth outcomes. When examining neonatal status at birth mortality ORs were calculated using logistic regression with and without adjustment for age and gestation. For neonatal morbidity at birth and readmission, χThe PDC dataset for the time period 1 July 2000 to 2 June 2008 contained the antenatal, birth and postnatal details on 691 738 births. The APDC for the time period 1 July 2000 to 30 June 2008 contained >1.1 million admissions for the neonates/children of these women.From the total population of primiparous women (288 309 women), 29 597 low-risk primiparous women gave birth in private hospitals in NSW and 79 792 low-risk primiparous women gave birth in public hospitals. The rates of obstetric intervention were much higher among those who gave birth in private hospitals compared to those who gave birth in public hospitals when all interventions for prespecified medical reasons were removed. Low-risk primiparous women giving birth in private hospitals compared to low-risk primiparous women giving birth in public hospitals had higher rates of induction for non-medical reasons (19% vs 7%), instrumental birth (30% vs 20%), caesarean section (25% vs 16%), epidural (71% vs 35%) and episiotomy (42% vs 23%). Severe perineal trauma  was lower in a private hospital in first-time mothers , 28 703 low-risk multiparous women gave birth in private hospitals and 99 212 low-risk multiparous women gave birth in public hospitals. The rate of obstetric intervention was significantly higher among those who gave birth in private hospitals in NSW compared to those who gave birth in public hospitals when all interventions for specific medical reasons were removed. Low-risk multiparous women who gave birth in private hospitals compared to low-risk multiparous women giving birth in public hospitals had higher rates of induction for non-medical reasons (32% vs 10%), instrumental birth (8% vs 3%), epidural (34% vs 10%) and episiotomy (16% vs 5%) and similar rates of severe perineal trauma (0.9%). The caesarean section rate still remained higher in the private cohort (5.9% vs 4.5%) though this was mostly associated with elective caesarean section .There was no difference in birth weight between babies born in a private and public hospital. Babies born in a private hospital were more likely to be born at 37, 38, 39 and 40 weeks and less likely to be born at 41 weeks gestation .Babies of primiparous women who gave birth in a private hospital were less likely to have an Apgar of <7 at 5 min (adjusted OR (aOR) 1.34 95% CI 1.18 to 1.53; p<0.001) as were babies of multiparous women who gave birth in private hospitals . Babies born in private hopsitals were less likely to have no resuscitation . Babies born to low-risk primiparous women in a private hospital were no more likely to be admitted to special care and/or neonatal intensive care  and were less likely to have their baby transferred to another hospital . There was no difference in the perinatal mortality rate for babies of primiparous women born in private or public hospitals . Babies born in a private hospital were more likely to have been affected by a forceps or vacuum delivery and were more likely to have trauma to the scalp (3.22% vs 2.22%), intrauterine hypoxia (1.70% vs 1.21%), jaundice (4.68% vs 2.89%), minor cardiac murmurs (0.24% vs 0.17%), conjunctivitis (2.98% vs 1.27%), respiratory conditions (0.96% vs 0.57%), temperature regulation issues (2.08% vs 1.27%), feeding difficulties (3.83% vs 2.32%), carbohydrate metabolism issues (0.86% vs 0.53%), vomiting (0.55% vs 0.39%) and to be circumcised during the birth admission if a male (5.31% vs 0.21%). Babies born in a public hospital were more likely to be admitted for observation and evaluation (6.35% vs 3.75%) have prophylactic antibiotics (0.52% vs 0.16%) and be admitted for socioeconomic circumstances  (0.57% vs 0.05%)  in the private sector compared to the public sector (40.0% vs 53.9%) due to the added clinical and social maternal complexity in the public sector. There were however some significant differences noted under the main ICD-10-AM Grouping s 0.05%) .We examined the reasons for transfer or readmission of babies up until 28 days of age and found, that though the numbers are small, more babies born in private hospitals were readmitted compared to babies born in a public hospital , circumcision if a male (5.6 vs 0.3), birth trauma  (5% vs 3.6%), jaundice (4.8% vs 3.0%), hypoxia (1.7% vs 1.2%), respiratory disorders (1.2% vs 0.8%) and sleep/behavioural issues (0.2% vs 0.1%). Babies born in public hospitals were more likely to be admitted for socioeconomic circumstances such as housing, distance, adoption or assumption of care (0.7% vs 0.1%) and prophylactic antibiotics (0.6% vs 0.2%) .Despite being an extremely low-risk cohort, less than half the primiparous women in this study giving birth in a private hospital had a normal vaginal birth (45% vs 65%); this was 20% lower than in the public cohort. One in five primiparous women giving birth in a private hospital were induced and nearly one in two had an episiotomy. For low-risk multiparous women giving birth in a private hospital nearly one in three were induced. The trend for higher intervention rates has been reported for low-risk women giving birth in the private sector in Australia previously and continues to show an increase.We found that babies born in a private hospital were much more likely to experience some form of resuscitation, in particular twice the rate of suctioning at birth. Routine suctioning for infants born with clear and/or meconium stained amniotic fluid is not recommendedWe found some interesting differences in morbidity however when examining morbidity attached to the birth admission and readmission to hospital in the first 28 days for codes that may be associated with the higher rates of obstetric intervention in the private sector and a different sociodemographic profile in the public sector. While increasingly preterm babies >35 weeks/ and or >2.2k and some cases of jaundice may be managed at the bedside in some hospitals, this is less likely to occur in a private hospital. It is more likely to occur in large maternity units.Birth trauma, in particular injuries to the scalp, were significantly more common in the private sector and these are generally associated with instrumental birth, including vacuum extraction.22Jaundice was observed to be higher in the private sector, which may be related to several factors, such as the elective delivery of babies at an earlier gestation, the increased scalp trauma due to the high instrumental birth rate, as discussed above and potential breastfeeding difficulties due to higher use of epidural analgesia. Jaundice has been associated with birth trauma, in particular delivery by vacuum extraction and problems with feeding, especially supplementary feeding.While there have been studies associating difficulties with breastfeeding and higher rates of jaundice, the recent publication from the Universal Screening for Hyperbilirubinemia Study Group found difficulties with breastfeeding was a minimal risk factor.24Nearly twice as many babies who were born in a private hospital in this study were admitted or readmitted with feeding problems compared to babies born in a public hospital. Feeding difficulties are associated with operative birth interventions and being early term.41In a previous paper43Babies born in a private hospital were significantly more likely to be circumcised in the first 28 days of life. This may be due to different information being given in private hospitals about the procedure or easy access to providers who perform the procedure. Circumcision rates are estimated to be between 10% and 20% in Australia44The difference in the socioeconomic status of the women giving birth in public compared to private hospitals appears to be demonstrated by the significantly higher rates of public hospital babies with a morbidity attached to the birth admission or readmission in the first 28 days for socioeconomic circumstances, including housing, distance, adoption and assumption of care. This again confirms what is already known that the two populations are very different sociodemographically with a greater disadvantage in the public sector.Our study is limited to providing a snapshot of perinatal outcomes in the most populous state in Australia in a defined time period for women who have no indicated risk at birth. However, this study provides useful data following on from our previous paper looking at obstetric intervention in private and public hospitals in NSW providing the reader with a detailed picture of perinatal mortality and morbidity. The advantages of using population-based datasets such as the PDC and the linkage to four other population-based databases include the size of the sample and the high level of accuracy of a validated dataset. The limitations are the restricted number of variables that are included and the scarcity of specific information on potential influencing variables. A small number of cases with a low linkage  rate (0.3%) were not included and so there is the possibility of missing adverse outcomes. A previous study showed where stillbirths are excluded due to low linkage these are at lower gestational ages and not term infants as were the focus in this study.The continual rise in obstetric intervention for low-risk women in Australia, especially in private hospitals, may be contributing to increased morbidity for healthy women and babies and higher cost of healthcare. The fact that these procedures which were initially life-saving are now so commonplace and do not appear to be associated with improved rates of perinatal mortality or morbidity demands close review. Early term delivery and instrumental births may be associated with increased morbidity in neonates and this requires urgent attention. Previous claims that high-intervention rates in private hospitals lead to better perinatal outcomes than those seen in public hospitals need to be questioned.


