The impact of chorionicity on pregnancy outcome and neurodevelopment at 2 years old among twins born preterm: the EPIPAGE-2 cohort study.

OBJECTIVE: To compare the short- and mid-term outcomes of preterm twins by chorionicity of pregnancy. DESIGN: Prospective nationwide population-based EPIPAGE-2 cohort study. SETTING: 546 maternity units in France, between March and December 2011. POPULATION: A total of 1700 twin neonates born between 24 and 34 weeks of gestation. METHODS: The association of chorionicity with outcomes was analysed using multivariate regression models. MAIN OUTCOME MEASURES: First, survival at 2-year corrected age with or without neurosensory impairment, and second, perinatal, short-, and mid-term outcomes (survival at discharge, survival at discharge without severe morbidity) were described and compared by chorionicity. RESULTS: In the EPIPAGE 2 cohort, 1700 preterm births were included (850 twin pregnancies). In all, 1220 (71.8%) were from dichorionic (DC) pregnancies and 480 from monochorionic (MC) pregnancies. MC pregnancies had three times more medical terminations than DC pregnancies (1.67 versus 0.51%, P < 0.001), whereas there were three times more stillbirths in MC than in DC pregnancies (10.09 versus 3.78%, P < 0.001). Both twins were alive at birth in 86.6% of DC pregnancies compared with 80.0% among MC pregnancies (P = 0.008). No significant difference according to chorionicity was found regarding neonatal deaths and morbidities. Likewise, for children born earlier than 32 weeks, the 2-year follow-up neurodevelopmental results were not significantly different between DC and MC twins. CONCLUSIONS: This study confirms that MC pregnancies have a higher risk of adverse outcomes. However, the outcomes among preterm twins admitted to neonatal intensive care units are similar irrespective of chorionicity. TWEETABLE ABSTRACT: Monochorionicity is associated with adverse perinatal outcomes, but outcomes for preterm twins are comparable irrespective of their chorionicity.

Gut microbiota analysis reveals a marked shift to bifidobacteria by a starter infant formula containing a synbiotic of bovine milk-derived oligosaccharides and Bifidobacterium animalis subsp. lactis†CNCM I-3446.

Non-digestible milk oligosaccharides were proposed as receptor decoys for pathogens and as nutrients for beneficial gut commensals like bifidobacteria. Bovine milk contains oligosaccharides, some of which are structurally identical or similar to those found in human milk. In a controlled, randomized double-blinded clinical trial we tested the effect of feeding a formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS) generated from whey permeate, containing galacto-oligosaccharides and 3'- and 6'-sialyllactose, and the probiotic Bifidobacterium animalis subsp. lactis (B. lactis) strain CNCM I-3446. Breastfed infants served as reference group. Compared with a non-supplemented control formula, the test formula showed a similar tolerability and supported a similar growth in healthy newborns followed for 12 weeks. The control, but not the test group, differed from the breast-fed reference group by a higher faecal pH and a significantly higher diversity of the faecal microbiota. In the test group the probiotic B. lactis increased by 100-fold in the stool and was detected in all supplemented infants. BMOS stimulated a marked shift to a bifidobacterium-dominated faecal microbiota via increases in endogenous bifidobacteria (B. longum, B. breve, B. bifidum, B. pseudocatenulatum).

Posture and movement in very preterm infants at term age in and outside the nest.

OBJECTIVE: The objective of this study is to evaluate the use of nests on general movements (GM) and posture in very preterm infants at term age. METHOD: Seventeen high-risk preterm infants-less than 30 weeks of gestation (GA)-underwent a video recording, lying in supine position, with or without nest. Posture, GM quality, and movements made around the child's midline, as well as abrupt movements and frozen postures-in extension or flexion of the four limbs-were analyzed. RESULTS: Nest did not modify quality of GM. Children significantly adopted a curled-up position. The nest system was associated with an increase in movements toward or across the midline, as well as reduction of the hyperextension posture and head rotation movements. Frozen postures in flexion or extension, as well as abrupt movements of the four limbs, were reduced but not significantly. CONCLUSIONS: Nest helps very preterm infants to adopt semi-flexed posture and facilitates movements across the midline and reduces movements of spine hyperextension, without GM global quality modifications.

Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview.

Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Premature newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intestinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC­PUFA, sphingomyelin, IGF­I and IGF­II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC­PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR­2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC­1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC­PUFA, lactoferrin, probiotics, prebiotics). A synergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action.

Preterm birth affects dorsal-stream functioning even after age 6.

With increasing numbers of preterm infants surviving, the impact of preterm birth on later cognitive development presents a major interest. This study investigates the impact of preterm birth on later dorsal- and ventral-stream functioning. An atypical pattern of performance was found for preterm children relative to full-term controls, but in the dorsal-drawing task only. These findings suggest that the number of gestational weeks does affect dorsal-stream functioning, even after more than 6 years of favorable environmental conditions in healthy preterm children.

[Newborn outcomes after radiofrequency ablation for selective reduction in the complicated monochorionic pregnancies]. / Devenir neurodéveloppemental des nouveau-nés issus de grossesses monochoriales compliquées avec interruption sélective par ablation par radiofréquence.

OBJECTIVE: To describe perinatal data and to evaluate the neonatal neurological outcome of monochorionic twin pregnancies with selective termination by radiofrequency ablation. METHODS: Retrospective data of perinatal data for nine consecutive monochorionic pregnancies eligible for radiofrequency ablation from January 2013 to August 2015 were collected. A prospective observational study of the neurological outcome of nine children was conducted using the Ages & Stages Questionnaire (ASQ), 2nd edition, French version, adapted to the age. RESULTS: The radiofrequency procedures were performed at a mean gestational age (GA) of 21.4 weeks (±7 weeks). The indications for a selective interruption of a pregnancy were: acardiac twin (n=4), brain malformation (n=1), severe intrauterine growth restriction (IUGR) with massive cerebral ischemia in the context of twin-twin transfusion syndrome grade III (n=1), severe selective IUGR associated with a polymalformative syndrome (n=1) and severe selective IUGR (n=2). The mean GA at birth was 36.7 weeks GA (±3.8 weeks). No infant showed neurological neonatal morbidity. Any ASQ area explored was pathological (<-2SD) for the nine children (mean age at follow-up [±SD], 14.8 months [±8.8 months]). CONCLUSION: This work constitutes a preliminary study for developing long-term follow-up and early care programs for those children born subsequent to a radiofrequency ablation for selective reduction.

Leigh syndrome: pyruvate dehydrogenase defect. A case with peripheral neuropathy.

Pyruvate dehydrogenase deficiency is one of the most common causes of encephalopathy associated with lactic acidosis and is known to account for congenital lactic acidosis, recurrent ataxia, and infantile Leigh syndrome. Hitherto, however, peripheral neuropathy has not been regarded as a presenting symptom of pyruvate dehydrogenase deficiency. Here, we report on a boy who presented peripheral neuropathy with severe limb hypotonia, absent deep-tendon reflexes, and reduced motor nerve conduction velocities at 8 months of age. Persistent hyperpyruvicemia with normal lactate/pyruvate molar ratios in plasma were highly suggestive of a pyruvate dehydrogenase deficiency, and the determination of pyruvate dehydrogenase activity in circulating lymphocytes led to the diagnosis of pyruvate decarboxylase (PDH-E1) deficiency in the proband. Based on this observation, we suggest that pyruvate dehydrogenase deficiency should be considered in the diagnosis of peripheral neuropathy in infancy, especially when associated with persistent hyperpyruvicemia, normal lactate/pyruvate molar ratios in plasma, and recurrent episodes of drowsiness and hypotonia of unknown origin.

[Early cerebral MRI in preterm infants: correlations with EEG and outcome]. / Intérêt de la réalisation d'une IRM cérébrale précoce chez le prématuré: corrélation avec l'EEG et le devenir.

