Use of antidepressants during pregnancy in the Netherlands: observational study into postpartum interventions.

BACKGROUND: Psychiatric disorders and use of selective antidepressants during pregnancy can have negative effects on mother and infant postpartum. This study aimed to provide evidence-based recommendations on observation of antidepressant-exposed mother-infant dyads. METHODS: In this observational study, mother-infant dyads were observed for possible consequences of either the maternal psychiatric disorder or fetal exposure to selective antidepressants during pregnancy. These possible complications can lead to medical interventions, including 1. adjustment of antidepressants 2. admission to the psychiatric department 3. additional investigations due to indistinctness about the origin of neonatal symptoms 4. treatment of poor neonatal adaptation and 5. consultation of an external organization for additional care. The type, number and time to medical interventions were analyzed. RESULTS: In 61% of the 324 included mother-infant dyads one or more intrventions were performed. Adjustment of antidepressants and treatment of poor neonatal adaptation were most prevalent. In 75% of dyads the final intervention was performed within 48 h. CONCLUSIONS: The high prevalence and type of medical interventions requires professional observation of all mother-infant dyads exposed to selective antidepressants. In the absence of specialized home care, hospital admission is indicated whereby an observational period of 48 h seems sufficient for most dyads.

Serotonin and poor neonatal adaptation after antidepressant exposure in utero.

OBJECTIVE: Infants exposed to selective antidepressants (SADs) in utero are at risk to develop poor neonatal adaptation (PNA) postpartum. As symptoms are non-specific and the aetiology of PNA is unknown, the diagnostic process is hampered. We hypothesised that the serotonin metabolism plays a role in the aetiology of PNA. METHODS: In this controlled study, infants admitted postpartum from February 2012 to August 2013 were included and followed for 3 days. Infants exposed to SADs during at least the last 2 weeks of fetal life were included in the patient group (n=63). Infants not exposed to psychotropic medication and admitted postpartum for another reason were included in the control group (n=126). The neonatal urinary 5-hydroxyindoleacetid acid (5-HIAA) levels of SAD-exposed infants who developed PNA, SAD-exposed infants who did not develop PNA and control infants were compared. RESULTS: The course of the 5-HIAA levels over the first 3 days postpartum differed between infants with and without PNA (p≤0.001) with higher 5-HIAA levels in infants with PNA on day 1 (2.42 mmol/mol, p=0.001). Presence of maternal psychological distress modified this relationship. CONCLUSIONS: A transient disturbance of the neonatal serotonergic system may play a role in the aetiology of PNA. Other factors, including the presence of maternal psychological distress, also seem to play a role.

Risk factors for poor neonatal adaptation after exposure to antidepressants in utero.

AIM: Infants exposed to antidepressants in utero are at risk of developing poor neonatal adaptation (PNA). This study identified risk factors for PNA. METHODS: In this cohort study, data on mothers and infants admitted to the maternity ward of a general hospital between 2007 and 2012 were analysed. All infants were exposed to an antidepressant during the last trimester of foetal life. The main outcome measure was PNA, defined as at least one Finnegan scores of four or more during admission. Risk factors analysed for their possible association with PNA included type of feeding, type and dosage of antidepressant, prematurity and maternal smoking, anxiety and depression. RESULTS: We included 247 infants in the study and 157 (64%) developed PNA. Formula feeding was associated with an increased risk of PNA compared to breastfeeding or mixed feeding (OR 3.16 95% CI 1.40-7.13 p = 0.003). Selective serotonin reuptake inhibitors (SSRIs) were associated with an increased risk of PNA compared to serotonin and noradrenaline reuptake inhibitors (OR 2.52 95% CI 1.07-5.95 p = 0.04). Dosage did not influence the risk of PNA (OR 1.50 95% CI 0.89-2.52 p = 0.13). CONCLUSION: Formula feeding and exposure to SSRIs were associated with development of PNA, but dosage was not.

LC-MS/MS-based reference intervals for hair cortisol in healthy children.