P = 8.0 × 10−9, fully-adjusted model). Earlier age at menarche  and earlier year of birth were also associated with EM . We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence (‘early-life risk factors’) could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006–2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls , in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82,  Age at menopause influences health in later life with earlier menopause associated with increased osteoporosis and cardiovascular disease, and poorer cognitive function, but lower risks of several reproductive cancers1Natural menopause occurs on average at 51 years of age in Caucasian populations when the number of oocytes in the ovary are reduced below about 1000, however the factors that determine the timing of this event are poorly understoodEarly life events  have shown inconsistent relationships with age at menopause781113711101819We hypothesised that pre-birth and early-life events could influence the oocyte pool and thus influence the timing of menopause. In this, one of the largest epidemiological analyses of age at menopause, we investigated whether early life variables are associated with the clinically-relevant outcome of menopause below the age of 45 years (early menopause (EM)). We investigated the early-life risk factors birth year, maternal smoking around birth, birth weight, being part of a multiple birth, whether breastfed as a baby, whether adopted as a child, handedness, comparative height and body size at age 10, age of menarche and illnesses occurring at under 20 years-of-age.We analysed data from 273,474 women from the UK Biobank, which includes 503,325 people aged 40–69 years recruited in 2006–2010 from across the UKWe considered the outcome EM in our analyses, since this is clinically relevant and captures the lower extreme of normal reproductive ageing. EM cases were women with menopause under 45 years while controls had menopause or were known to be pre-menopausal at age 45 or over. Age at natural menopause was defined as age at last menstrual period excluding those with surgical menopause or taking hormone replacement therapy . All analyses were performed in Stata/SE v13.1. We restricted our analyses to women of white ethnicity (95% of cohort) and removed extreme outliers as appropriate : both sets of results were consistent. Due to the number of variables present in our UK Biobank data (approximately 1000), we used a conservative significance threshold of P < 5 × 10−5 for all tests and calculated 99.995% confidence intervals (CIs) around the odds ratio (OR).We included all available individuals including those with some missing data in each analysis. We also conducted sensitivity analyses in women with only complete data for all variables tested . To investigate the sensitivity of our results to age at recruitment which was different in cases and controls  (P = 2.5 × 10−10 for never drinking compared with drinking 1–2 times per week), decreasing educational level , and fewer live births .Being a current smoker had the largest effect on EM   (Supplem× 10−15) . Other nP = 8 × 10−6) in the partially- and fully-adjusted models, as was decreasing birth weight and being part of a multiple birth  was similar to that of being a current smoker . These associations remained when multiple birth, decreasing birth weight and maternal smoking were considered in the same logistic regression model , indicating that the association was with birth weight and not change in size.Since the association of EM with birth weight is adjusted for BMI, it could be considered that this is actually an association between EM and change in sizeP = 2.5 × 10−6), but not the partially-adjusted model (P = 3.5 × 10−6 for fully-adjusted)  . When codjusted) , both redjusted)  (Supplemdjusted) .P = 2.4 × 10−5). There were no significant associations with allergy, gynaecological problems, infections and headache/migraine.Considering illnesses under the age of 20, only cancer was associated with EM , but onlUsing Cox proportional hazards regression, we were able to explore whether associations with EM also held for menopause as a quantitative trait, where the outcome is hazard ratio (HR) of menopause. The potential confounding variables that were significantly associated with EM – drinking alcohol, educational level, number of live births, and smoking – also had consistent directions of effect in the Cox model. Increasing social deprivation, lower BMI and not eating meat were associated with increased HR of menopause, though these risk factors were not associated with EM  Supplem. The dirP = 7.27 × 10−6) and being part of a multiple birth  remained significantly associated with EM , only the risk factors younger age at menarche  and five loci associated with age at menopause contain genes associated with hypogonadotropic hypogonadism50. We found that being thinner at age 10 was associated with increased odds of EM. It is unlikely that this association is driven by an effect on menarche timing as being thinner in childhood is associated with delayed menarche3511711The association between earlier age at menarche and increased odds of EM agrees with another analysis using the UK Biobank dataIn our cohort of women born in 1936–1970, there was an increased odds of EM in women born in earlier birth years. We estimate an increase in age at menopause of about 1.3–2.5 months per year of later birth (data not presented), which agrees with two smaller studies on cohorts born between 1908–1930 in Sweden  and 1912–1969 in the USA 34In our analysis of illnesses occurring before the age of 20, only cancer showed an association with EM. It is likely that cancer treatment will have had an effect on age at menopause – such treatment is known to affect fertility4042A limitation of this study is that the UK Biobank data is based on volunteers and so there may be selection bias. The data used in our analysis was collected retrospectively and so may be subject to recall bias. Clear rounding of menopause age was evident, as has been seen in previous studies451518in utero or in early development and could be mediated through increased stress to oocytes, perhaps caused by reduced nutritional or oxygen availability. In rats, suboptimal nutrition during pregnancy is associated with transgenerational accelerated female reproductive ageing48Due to the number of women included in this study, we provide powerful evidence for the influence of early-life risk factors on EM, and hence women’s health. More specifically, that being a multiple birth, having menarche at a younger age, and being born in an earlier birth cohort are associated with EM. It is plausible that early-life events could influence the oocyte pool since the number of ovarian follicles is determined before birth and the number of primary oocytes decline dramatically prior to puberty – from about 7 million oocytes at 6 months post conception to about 400,000 oocytes by puberty. Early life events identified in our study could affect the oocyte reserve How to cite this article: Ruth, K. S. et al. Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study. Sci. Rep.6, 24710; doi: 10.1038/srep24710 (2016).