AIM OF THE STUDY: Assess the potential benefits of performing an early cerebral MRI to evaluate the gravity of cerebral lesions among premature neonates at risk of neurologic sequels and establish correlations between EEG findings, abnormal neuroimaging findings and neurodevelopment. METHODS: A MRI was performed in 34 premature newborn babies with abnormal neurological clinical signs, and/or with two abnormal EEG and/or with two abnormal cerebral ultrasound scans. The mean age and the adjusted age of our population were 5 weeks (range 1-11 weeks) and 35 weeks of adjusted age (range 29-40 weeks) respectively. The neuroimaging findings were correlated to the results of three EEGs (recorded before 15 days old, between 15 days and one month old, and after the first month of life) and to neurodevelopment. RESULTS: Two statically significant correlations were found between: 1) the severity of brain injuries observed in MRI and the results of the latest EEG (sensitivity 100%, specificity 60%), 2) the severity of brain injuries observed in MRI and abnormal neurodevelopment (sensitivity 75%, specificity 80%). There was no correlation between the abnormal development and the results of EEG recordings. CONCLUSION: Early cerebral MRI is justified in a selected premature population. It is useful for the diagnosis, the evaluation of the severity of brain injury and for the management of these children. The correlation with EEGs traces allows the detection of the majority of prematures babies that will develop sequels.

[Hypoxic-ischemic encephalopathy in the full-term newborn. Contribution of electroencephalography and MRI or computed tomography to its prognostic evaluation. Apropos of 26 cases]. / Encéphalopathie hypoxo-ischémique du nouveau-né à terme. Apport de l'électroencéphalogramme et de l'IRM ou de la TDM à l'évaluation pronostique. A propos de 26 observations.

OBJECTIVES: Perinatal asphyxia complicated by hypoxic ischemic brain injury still remains the source of neurological lesions often serious and definitive. A major aim of neonatologists is to appreciate the severity of the hypoxic ischemic brain injury in the first days of life and to evaluate the forecast. The purpose of this work is to establish a relation between clinical signs, EEG, neuroimaging (MRI and CTS) and neuro-development. MATERIALS AND METHODS: 26 neonates from paediatric resuscitation unit (Hospital North, Marseille) were enrolled in a retrospective study since February 1994 to December 1997. All the newborns had at least one anamnestic criteria of perinatal asphyxia, an early electroencephalogram in the first two days of life and another between the third and the seventh day of life, and neuroimaging in the first 15 days of life: CTS in five cases and MRI in 21 cases. RESULTS: There was a good electro-clinic (P: 0.01) and prognostic (P: 0.03) correlation in patients within stage 3 of the "Sarnat classification". In the stage 2, the EEG did not provide valuable information about severity of the injury, and neuroimaging (especially MRI) allowed better prognosis. Diffuse brain injury or lesions of basal ganglia in MRI were associated, independently of clinical settings and EEG tracings, with a poor neurodevelopmental outcome (P: 0.02). The MRI was diagnostic in four cases of congenital encephalopathy complicated with neonatal suffering. CONCLUSION: Our study confirms the interest of the association of clinical settings, EEG tracings and MRI in the diagnosis and the prognostic of the hypoxic-ischemic encephalopathy in term neonate.

Epileptic nystagmus: electroclinical study of a case.

Epileptic nystagmus (EN) is a rare form of nystagmus that occurs only during epileptic seizures. We report a case in which EN was first noted in an 8 year-old boy. Neuro-imaging was normal. Sharp waves from the left occipital lobe characterised the interictal EEG. Ictal video-EEG showed the aspects of electric seizures during clinical manifestations e.g. nystagmus. Ambulatory EEG displayed numerous diurnal and nocturnal seizures, but exclusively in REM sleep. After two weeks of sodium valproate treatment, the seizures, EEG focus spikes and nystagmus, as well as the squint, disappeared. During a two-year follow-up the child had no further seizures, EEG was normal and the school performance was unaffected. This case has the main features of benign epilepsy, although there are unusual features such as epileptic nystagmus, permanent squint, reduction of EEG paroxysmal abnormalities during NREM, and the presence of seizures during REM sleep. The observation and the significance of EN are discussed with reference to the literature.

