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1.  Maternal Factors Associated with Fetal Growth and Birthweight Are Independent Determinants of Placental Weight and Exhibit Differential Effects by Fetal Sex 
PLoS ONE  2014;9(2):e87303.
Maternal nutritional and metabolic factors influence the developmental environment of the fetus. Virtually any nutritional factor in the maternal blood has to pass the placental membranes to reach the fetal blood. Placental weight is a commonly used measure to summarize placental growth and function. Placental weight is an independent determinant of fetal growth and birthweight and modifies the associations between maternal metabolic factors and fetal growth. We hypothesized that maternal factors known to be related to fetal growth, newborn size and body composition are determinants of placental weight and that effects of maternal metabolic factors on placental weight differ between the genders.
The STORK study is a prospective longitudinal study including 1031 healthy pregnant women of Scandinavian heritage with singleton pregnancies. Maternal determinants (parity, body mass index, gestational weight gain and fasting plasma glucose) of placental weight were explored by linear regression models, stratified by fetal sex.
Parity, maternal BMI, gestational weight gain and fasting glucose had positive effects on placental weight. There was a sex specific effect in these associations. Fasting glucose was significantly associated with placental weight in females but not in males.
Maternal factors known to influence fetal growth, birthweight and neonatal body composition are determinants of placental weight. The effect of maternal factors on placental weight is influenced by sex as illustrated in the relation between maternal glucose and placental weight.
PMCID: PMC3916298  PMID: 24516548
2.  Maternal Psychological Distress and Placental Circulation in Pregnancies after a Previous Offspring with Congenital Malformation 
PLoS ONE  2014;9(1):e86597.
Antenatal maternal psychological distress may be associated with reduced placental circulation, which could lead to lower birthweight. Studies investigating this in humans show mixed results, which may be partially due to type, strength and timing of distress. In addition, the arterial vascular resistance measures often used as outcome measures do not detect smaller changes in placental volume blood flow. We aimed to investigate the effect of a specific stressor, with increased levels of stress early in pregnancy, on the fetoplacental volume blood flow in third trimester.
This was a prospective observational study of 74 pregnant women with a congenital malformation in a previous fetus or child. Psychological distress was assessed twice, around 16 and 30 weeks' gestation. Psychometric measures were the General Health Questionnaire-28 (subscales anxiety and depression), Edinburgh Postnatal Depression Scale, and Impact of Event Scale-22 (subscales intrusion, avoidance, and arousal). Placental circulation was examined at 30 weeks, using Doppler ultrasonography, primarily as fetoplacental volume blood flow in the umbilical vein, normalized for abdominal circumference; secondarily as vascular resistance measures, obtained from the umbilical and the uterine arteries.
Maternal distress in second but not third trimester was associated with increased normalized fetoplacental blood flow (P-values 0.006 and 0.013 for score > mean for depression and intrusion, respectively). Post-hoc explorations suggested that a reduced birthweight/placental weight ratio may mediate this association. Psychological distress did not affect vascular resistance measures in the umbilical and uterine arteries, regardless of adjustment for confounders.
In pregnant women with a previous fetus or child with a congenital malformation, higher distress levels in second trimester were associated with third trimester fetoplacental blood flow that was higher than expected for the size of the fetus. The results do not support placental blood flow reduction as a pathway between maternal distress and reduced birthweight.
PMCID: PMC3903559  PMID: 24475155
3.  Paternal psychological response after ultrasonographic detection of structural fetal anomalies with a comparison to maternal response: a cohort study 
In Norway almost all pregnant women attend one routine ultrasound examination. Detection of fetal structural anomalies triggers psychological stress responses in the women affected. Despite the frequent use of ultrasound examination in pregnancy, little attention has been devoted to the psychological response of the expectant father following the detection of fetal anomalies. This is important for later fatherhood and the psychological interaction within the couple. We aimed to describe paternal psychological responses shortly after detection of structural fetal anomalies by ultrasonography, and to compare paternal and maternal responses within the same couple.
A prospective observational study was performed at a tertiary referral centre for fetal medicine. Pregnant women with a structural fetal anomaly detected by ultrasound and their partners (study group,n=155) and 100 with normal ultrasound findings (comparison group) were included shortly after sonographic examination (inclusion period: May 2006-February 2009). Gestational age was >12 weeks. We used psychometric questionnaires to assess self-reported social dysfunction, health perception, and psychological distress (intrusion, avoidance, arousal, anxiety, and depression): Impact of Event Scale. General Health Questionnaire and Edinburgh Postnatal Depression Scale. Fetal anomalies were classified according to severity and diagnostic or prognostic ambiguity at the time of assessment.