Birth interval is an important and potentially modifiable factor that is associated with child health. Whether an association exists with longer-term outcomes in adults is less well known.Using the 1982 Pelotas (Brazil) Birth Cohort Study, the association of birth interval with markers of cardiovascular health at 30 years of age was examined. Multivariable linear regression was used with birth interval as a continuous variable and categorical variable, and effect modification by gender was explored.Birth interval and cardiovascular data were present for 2,239 individuals. With birth interval as a continuous variable, no association was found but stratification by gender tended to show stronger associations for girls. When compared to birth intervals of <18 months, as binary variable, longer intervals were associated with increases in height  and lean mass . No difference was seen with other cardiovascular outcomes.An association was generally not found between birth interval and cardiovascular outcomes at 30 years of age, though some evidence existed for differences between males and females and for an association with height and lean mass for birth intervals of 18 months and longer. According to the ‘developmental origins of adult disease’ hypothesis, patterns of fetal growth and development shape susceptibility to chronic non-communicable diseases in adult life. Early work focused on the long-term health consequences of low birth weight, which was assumed to indicate fetal malnutrition. Increased non-communicable disease risk following fetal exposure to maternal starvation during the "Dutch hunger winter" seemed to support this hypothesis. However,In fact, the dominant environmental influence on the fetus is maternal phenotype, which has multiple dimensions of variability. These include relatively stable traits, such as maternal height and lean mass, and more labile traits such as physical activity profile, micronutrient status, glycemic control and adiposity. The simpAn alternative marker of fetal nutritional investment, potentially marking maternal supply rather than fetal acquisition, is the duration of the inter-birth interval. From an evolutionary perspective, mothers must acquire resources from the environment in order to invest in offspring. A shorter period between births may reduce the ability of the mother to replenish her reserves adequately for this purpose or provide competition for her resources. This parameter merits study, because unlike stable maternal traits such as stature, the length of a birth interval is potentially amenable to public health interventions.Most research on birth interval has tended to focus on its association with perinatal outcomes. Short inter-pregnancy intervals of less than six months from birth to the next conception, including after an aborted pregnancy,  are assoPrevious analysis of data from Pelotas, Brazil showed that children born after birth intervals of <18 months were at greater risk of neonatal mortality, of being born with low birthweight and poor growth in childhood. At 19 months of age, children born after <18 month birth interval compared to >71 months had a 0.49 z score lower height-for-age (~1.5 cm) and 0.41 lower weight-for-age (~0.5 kg). Restricting the analysis to children with known gestational age did not alter the outcomes. There is evidence that birth spacing is associated with childhood nutritional status and child malnutrition, for examThe 1982 Pelotas (Brazil) Birth Cohort Study with follow-up at 30 years was used for this analysis . Visceral and subcutaneous abdominal fat and carotid intima-media thickness were measured using ultrasound (Toshiba Xario). Blood samples were collected by the research team, stored at the research centre and later analyzed commercially.The study was approved by the Research Ethics Committee of the Faculty of Medicine, Federal University of Pelotas  and all subjects provided written informed consent.The exposure variable was birth interval in months (defined as the time period from the birth of the previous sibling to the beginning of the pregnancy of the index child) by maternal recall, treated both as a continuous and a categorical variable. For comparison purposes, we chose the categories previously used in the same cohort: <18 months, 18 to <24 months, 24 to <36 months, 36 to <48 months, 48 to <71 months, ≥71 months.  This gavFor the outcome measures we defined cardiovascular risk factors as body composition , body mass index (BMI), blood pressure, carotid arterial thickness, lipid profile, glucose and insulin concentrations at 30 years of age. BMI was calculated as weight (kg) divided by height (m) squared.a priori based on previous knowledge. The variables included were maternal age, education and BMI at the beginning of pregnancy, family income at birth and birth order. [Potential confounding variables were decided h order. , 19 The Univariable and multi-variable linear regression analyses were performed with birth interval  as the independent variable and cardiovascular risk factors as the outcome variables. The primary analyses included birth interval as a continuous variable. To investigate potential threshold effects, we then included birth interval as a categorical variable. We also stratified by child sex. Model assumptions were tested for linearity by plotting residuals against each covariate and for normality by examining a kernel density plot of residuals. Non-normal residual distributions were seen for glucose and triglyceride values and these were transformed using natural logarithms. Fat-free mass had a binomial distribution, so was adjusted with robust standard errors using the Huber and White method. AnalysisOffspring were seen at a mean age of 30.2 years. The follow-up rate was 68.1% of the original cohort . The main cohort characteristics have been described previously.  Birth inMultivariable regression analyses found no association between birth interval and cardiovascular risk factors. Inclusion of fat-free mass in the models to adjust for stature made little difference to the outcomes (data not shown). Stratification by gender tended to show stronger associations with birth interval in females than males for anthropometry, body composition and cholesterol  but therWhen considering birth interval as a categorical variable, compared to <18 months, longer intervals were associated with increases in height of approximately 1.6 cm and with increases in lean mass which were mostly just below the threshold of significance . No diffThis study performed an analysis of prospectively collected cohort data and sought to investigate whether a lasting association exists between the length of the birth interval and a range of cardiovascular outcomes at 30 years of age. Overall an association was not found, though potentially differences did exist between males and females, and compared to birth intervals of <18 months, longer birth intervals resulted in increases in adult height of 1–2 cm, with some evidence of increases in lean mass. This association with height is potentially important due to its association with adult health and income. WHO recommends birth intervals of greater than 24 months. ChangingPrevious research has shown an association of birth interval with birth weight. A meta-analysis of five cohort studies  has shown that birth intervals of less than 18 months and longer than 60 months increased the risk of being born small for gestational age, preterm and infant mortality.  