[Neonatal hyperthyroidism in a premature infant born to a mother with Grave's disease]. / Hyperthyroïdie néonatale chez un prématuré né de mère atteinte d'une maladie de Basedow.

BACKGROUND: Neonatal thyrotoxicosis is most commonly due to transplacental transfer of maternal thyroid-stimulating hormone receptor antibodies (TRAb). Bioassay of thyrotropin receptor antibodies may help to determine the risk for neonatal hyperthyroidism. CASE REPORT: Thyrotoxicosis developed in a premature infant born to a mother with Graves' disease, with a low level of TRAb by bioassay. The infant was treated with carbimazole for two months, until TRAb had disappeared. CONCLUSION: Bioassay TRAb is not always reliable for predicting the development of neonatal hyperthyroidism in infants born to mothers with Graves' disease. Thyroid function should be measured in all these neonates.

[Treatment of infantile visceral leishmaniasis]. / Traitement de la leishmaniose viscérale infantile.

Visceral leishmaniasis is an endemic disease in the Mediterranean Basin. Children are one of the targets of the infection. Treatment usually requires parenteral injections of pentavalent antimony (Glucantime or Pentostam), but the high frequency of adverse events and the occurrence of primary or secondary resistance cases limit the use of these medications. Diamidines (Pentacarinat) or amphotericin B derivatives are alternatives to antimony. Unfortunately, pharmacokinetics and optimal dosage of diamidines are not well-known, and numerous adverse events are described. Liposomal preparations of amphotericin B enhance its efficiency and tolerance, and the duration of treatment may be reduced to 5 days. Moreover, primary resistance to amphotericin B is not described in immunocompetent children. Allopurinol associated with antimony seems no more efficient than antimony alone. Aminosidine is not evaluated.

[Imaging of neonatal neurological disorders]. / Imagerie des désordres neurologiques néonataux.

Neonatal brain disorders consist of a wide chapter including brain malformations, hypoxic-ischemic encephalopathy, intracranial infections, perinatal trauma and metabolic encephalopathies. The aim of this review paper is to describe the main imaging modalities (ultrasonography, CT, MRI) that are used extensively for the diagnosis of neonatal brain disorders, with their respective advantages and limitations, to illustrate and describe the main brain lesions encountered in the neonatal period, particularly with MRI since its role has increased over the recent years. We will focus on hypoxic-ischemic encephalopathy, materno-fetal infections, metabolic encephalopathies and stroke, those four conditions being the most frequent so far. Imaging modalities, especially MRI, by showing the extent of brain damage, are part of the prognostic factors in cases of infective causes and of hypoxic-ischemic origin. MRI is also very efficient in showing brain damage as atrophy and white matter abnormalities suggestive of an underlying abnormal brain of metabolic origin.

[MRI and in utero ventriculomegaly]. / IRM et ventriculomégalie in utero.

Ventriculomegaly constitutes the major indication of fetal brain MRI. MRI is therefore of utmost importance to look for a cause through the depiction of criteria of malformations and through the definition of criteria of destructive lesions. Malformations and destructive lesions are the most common causes of ventricular dilatation. Some challenging points are worth mentioning in term of mechanism with the challenge of hydrocephalus (in term of increased in intracranial pressure) and of isolated ventriculomegaly. The image itself is also challenging since a similar image may be of different origin. In term of natural history of fetal brain injury an irregular, nodular aspect of the ventricular wall and/or the germinal matrix is often the only pathologic MRI finding that is known to be of clastic origin. In term of prognosis the challenge is represented by the isolated mild ventriculomegaly, the literature being quite confusing. The purpose of this review paper is to highlight the underlying mechanisms and pathophysiology of ventricular dilatation based on results from the literature as well as from personal experience.

[Neonatal consequences of preterm premature rupture of membrane (PPROM) at 24-34 WG: 118 singleton pregnancies]. / Conséquences néonatales de la rupture prématurée des membranes entre 24 et 34 semaines d'aménorrhée: à propos de 118 grossesses uniques.