BACKGROUND: Human scalp hair is a valuable matrix for determining long-term cortisol concentrations, with wide-spread applicability in clinical care as well as research. However, pediatric reference intervals are lacking. The aim of this cross-sectional study is to establish age-adjusted reference intervals for hair cortisol in children and to gain insight into hair growth velocity in children up to 2 years old. METHODS: A total of 625 healthy children were enrolled through recruitment in pregnancy, infant-welfare clinics, and school visits. Scalp hair cortisol levels were measured using liquid chromatography-tandem mass spectrometry. Age-adjusted reference intervals were established in children from birth to 18 years old. Hair growth velocity was determined in children 0-2 years of age by measuring hair length at 4- to 10-week intervals. RESULTS: Hair cortisol levels were high (162.4 pg/mg, 2.5th-97.5th percentile: 28.8-961) after birth with a sharp fall in the first 3 months of life. This is followed by lower values until age 6 and then by graduated and subtle higher values to adult concentrations are reached at the age of 18 years (3.0 pg/mg, 2.5th-97.5th percentile: 0.53-17.8). Average hair growth velocity measured in mm/month was significantly lower in infants 0-6 months of age compared to children 12-24 months (3.5 versus 9.4, P < 0.001). CONCLUSIONS: This is the first study to provide age-adjusted reference intervals for hair cortisol in children from 0-18 years. Higher hair cortisol concentrations in infants might be explained by the significantly lower hair growth rate in the first year of life. The establishment of pediatric hair cortisol reference ranges broadens the potential applications of this biomarker in pediatric clinical care.

Predicting Early Mortality After Hip Fracture Surgery: The Hip Fracture Estimator of Mortality Amsterdam.

OBJECTIVES: Early mortality after hip fracture surgery is high and preoperative risk assessment for the individual patient is challenging. A risk model could identify patients in need of more intensive perioperative care, provide insight in the prognosis, and allow for risk adjustment in audits. This study aimed to develop and validate a risk prediction model for 30-day mortality after hip fracture surgery: the Hip fracture Estimator of Mortality Amsterdam (HEMA). METHODS: Data on 1050 consecutive patients undergoing hip fracture surgery between 2004 and 2010 were retrospectively collected and randomly split into a development cohort (746 patients) and validation cohort (304 patients). Logistic regression analysis was performed in the development cohort to determine risk factors for the HEMA. Discrimination and calibration were assessed in both cohorts using the area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow goodness-of-fit test, and by stratification into low-, medium- and high-risk groups. RESULTS: Nine predictors for 30-day mortality were identified and used in the final model: age ≥85 years, in-hospital fracture, signs of malnutrition, myocardial infarction, congestive heart failure, current pneumonia, renal failure, malignancy, and serum urea >9 mmol/L. The HEMA showed good discrimination in the development cohort (AUC = 0.81) and the validation cohort (AUC = 0.79). The Hosmer-Lemeshow test indicated no lack of fit in either cohort (P > 0.05). CONCLUSIONS: The HEMA is based on preoperative variables and can be used to predict the risk of 30-day mortality after hip fracture surgery for the individual patient. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Maternal Stress During Pregnancy Is Associated with Decreased Cortisol and Cortisone Levels in Neonatal Hair.

BACKGROUND: Hair glucocorticoids (GCs) offer a retrospective view on chronic GC exposure. We assessed whether maternal pre- and postnatal stress was associated with neonatal and maternal hair GCs postpartum (pp). METHODS: On the first day pp 172 mother-infant pairs donated hair, of whom 67 had consulted a centre of expertise for psychiatric disorders during pregnancy. Maternal stress was scored on the Hospital Anxiety and Depression Scale during the first/second (n = 46), third trimester (n = 57), and pp (n = 172). Hair cortisol and cortisone levels were determined by liquid chromatography-tandem mass spectrometry, and associations with maternal hospital anxiety subscale (HAS) and hospital depression subscale (HDS) scores, and antidepressant use were analyzed with linear regression. RESULTS: Neonatal hair GCs were negatively associated with elevated HAS-scores during the first/second trimester, log 10 (ß [95% CI]) cortisol -0.19 (-0.39 to 0.02) p = 0.07, cortisone -0.10 (-0.25 to 0.05) p = 0.17; third trimester, cortisol -0.17 (-0.33 to 0.00) p = 0.05, cortisone -0.17 (-0.28 to -0.05) p = 0.01; and pp, cortisol -0.14 (-0.25 to -0.02) p = 0.02, cortisone -0.07 (-0.16 to 0.02) p = 0.10. A similar pattern was observed for elevated HDS-scores. Maternal hair GCs were positively associated with elevated HAS-scores pp (cortisol 0.17 [0.01 to 0.32] p = 0.04, cortisone 0.18 [0.06 to 0.31] p = 0.01), but not prenatally or with elevated HDS-scores. Antidepressant use was associated with elevated maternal hair GCs (p ≤ 0.05), but not with neonatal hair GCs. CONCLUSION: Exposure to excessive pre- and perinatal maternal stress was associated with a decrease in neonatal hair GCs, while elevated stress-scores around birth were associated with increased maternal hair GCs and elevated stress-scores earlier in gestation were not associated with maternal hair GCs pp. Further studies are needed to test associations with infant neurodevelopment.