Other evLong-term effects are mediated via in-utero and postnatal growth. The mechanisms by which these arise are through maternal folate depletion, sub-optimal breastfeeding or when breastfeeding overlaps with a pregnancy, transmission of infection both vertically and from siblings and other forms of sibling competition. Though pWhy might no relationship be seen in cardiovascular outcomes in adults if birth interval is associated with childhood outcomes? There are several possible explanations. Firstly there may truly be no association with adult outcomes. Compensatory mechanisms in childhood could lead to phenotypes and physiology becoming similar within the population over time, erasing effects apparent at earlier ages.Second, thirty years may not be the best age to evaluate variability in all cardiovascular outcomes. Overt disease tends to occur later in middle-age following decades of unhealthy lifestyle, and it may be that young adults might not reveal deleterious consequences of poor fetal development.Third, removing firstborns from the analysis was necessary but this might weaken associations between markers of fetal nutrition and adult cardiovascular health. The sample size, while large, would have been insufficient to detect small effects. Studies have shown that firstborns are at elevated risk of chronic diseases in adulthood, in part due to their low birth weight. Research using the same 1982 Pelotas cohort showed increased cardiovascular risk in firstborns, potentially mediated by having a lower birthweight and evidence from a subsequent cohort in Pelotas at 13 years of age, showed an association between being born first and height and blood pressure. , 27Fourth, the inter-birth interval may not index aspects of maternal investment that matter for adult health. The evolutionary ‘maternal capital’ hypothesis assumes that mothers with greater nutritional resources can invest more in their offspring during fetal life, increasing their homeostatic capacity in adult life. However, there are numerous dimensions of maternal capital, some of which may be more influential than others on fetal development. AlthoughFinally, it may be that birth interval is more important in populations that have a greater proportion of under-nourished mothers. The mother’s BMI in our sample was within the normal range for all birth interval categories. In this population, the majority of mothers may have had ample time to replenish any nutrient reserves, resulting in our null findings. We should therefore be cautious about generalizing our results to other developing countries where the mothers have poorer nutrition.The main strength of this study was the use of a prospective, 30-year cohort study with high follow up rates. The cohort is also one of the largest of its kind and covered >99% of births in the city in one year, so is representative of its location.  Loss to It is possible that residual confounding exists. Contraception use for example was unknown but a later cohort in 1986 showed that contraception was being used by all women who wanted it.  Other faCalls have been made to encourage increases in birth intervals to be incorporated into international policy. , 31 An aWhile short-term advantages in health can be gained by increasing birth intervals to an optimum length, an association was generally not found between birth interval and cardiovascular outcomes at 30 years of age, though some evidence existed for differences between boys and girls and for an association with height and lean mass for birth intervals of 18 months and longer.S1 File(PDF)Click here for additional data file.S2 FileRegression coefficients (95% CI) for birth interval, as a continuous outcome variable, and confounding variables (Table A). Regression coefficients (95% CI) for cardiovascular risk factors at age 30 years and confounding variables (Table B). Maternal and Offspring Characteristics averages (mean or median) at 30 years, Stratified by Birth Interval and by gender (Table C).(DOCX)Click here for additional data file.


Literature reports have indicated an increase in research evidence suggesting association between periodontal disease and the risk of pre-term birth (PTB) and low birth weight (LBW). Periodontal diseases in Uganda have been documented as a public health problem, but their association to adverse pregnancy outcomes is unknown. This study was conducted to assess the association between periodontital diseases in postpartum mothers and PTB and LBW of babies in Mulago and Mbarara referral hospitals.This was a cross sectional study using medical records, clinical examination and oral interview of mothers at the two tertiary health facilities. Mothers with singleton babies from Mulago (n = 300) and Mbarara Hospital (n = 100) were recruited for the study. The women were clinically examined for periodontal disease by 2 trained and calibrated dentists. Data on PTB and LBW were retrieved from medical records. The data were analyzed to determine the relationship between the four parameters for periodontal disease  and the adverse pregnancy outcomes. Frequency distribution was used to describe the data. Bivariate and multivariate analyses were used to study the association between the periodontal diseases and adverse pregnancy outcomes.Approximately 26% and 29% of the postpartum mothers examined had bleeding gingiva and periodontal pockets of 4 mm or more deep, respectively. Advanced periodontitis i.e. pocket depth ≥ 6 mm was recorded in 13 (3.6%) of the mothers. Calculus with plaque deposits were recorded in 86% (n = 343) of the mothers. Gingival recession was recorded in 9.0% of the mothers and significantly and directly related to birth weight (p < 0.05).Periodontal conditions of postpartum mothers in this study were found to be better than previously reported amongst the Ugandan population. Bivariate analysis showed a significant association only between gingival recession and low birth weight. However, this finding should be interpreted with caution as it could have occurred by chance. Periodontal diseases are a group of oral inflammatory diseases caused by bacterial plaque and influenced by host response factors. There aSome of the important clinical features include alterations in the gingival color, pocket depth, position of the epithelial attachment and tendency to bleeding. In mostNamiro et al. also found that preterm birth (PTB) and low birth weight (LBW) are more prevalent in developing than developed countries. South AAlthough a number of studies have shown that bacterial vaginosis is related to preterm birth and low birth weight, which in effect is a significant cause of morbidity and mortality, it is also possible that other infectious processes including periodontal disease contribute to PT/LWB.Indeed recent years have witnessed an increase in research evidence suggesting associations between periodontal disease and an increase in systemic disease. After tPorphyromonas gingivalis, Bacteroides forsythus, Actinobacillus actinomycetemcomitans and Treponema denticola, organisms normally associated with