OBJECTIVES: To evaluate the outcome of preterm infants born after preterm premature rupture of membranes (PPROM) between 24 and 34 weeks gestation (WG). METHODS: One hundred and eighteen consecutive singleton infants were included in a prospective unicenter study during 3 years. A PPROM management had been instituted by the local obstetrician's board committee. In case of suspected chorioamniotitis defined by maternal or fetal criteria or in case of fetal heart rate abnormalities, a fetal extraction was decided. Diagnosis of chorioamnionitis was confirmed regarding the results of placenta culture and/or histology. Neonatal sepsis was defined by positive blood placenta culture or by the association of 2 positive bacterial cultures with a CRP>15 mg/l. RESULTS: The mean gestational age was 29.8 WG (24-34 SA) for PPROM and 30.4 WG for delivery. Mean latency period between PPROM and delivery was 119 hours +/- 208. The incidence of choriamnionitis was 31%. The overall incidence of neonatal sepsis was 15%. Neonatal mortality was 11.7%. Bronchopulmonary dysplasia occured in 8.4% of the liveborn cases and cranial ultrasound abnormalities (HIV III-IV, kystic LPV) in 11.7% of overall cases. Cerebral lesions were positively correlated with hypotension and negatively correlated with GA. Cerebral lesions seemed to occur more frequently in case of chorioamnionitis but it is not significant. CONCLUSION: In this study, in case of PPROM between 24-34 SA, gestational age and hypotension are correlated with neurologic injury.

[Prenatal diagnosis of fetal goiter revealing iodine utilization defect]. / Goitre néonatal découvert in utero, révélateur d'un trouble de l'organification de l'iode.

We report on a case of fetal goitrous diagnosed on ultrasonogram done at 31 weeks of gestation. Thyroid maternal function was normal and no therapeutic was responsible. Hormonal test done on cord blood supported diagnosis of prenatal hypothyroidism. The infant was born prematurely at gestation age of 34 without antenatal treatment. He was eutrophic with clinical and biological signs of hypothyroidism and a large goiter. Therapy with thyroxine was instituted on the third day of life. At 9 months, growth and development are normal. Congenital hypothyroidism has an incidence of approximately 1 in every 4000-5000 live births. Rarely fetal goitrous hypothyroidism have been attributed to thyroid hormone dyshormonogenesis. When fetal goiter is diagnosed on ultrasonography, without maternal hypothyroidism or therapeutic and when hypothyroidism is confirmed on fetal blood, this diagnosis must be suspected.

[Congenital toxoplasmosis and cerebral involvement inspite of prenatal treatment]. / Toxoplasmose congénitale et atteinte cérébrale malgré un traitement anténatal.

BACKGROUND: Maternal toxoplasmosis seroconversion during the first trimester of pregnancy raises an important risk of toxoplasmic fetopathy. CASE REPORT: Primary toxoplasmosis was identified between 9 and 17 weeks of gestation. PCR analysis of the amniotic fluid confirmed fetal infection. The mother was given a sulfadoxine-piremythamine combination and monthly ultrasonographic surveillance was initiated. At birth, the female infant was found to have diffuse cortical lesions and a chorioretinitis compatible with toxoplasmic fetopathy. She was given sulfadoxine-piremythamine. At 2 years, the clinical and neuroradiological course has been favorable. CONCLUSION: Despite antenatal and postnatal treatment and despite ultrasonographic surveillance, it is difficult to predict the course of congenital toxoplasmosis. This case illustrates the importance of informing parents of the risk and the requirement for careful follow-up after antenatal diagnosis of first-trimester toxoplasmosis.

[Prenatal screening of kidney pelvis ectasia, frequently caused by vesico-ureteral reflux detected after birth. Analysis of a series of 159 cases in 4 years at a maternal-child unit]. / Le dépistage anténatal des ectasies pyéliques, souvent dues à un reflux vésico-urétéral dépisté après la naissance. Analyse d'une série de 159 dépistages en 4 ans dans une unité mère-enfant.