Median (range) gestational age at inclusion in the study and comparison group was 19 (12–38) and 19 (13–22) weeks, respectively. Men and women in the study group had significantly higher levels of psychological distress than men and women in the comparison group on all psychometric endpoints. The lowest level of distress in the study group was associated with the least severe anomalies with no diagnostic or prognostic ambiguity (p < 0.033). Men had lower scores than women on all psychometric outcome variables. The correlation in distress scores between men and women was high in the fetal anomaly group (p < 0.001), but non-significant in the comparison group.
Severity of the anomaly including ambiguity significantly influenced paternal response. Men reported lower scores on all psychometric outcomes than women.
This knowledge may facilitate support for both expectant parents to reduce strain within the family after detection of a fetal anomaly.
PMCID: PMC3724589  PMID: 23845090
Fetal anomaly; Paternal psychological response; Pregnancy; Prenatal diagnosis; Psychological distress; Ultrasonography
4.  Does Antenatal Maternal Psychological Distress Affect Placental Circulation in the Third Trimester? 
PLoS ONE  2013;8(2):e57071.
Some types of antenatal maternal psychological distress may be associated with reduced fetal growth and birthweight. A stress-mediated reduction in placental blood flow has been suggested as a mechanism. Previous studies have examined this using ultrasound-derived arterial resistance measures in the uterine (UtA) and umbilical (UA) arteries, with mixed conclusions. However, a reduction in placental volume blood flow may occur before changes in arterial resistance measures are seen. Fetoplacental volume blood flow can be quantified non-invasively in the umbilical vein (UV). Our objective was to study whether specific types of maternal psychological distress affect the placental circulation, using volume blood flow quantification in addition to arterial resistance measures.
This was a prospective observational study of 104 non-smoking pregnant women (gestational age 30 weeks) with uncomplicated obstetric histories. Psychological distress was measured by General Health Questionnaire-28 (subscales anxiety and depression) and Impact of Event Scale-22 (subscales intrusion, avoidance and arousal). UtA and UA resistance measures and UV volume blood flow normalized for fetal abdominal circumference, were obtained by Doppler ultrasound.
IES intrusion scores above the mean were associated with a reduction in normalized UV volume blood flow (corresponding to –0.61 SD; P = 0.003). Adjusting for UA resistance increased the strength of this association (difference –0.66 SD; P<0.001). Other distress types were not associated with UV volume blood flow. Maternal distress was not associated with arterial resistance measures, despite adjustment for confounders.
Intrusive thoughts and emotional distress regarding the fetus were associated with reduced fetoplacental volume blood flow in third trimester. Uterine and umbilical artery resistance measures were not associated with maternal distress. Our findings support a decrease in fetoplacental blood flow as a possible pathway between maternal distress and reduced fetal growth.
PMCID: PMC3577751  PMID: 23437312
5.  Fetal Liver Blood Flow Distribution: Role in Human Developmental Strategy to Prioritize Fat Deposition versus Brain Development 
PLoS ONE  2012;7(8):e41759.
Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.
PMCID: PMC3425554  PMID: 22927915
6.  Fetal Growth versus Birthweight: The Role of Placenta versus Other Determinants 
PLoS ONE  2012;7(6):e39324.
Birthweight is used as an indicator of intrauterine growth, and determinants of birthweight are widely studied. Less is known about determinants of deviating patterns of growth in utero. We aimed to study the effects of maternal characteristics on both birthweight and fetal growth in third trimester and introduce placental weight as a possible determinant of both birthweight and fetal growth in third trimester.
The STORK study is a prospective cohort study including 1031 healthy pregnant women of Scandinavian heritage with singleton pregnancies. Maternal determinants (age, parity, body mass index (BMI), gestational weight gain and fasting plasma glucose) of birthweight and fetal growth estimated by biometric ultrasound measures were explored by linear regression models. Two models were fitted, one with only maternal characteristics and one which included placental weight.
Placental weight was a significant determinant of birthweight. Parity, BMI, weight gain and fasting glucose remained significant when adjusted for placental weight. Introducing placental weight as a covariate reduced the effect estimate of the other variables in the model by 62% for BMI, 40% for weight gain, 33% for glucose and 22% for parity. Determinants of fetal growth were parity, BMI and weight gain, but not fasting glucose. Placental weight was significant as an independent variable. Parity, BMI and weight gain remained significant when adjusted for placental weight. Introducing placental weight reduced the effect of BMI on fetal growth by 23%, weight gain by 14% and parity by 17%.
In conclusion, we find that placental weight is an important determinant of both birthweight and fetal growth. Our findings indicate that placental weight markedly modifies the effect of maternal determinants of both birthweight and fetal growth. The differential effect of third trimester glucose on birthweight and growth parameters illustrates that birthweight and fetal growth are not identical entities.
PMCID: PMC3377679  PMID: 22723995

Results 1-6 (6)