periodontal disease, in mothers of PTB and LBW babies as compared to normal controls[Clinical trials at the Center for Oral and Systemic Disease at the University of North Carolina, reported the presence of higher levels of controls.Opinion seemed to defer early when investigators like McGaw (2002) suggested that prospective and eventually interventional studies are necessary before periodontitis can be considered as a causal factor for PLBW. In a meSome intervention studies suggest a reduction in the risks of preterm birth and preterm low birth weight after mechanical periodontal therapy during pregnancy. López et al. found a reduction in the rate of preterm births and/or low birth weight in women that received periodontal treatment before the 28th gestation week when they were compared with women that did not receive any treatment. This reduction was significant for periodontally healthy women compared with women with gingivitis, and witIn a systematic review by Scannapieco et al., where tAnother systematic review published in 2005 by Xiong et al. analyzed the results of 25 articles. The majority, 18 out of the 25 studies, suggested an association between periodontal disease and increased risk of adverse pregnancy outcomes. PaquettFusobacterium nucleatum and Capnocytophaga spp have been associated with intrauterine infections; F. nucleatum being one of the most frequently isolated microorganism from the infected uterus[On the other hand, some clinical and laboratory studies have shown that intrauterine infections are highly prevalent among women who give birth prematurely. Althougd uterus,22.F. nucleatum resulted in preferential localization to placental blood vessels from which it crossed the endothelium to the amniotic fluid and induced premature delivery, and stillbirths in a pattern similar to that observed in humans. This finding supports the hypothesis that after transient bacteremia, oral F. nucleatum translocates to the pregnant uterus and possibly to the fetus hematogenously[In periodontal disease, transient bacteremia may occur probably leading to selective colonization of undesired sites. Studiesgenously. Observagenously showed tUganda has a big economically disadvantaged population and, periodontal diseases have been documented as a public health problem especially in the rural communities with a prevalence of 62% in adults. CoincidThis was a cross sectional study conducted in maternity units in Mulago and Mbarara hospitals between May and November 2012. The two health facilities are national referral and teaching hospitals in Uganda. Mulago Hospital has a capacity of 1,500 beds and is located in Kampala, the capital city of Uganda. Mbarara Hospital has a 300 bed capacity and is about 280 km west of Kampala. Mulago and Mbarara hospitals attend to approximately 80 and 40 deliveries per day, respectively.The study population included postpartum mothers aged 18 years or above who delivered singleton babies within one or two days prior to recruitment into the study in both hospitals. The women were selected consecutively from the maternity units. Mothers of infants with severe congenital malformations, systemic conditions such as HIV infection, uncontrolled diabetes mellitus, or any medical condition requiring chronic medication and those without teeth in one or more sextants were excluded. Based on proportionate sampling, 300 and 100 mothers were recruited from Mulago and Mbarara hospitals, respectively.One to two days after delivery, the mothers were clinically examined for their periodontal diseases in their hospital room by two trained and calibrated dentists. The examiners were blinded to the physical condition of the baby to minimize bias. We defined periodontal disease by a combination of the following four parameters: 1) Probing pocket depth (PPD), 2) Bleeding on probing (BOP), 3) Calculus with plaque deposits (CD) and 4) Gingival recession (GR) using the modified Community Periodontal Index (CPI) with the following criteria.0. No periodontal disease1. Bleeding on probing2. Calculus with plaque seen or felt by probing3. Pathological pocket 4 – 5 mm4. Pathological pocket 6 mm or more5. Gingival recessionWe recorded pocket probing depth and gingival recession using a World Health Organization recommended Community Periodontal probe , at six sites per tooth on the 6 index teeth  translating into 36 sites per participant. If the index tooth was not present, the next tooth was examined. Probing pocket depth was measured in mm as the distance from the gingival margin to the bottom of the pocket.Medical history was obtained through oral interview after the oral examination to get background information on maternal age, nationality, educational level, marital status, and employment during pregnancy, tobacco smoking before and during pregnancy, and number of prenatal visits. Other information included: birth weight of the baby, parity, infection, complications during pregnancy, intra-uterine growth retardation (IUGR), preterm premature rapture of the membranes (PPROM), maternal hemorrhage and onset of labor. Induced preterm birth included both induction of labor and caesarean section before labor.All procedures conformed to the protocol approved by Makerere University, School of Health Sciences Institutional Review Board and the respective hospital research and ethics committees. Informed consent was obtained from the participating mothers in accordance with Helsinki Declaration. No persThe data were double checked for errors and completeness at the end of each day’s work. Assessment of periodontal diseases was standardized through training of the two examiners by an experienced clinician (ML) on 20 patients in Makerere University Dental clinic before the start of the study. The inter-class correlation coefficients were useThe data were double checked for errors and completeness and entered into a computer for analyses using Statistical Package for Social Sciences Inc. . The frequency distribution was used to describe the data. The infant’s birth weight was categorized as 0 = <2.5 kg and 1 = ≥2.5 kg. The gestation age was categorized as 0 = 28–36 weeks and 1 = ≥37 weeks. The periodontal diseases  were individually categorized as 0 = no, and 1 = yes. The demographic and obstetric factors were also categorized  of the postpartum mothers were ≤ 25 years Table  with no Most mothers were at para 2 and 3,and had unspecified employment Table . Most ofGenerally, tooth 16/17 and 26/27 had more prevalence of periodontal diseases (CPI score 1–5) than the rest of the teeth. On the other hand the upper central incisor (#11) had the lowest prevalence of periodontal diseases as compared to the rest of the teeth. Approximately 26% and 29.4% of the mothers had bleeding gingiva and periodontal pockets of 4–5 mm deep, respectively Table , but notThis was a pilot study based on a sample of postpartum mothers (n = 400) in two tertiary health facilities in Uganda. This study shows a significant association between gingival recession and low birth weight, indicating that periodontal disease maybe a factor influencing pregnancy outcomes in Ugandan women. However, there is a 50% probability of getting this positive finding just by the play of chance. Never the less, many of the studies carried out in economically