UNLABELLED: To describe the pre- and post-natal management of vesico-ureteric reflux in a prospective study of babies presenting with vesico-ureteric reflux suspected from pre-natal ultrasonography in a tertiary paediatric center. PATIENTS AND METHODS: Between 1997 and 2001, 35 children (25 boys and 10 girls) with were vesico-ureteric reflux followed for 12 to 36 months after the pre-natal detection of urinary tract anomalies. Ultrasound examination was realized at the 5th of life, retrograde cystography at the 15th if the renal pelvic dilatation measured at least 10 mm of diameter. In 11 the reflux was bilateral and 46 refluxing units were reviewed. RESULTS: According to the international classification of, 7% vesico-ureteric reflux were grade I, 20.5% were grade II, 32% were grade III, 18% were grade IV, 22.5% were grade V. Fourteen patients (17 refluxing units) underwent ureteric-reimplantation. Four total and two partial nephrectomics were carried out in patients < 2 years old; in 8 patients the VUR resolved spontaneously. Of the latter, 7 patients (ten refluxing grade III-IV units) are still being followed and awaiting a decision on treatment. CONCLUSION: This study confirms the predominance of boys in those with antenatally suspected vesico-ureteric reflux. The spontaneous resolution or improvement during the first 3 years of life was apparent in most cases, even in those with severe reflux (grade III-V).

[Palliative care birth plan: a field of perinatal medicine to build]. / Projets de naissance en soins palliatifs : un domaine de la périnatalité à construire.

Some couples may choose to continue the pregnancy unable to decide for termination of pregnancy. Such situations recently occurred in neonatology units and may lead to neonatal palliative care. Faced with all uncertainties inherent to medicine and the future of the baby, medical teams must inform parents of different possible outcome step by step. Consistency in the reflection and intentionality of the care is essential among all different stakeholders within the same health team to facilitate support of parents up to a possible fatal outcome. This issue in perinatal medicine seems to be to explore how caregivers can contribute in the construction of parenthood in a context of a palliative care birth plan.

Quality of life of early school-age French children born preterm: a cohort study.

OBJECTIVES: To describe the health-related quality of life (HRQL) of a cohort of children aged 6-10 years who were born preterm; and to determine whether sociodemographic factors, neonatal features and neurocognitive status were affecting their HRQL. STUDY DESIGN: All singleton infants born between 24 and 32 weeks of gestation between January 1997 and December 2001 at the study hospital, who were still alive in 2007 (age 6-10 years), and who had undergone complete clinical paediatric follow-up were included in the study. Maternal and perinatal data were obtained by chart review and regular clinical examination. The 'Battery for Rapid Evaluation of Cognitive Functions' (BREV) was used for cognitive evaluation when children were aged 4-8 years. HRQL data were collected in 2007 using the 'Vécu et Santé Perçue de l'Adolescent et de l'Enfant' (VSP-A) questionnaire (parent version). The HRQL of the preterm children was compared with that of a French reference population. RESULTS: Of 202 children who fulfilled the inclusion criteria, 82 children participated in the study. Their mean age was 7.9 years [standard deviation (SD) 1.4], mean birth weight was 1130.0 g (SD 361.4), 23 children were born before 28 weeks of gestation, 46 were female and 11 had major neurocognitive disorders. These data were not significantly different for the non-respondents (n=120). Parents of preterm children reported a significantly lower perception of HRQL of their child compared with parents of children in the reference population, as reflected by VSP-A global index scores and scores for the 'body image', 'vitality', 'psychological well-being' and 'school performance' dimensions. In multivariate analyses, three factors were found to be significantly associated with at least one dimension in the VSP-A scale in the preterm children: presence of major neurocognitive disorders, negatively correlated with 'vitality', 'relationships with friends', 'physical well-being' and 'school performance' dimensions; maternal parity, positively correlated with the 'psychological well-being' dimension; and socio-economic status of family, positively correlated with the 'relationships with friends' dimension. The maximum R(2) was 15%. CONCLUSION: In addition to neurocognitive disorders, other variables such as socio-economic status of the family have a significant impact on the HRQL of preterm children at 6-10 years of age. Given the low proportion of variability in HRQL explained by the models, there is a need to explore other factors (e.g. environmental).