disadvantaged populations suggest that periodontal disease is associated with increased risk of adverse pregnancy outcomes such as preterm birth and low birth weight,13.It should be noted that mothers who had still births were excluded in the present study due to fear of further traumatizing them. This exclusion may have led to loss of data resulting into inadequate statistical power and imprecise results. The examiners were calibrated and the reliability test in recording periodontal diseases gave an almost perfect agreement, a furthOver all, in the present study, about 26% and 29.4% of the mothers had gingival bleeding and periodontal pocket depth of 4 mm or more, respectively Table . GingivaIn the present study, about 9 out of 10 mothers had a fundal height of 37 cm and more, which corresponds to the reported gestation age of pregnancy before delivery Table . This coGenerally, the periodontal conditions of these postpartum mothers were found to be better than previously reported amongst the Ugandan population. Bivariate analysis showed a significant association between gingival recession and low birth weight, however, no other parameters of periodontal disease were significantly related to adverse pregnancy outcomes. This finding should therefore be interpreted with caution as it could have occurred by chance.It is recommended that a large sample size be used to confirm whether the lack of association between other parameters of periodontal conditions and adverse pregnancy outcomes was real.The authors declare that there are no competing interests.LM, CMR, IO contributed to the design of the study. MN, AK performed the clinical examinations of postpartum mothers. GK, MK, GM did the analysis of the data. All authors contributed to the preparation of the manuscript and approval of the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6831/14/42/prepub


Prenatal exposure to bisphenol A (BPA) and phthalates may affect fetal growth; however, previous findings are inconsistent and based on few studies.We assessed whether prenatal exposure to BPA and phthalates was associated with fetal growth in a Spanish birth cohort of 488 mother–child pairs.We measured BPA and eight phthalates  in two spot-urine samples collected during the first and third trimester of pregnancy. We estimated growth curves for femur length (FL), head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and estimated fetal weight (EFW) during pregnancy (weeks 12–20 and 20–34), and for birth weight, birth length, head circumference at birth, and placental weight.Overall, results did not support associations of exposure to BPA or DEHPm during pregnancy with fetal growth parameters. Prenatal MBzP exposure was positively associated with FL at 20–34 weeks, resulting in an increase of 3.70% of the average FL  per doubling of MBzP concentration. MBzP was positively associated with birth weight among boys  but not in girls  . The LMWPm mono-n-butyl phthalate (MnBP) was negatively associated with HC at 12–20 pregnancy weeks [–4.88% of HC average ].This study, one of the first to combine repeat exposure biomarker measurements and multiple growth measures during pregnancy, finds little evidence of associations of BPA or phthalate exposures with fetal growth. Phthalate metabolites MBzP and MnBP were associated with some fetal growth parameters, but these findings require replication.Casas M, Valvi D, Ballesteros-Gomez A, Gascon M, Fernández MF, Garcia-Esteban R, Iñiguez C, Martínez D, Murcia M, Monfort N, Luque N, Rubio S, Ventura R, Sunyer J, Vrijheid M. 2016. Exposure to bisphenol A and phthalates during pregnancy and ultrasound measures of fetal growth in the INMA-Sabadell cohort. Environ Health Perspect 124:521–528; http://dx.doi.org/10.1289/ehp.1409190 Bisphenol A (BPA) and phthalates are a class of synthetic chemicals produced and used in large quantities worldwide and present in many kind of articles including plastics, cosmetics, carpets, building materials, toys, or cleaning products . In 1999in vivo studies have revealed sex-dependent effects on body weight in rodents exposed perinatally to BPA  is a population-based birth cohort study that recruited 657 pregnant women in the Spanish region of Sabadell between 2004 and 2006  or polyethylene tubes  at –20°C. Total BPA (free plus conjugated) was quantified by liquid chromatography–mass spectrometry in the Department of Analytical Chemistry laboratory–University of Cordoba (Spain) (© reactive in AU5400 (IZASA®). All BPA and phthalate metabolites concentrations were divided by urinary creatinine concentrations to control for urine dilution. Selection of women for BPA and phthalates measurements was based on criteria set in previous studies conducted in this population ( (Spain) . Eight p (Spain) . Limits pulation : BPA conFetal growth and birth outcomes. Routine fetal ultrasound examinations, regardless of study participation, were scheduled at 12, 20, and 34 weeks of pregnancy by obstetricians who specialized in conducting this type of examinations at the respective hospitals. The fetal parameters recorded (millimeters) were femur length (FL), head circumference (HC), abdominal circumference (AC), and biparietal diameter (BPD). Estimated fetal weight (EFW) was calculated using the Hadlock algorithm .lgorithm . We had p < 0.05) through a forward selection procedure. These physiological factors included maternal age, parity, country of origin, maternal height, maternal prepregnancy weight or body mass index (BMI), paternal height, weight or BMI, and child sex. Only the significant ones were included in the models . Growth models were then applied to calculated standard deviation (SD) scores at 12, 20, and 34 weeks of gestation, representing cross-sectional estimates of fetal size , and SD scores over the week intervals 12–20 and 20–34, representing fetal growth between two periods  . A detailed description of these growth curves is provided by 0 weeks) . Growth 0 weeks) . Because0 weeks)  and adjuCovariates. Information on maternal age, education, social class, country of origin, weight and height, parity, health history, marital status, dietary intake, use of household cleaning products, active smoking, time of urine collection, and season of birth was obtained by self-reported questionnaires administrated by trained interviewers at weeks 12 and 32 of pregnancy. Child sex was obtained from clinical records. Cotinine was determined in urine at 32 pregnancy weeks, using commercial competitive enzyme immunoassay microplate test kits  with a limit of quantification (LOQ) of 4.0 μg/L.Statistical analysis. Urinary concentrations of BPA and phthalate metabolites below the LOD were assigned a value of half the LOD. Reproducibility of urinary BPA and phthalate metabolites between the first and third trimesters was obtained by calculating the intraclass correlation coefficient (ICC) using random one-way intercept linear mixed models. We also calculated Pearson correlations of the log-transformed compounds concentrations. Because of the short biological half-lives of these compounds . Based on the DAGs, the final multivariate models were adjusted for maternal education , smoking during pregnancy , and parity . Departing from this multivariate model, we then conducted a forward stepwise selection procedure including other potential confounders and ancestors and testing if they changed the coefficient by > 10%: birth season, urinary cotinine levels during pregnancy, consumption of canned fish during pregnancy, time of urine collection, and use of household cleaning products. Birth season  and urinary cotinine levels during pregnancy  changed most of the coefficients by > 10% and hence they were included in all final models. Because fetal HC growth models were already adjusted for parity , this variable was not included in the fetal HC multivariate models. Finally, newborn’s HC models were also adjusted for type of delivery  because passage through the birth canal may influence HC at birth. We are only presenting the adjusted models because they yielded results similar to the unadjusted ones.Generalized additive models were used to evaluate linearity of our exposure–outcome relationships. Associations between BPA/phthalates and SD scores for fetal size/growth, and birth parameters were then examined by univariate and multivariate linear regression models. To determine the covariates included in the multivariate models, we applied directed acyclic graphs (DAGs) . Covarian-butyl phthalate)], and for each single phthalate metabolite. Because these parent and metabolites compounds are hormonally active, we report all primary analyses stratified by sex, in addition to reporting estimated for boys and girls combined. We performed likelihood ratio tests of interaction terms for exposure and sex to identify significant modification by sex based on p ≤ 0.1. To evaluate the robustness of our results, we conducted various sensitivity analyses and considered whether the findings were generally consistent throughout the different models. First, we repeated the models adjusting for urinary creatinine concentrations as has been performed in other studies (n = 40) to prevent “dilution effects” in the urine samples  of the four DEHP [di(2-ethylhexyl) phthalate] metabolites {ΣDEHPm: MEHP [mono(2-ethylhexyl) phthalate], MEHHP [mono(2-ethyl-5-hydroxyhexyl) phthalate], MEOHP [mono(2-ethyl-5-oxohexyl) phthalate], and MECPP [mono(2-ethyl-5-carboxypentyl) phthalate]}, MBzP , the sum (micrograms per liter) of the three LMWP metabolites [ΣLMWPm: MEP , MiBP , and MnBP  and/or phthalate metabolites concentrations (n = 390) and fetal growth parameters or birth outcomes . Women included in the study were more likely to be Spanish, well-educated, and from a higher socioeconomic position than INMA-Sabadell participants not included in the analysis (data not shown). Complete details of the characteristics of the study population are given in Supplemental Material, Table S2.n = 473) had one routine ultrasound examination in each trimester of pregnancy but 15 (3%) women had four to six examinations. The mean (± SD) gestational age, birth and placental weight were 39.7 ± 1.4 weeks, 3,319 ± 391 g, and 602 ± 110 g, respectively (data not shown).BPA and phthalate metabolites were detected in most of the urine samples (0–0.8% < LOD) . The unaBPA and fetal growth and birth outcomes. Exposure to BPA during pregnancy was negatively associated with FL and EFW from 12 to 20 weeks resulting in a percent reduction in SD scores of –4.26%  and –3.84% , respectively, for each doubling of concentration of maternal urinary BPA  (p interaction = 0.05), whereas at 20 weeks there was a weak positive association with EFW in girls and a stronger nonsignificant negative association in boys (p interaction = 0.05) (p interaction = 0.03) (nary BPA . Negativfor EFW) . Signifi = 0.05) . There w = 0.03) . Prenata = 0.03) . None ofPhthalate metabolites and fetal growth and birth outcomes. Exposure to ΣDEHPm and its single metabolites during pregnancy was not significantly associated with any of the fetal growth  or birth outcomes assessed (p interaction = 0.15) (p interaction = 0.04), and was positively associated with placental weight in boys  but negatively associated in girls  (p interaction = 0.02) ( = 0.15) . At birt = 0.02) . After cp interaction = 0.21 and 0.31, respectively) (p interaction = 0.29) . Further, the metabolite MiBP was associated with lower birth weight in girls  but not among boys  (p interaction = 0.08) . Associations of individual LMWP metabolites with other birth outcomes were not statistically significant overall or in girls or boys . Of the associations that were statistically significant in primary analyses, only the association between MnBP and HC growth from 12 to 20 weeks met our criteria for consistency .Exposure to ΣLMWPm was not significantly associated with any of the fetal size or fetal growth outcomes  or any of the birth outcomes assessed (ctively) . MnBP waIn this population of pregnant women with a common exposure to BPA and phthalates, we found few associations between these compounds and fetal growth and birth outcomes. The HMWPm MBzP was significantly associated with greater FL growth from 20 to 34 weeks in the overall population and with significantly higher birth weight in boys, but not in girls. In contrast, the LMWPm MnBP was associated with lower HC growth from 12 to 20 weeks in the overall population, with no evidence of sex differences. These associations persisted after sensitivity analyses, including adjustment for other pollutants. Maternal urinary BPA and DEHPm concentrations were not significantly associated with any of the growth outcomes assessed either during fetal life or at birth.n = 125 in n = 80 in Concentrations of BPA among pregnant women in our population were similar to populations in other studies where BPA and fetal growth outcomes were evaluated . In two Phthalate metabolite levels in urine of pregnant women from our population were of similar magnitude to those reported in other studies assessing phthalates in relation to birth outcomes . Two othThis study has some limitations. First, although we used the average of two BPA and phthalate measurements during pregnancy, the high within-person and within- and between-day variability of these compounds means that exposure misclassification cannot be ruled out. Such misclassification is likely to be random with respect to our outcomes, and is thus most likely to have led to an attenuation of associations . Second,The major strength of this paper relies on its prospective design and the use of repeated measurements of fetal biometry. Also, we had repeated measurements of BPA and phthalates at the first and third trimester of pregnancy in almost 500 pregnant women, making this, to our knowledge, the largest and most extensive study on this topic. Finally, we had data available for a large number of potential confounders.This study is one of the first to combine repeat exposure biomarker measurements and multiple growth measures during pregnancy. We did not find consistent or strong evidence of associations between BPA or phthalate exposures and fetal growth, though the phthalate metabolites MBzP and MnBP were associated with some fetal growth parameters. These findings require replication. Production of some phthalates and BPA has already been banned in some countries and replaced by other chemicals such as the BPA analogs BPE or BPF that can also have endocrine-disrupting activity . Investi(672 KB) PDFClick here for additional data file.


The epigenetic patterns established during development may influence gene expression over a lifetime and increase susceptibility to chronic disease. Being born preterm (<37 weeks of gestation) is associated with increased risk mortality and morbidity from birth until adulthood. This brief review explores the potential role of DNA methylation in preterm birth (PTB) and its possible long-term consequences and provides an overview of the physiological processes central to PTB and recent DNA methylation studies of PTB. Despite advances in healthcare, preterm birth (birth prior to 37 weeks gestation) remains a major global health problem . PretermThe molecular mechanisms that underlie the relationship between preterm birth and its developmental consequences are not clear, but advocates of the DOHaD hypothesis believe that epigenetics may play a key role  10]. Ep. Ep10]. This is not meant to serve as a comprehensive review of preterm birth. Other excellent reviews of its epidemiology, management, prediction, prevention, physiology, and proposed mechanisms have recently been published ,16,17,18Pregnancy initiates after fertilization of the female gamete and implantation of the embryo; it is the gestational period during which fetal development and growth occurs. The typical duration of human pregnancy is 280 days (40 weeks), though the actual length may vary considerably ,20. ObstThe relationship between the mother and fetus is considered to be semi-allografic because the fetus is genetically distinct and can be recognized as a foreign body by the maternal immune system. The placental barrier regulates the maternal–fetal interface by controlling substances transmitted to the fetus ,24. Both0/7–276/7 weeks), very early (280/7–316/7 weeks), moderate (320/7–336/7 weeks) and late (340/7–366/7 weeks) [While birth occurring before 37 weeks of gestation is considered preterm, the limit of viability is as low as 23 weeks in some medical centers . Thus, py 280/7–3/7 weeks,7 weeks) . In addi7 weeks) . Many PTly 280/7–6/7 weekste 320/7–6/7 weeks7 weeks) ,36,37, s7 weeks) ,40,41,427 weeks)  and medi7 weeks) ,45,46,47Medically indicated or iatrogenic preterm birth results from obstetrical, fetal or medical complications requiring early delivery for treatment or resolution. Common obstetrical indications for preterm delivery include gestational diabetes and severe preeclampsia  . Both thPremature rupture of membranes (PROM) involves a rupture of the fetal membranes prior to the onset of labor. In an uncomplicated term pregnancy, rupture of the membranes immediately precedes or occurs during labor , with pPSpontaneous PTB can happen either with or without rupture of membranes. Risk factors associated with PTB are similar to that of pPROM and include, but not limited to, prior preterm birth, intra-amniotic infections, stress, behavior, obesity and inter-pregnancy interval . AlthougThere are many hypotheses about the mechanisms that may contribute to PTB. Some note that PTB is heritable and seek to identify the genetic risk factors ,56,57. MPregnancy is a period of extensive stress, during which the hypothalamic pituitary adrenal (HPA) axis undergoes extensive changes ,59. HypoThe placenta releases CRH into maternal and fetal circulation in significant quantities. Placental CRH stimulates the maternal HPA axis, leading to an increase in total and free cortisol during pregnancy . The HPAThe neuroendocrine system plays an important role in timing of parturition. It is therefore not unexpected that dysregulation of the neuroendocrine system could be involved in the mechanism of PTB, particularly since stress is a risk factor for PTB . PhysicaThe neuroendocrine and immune systems are interconnected. Acute stress has an anti-inflammatory response, though chronic mental or physical stress can lead to a pro-inflammatory state and even glucocorticoid resistance ,71. ThisOver the course of a typical pregnancy, the maternal immune system is characterized by a shift from a pro-inflammatory state that is effective against intracellular pathogens such as viruses and bacteria to an anti-inflammatory state that targets extracellular pathogens using specific antibodies; however, it does so through a dynamic process ,77,78,79Inflammation is implicated in most PTB. Various infections such as urinary tract infections, bacterial vaginosis, sexually transmitted infections, malaria and even periodontal disease have associated with PTB ,85. EvenClinical advancements have significantly reduced the mortality rate of infants delivered preterm, but morbidity remains a substantial concern. It is unclear whether those born preterm are able to meet developmental milestones in a time frame that is comparable to their term-born peers. Even among those that do not have congenital malformations, many infants delivered preterm appear to have distinct developmental trajectories that differentiate them from term infants as they age. For example, some report that preterm infants are able to catch up in both weight and height in the first two years of life ,88,89,90In addition to the question of whether or not preterm infants catch up, it is unclear if there are additional consequences that result from accelerated growth rates. Catch up growth in early and late infancy has been associated with obesity, cardiovascular disease, and insulin resistance in adolescents ,7. For eNumerous studies report epigenetic differences associated with gestational age and growth patterns ,103,104.PTGER2 (prostaglandin E receptor 2) and reported associations with local inflammation and length of gestation [Because of the complexity of the maternal–fetal interface and the number of tissues involved in pregnancy and delivery, it is not always clear which tissues is the most appropriate for PTB studies. For example, a recent study evaluated myometrium, the middle layer of the uterine wall that induces contractions during labor ,118. By estation .RUNX3 (runt-related transcription factor 3) with smoking during pregnancy and lower gestational age [Other studies focus on the role of the placenta. For example, one study examined amnion tissue, the inner layer of the fetal membranes, from 121 term and preterm deliveries . This geonal age .PLAGL1 (pleiomorphic adenoma gene-like 1) and chorioamnionitis. In contrast, a comprehensive evaluation of umbilical cord blood in African Americans by Parets and colleagues identified thousands of CpG sites across the genome that associated with PTB; the associated genes were enriched for numerous development processes [Most preterm birth studies that examine DNA methylation use blood because of its accessibility. For example, a study using cord blood examined the association between DNA methylation of imprinted genes and both preterm birth and infection status . While trocesses . This strocesses  and withrocesses  in otherrocesses . While trocesses , DNA metCALCA . Though the study was preliminary, they report DNA methylation differences in this region in infants with early onset sepsis and late onset sepsis that were not present in matched controls or neonates with isolated infections. Epigenetic biomarkers have been utilized in a number of diseases that primarily affect adults [Many hope that DNA methylation studies will yield biomarkers that can be used to screen for preterm birth or its risk factors. One such study explored DNA methylation to diagnose bacterial sepsis, a generalized immune response that is likely to affect children who are born preterm with low birth weight or very low birth weight . The rest adults ,120,121.ALPL) associates with height, and the authors discuss the role of this gene in bone mineralization. Similarly, a longitudinal study comparing DNA methylation across the genome in 12 individuals born preterm to 12 born at term reported numerous methylation differences at birth. Interestingly, some of those CpG sites still distinguished preterm and term birth at 18 years of age [DNA methylation may provide insight into the long-term effects of PTB. In a comparison of children born preterm and at term, Relton and colleagues measured methylation of numerous genes at birth and reported an association with body size at approximately 9 years ; methylas of age . DespiteIGF2, GNASAS, INSIGF and LEP) and small for gestational age (SGA) among primarily preterm neonates [There are numerous challenges to incorporating DNA methylation into PTB studies as evidenced by the paucity of literature on the subject. The studies performed to date are conducted with relatively small sample sizes or limited to specific genes. While many findings have been reproducible, larger studies will identify differences of more subtle effect sizes. Another challenge involves the rates of extreme, early and late preterm inclusions as well as variations in fetal characteristics such as birth weight. For example, a study evaluated the association between DNA methylation in four genes (neonates . They reMany studies conducted to date exclusively collect samples at the time of delivery. While these cross-sectional studies provide insight into differences in methylation patterns between preterm and normal-term infants, they are not well suited to illuminate the consequences of those differences. While there are numerous DNA methylation differences between PTB and term births, similar differences are observed across gestational ages . DespiteTo assess the potential effects of DNA methylation on spontaneous parturition, rigorous studies examining DNA methylation signatures during pregnancy are necessary. Establishment of epigenetic reference panels in multiple tissues throughout pregnancy and early development will serve as an important resource for interpreting the functional significance of PTB-associated DNA methylation differences that have already been identified. Prospective studies should be conducted to include longitudinal sampling at varying time points during pregnancy, with follow up in the child and mother following preterm delivery. The field would further benefit by inclusion of clinical samples, such as amniocentesis or cell free fetal DNA, in those reference panels. This will allow researchers to better understand the factors that promote epigenetic differences and the predictive value of those differences.