Interpretation of glucocorticoids in neonatal hair: a reflection of intrauterine glucocorticoid regulation?

BACKGROUND: Glucocorticoids (GCs) measured in neonatal hair might reflect intrauterine as well as postpartum GC regulation. We aimed to identify factors associated with neonatal hair GC levels in early life, and their correlation with maternal hair GCs. METHODS: In a single-center observational study, mother-infant pairs (n = 107) admitted for >72 h at the maternity ward of a general hospital were included. At birth and an outpatient visit (OPV, n = 72, 44 ± 11 days postpartum), maternal and neonatal hair was analyzed for cortisol and cortisone levels by LC-MS/MS. Data were analyzed regarding: (1) neonatal GC levels postpartum and at the OPV, (2) associations of neonatal GC levels with maternal GC levels and (3) with other perinatal factors. RESULTS: (1) Neonatal GC levels were >5 times higher than maternal levels, with a decrease in ±50% between birth and the OPV for cortisol. (2) Maternal and neonatal cortisol, but not cortisone, levels were correlated both at postpartum and at the OPV. (3) Gestational age was associated with neonatal GC postpartum (log-transformed ß (95% CI): cortisol 0.07 (0.04-0.10); cortisone 0.04 (0.01-0.06)) and at the OPV (cortisol 0.08 (0.04-0.12); cortisone 0.00 (-0.04 to 0.04)), while weaker associations were found between neonatal GCs and other perinatal and maternal factors. CONCLUSIONS: Neonatal hair GCs mainly reflect the third trimester increase in cortisol, which might be caused by the positive feedback loop, a placenta-driven phenomenon, represented by the positive association with GA. Between birth and 1.5 months postpartum, neonatal hair cortisol concentrations decrease sharply, but still appear to reflect both intra- and extrauterine periods.

Is poor neonatal adaptation after exposure to antidepressant medication related to fetal cortisol levels? An explorative study.

BACKGROUND: As a marker for poor neonatal adaptation (PNA) is lacking, the diagnostic process is difficult and includes invasive additional testing. AIMS: In order to develop a marker, it is essential to gain insight into the etiology of PNA. We hypothesized that the fetal cortisol level may play a role in this etiology. STUDY DESIGN: Non-randomized, prospective controlled study. OUTCOME MEASURES: We examined hair cortisol levels of infants exposed and not exposed to selective antidepressants (SADs) during pregnancy. These cortisol levels represent the mean cortisol level during the last trimester of pregnancy. Infants exposed to SADs who developed PNA according to the pediatrician (PNA+, n=25), infants exposed to SADs who did not develop PNA (PNA-, n=40) and infants not exposed to SADs (controls, n=105) were compared. RESULTS: In infants with PNA, hair cortisol levels were higher compared to infants without PNA. However this difference was only statistically significant in female infants (girls B0.33, p=0.04, boys B0.05, p=0.82). There was no correlation between nonspecific distress, measured by the Finnegan score and fetal hair cortisol levels (B-0.15, p=0.30). All analyses were adjusted for type of delivery and gestational age. CONCLUSIONS: Our results suggest that the hypothalamic pituitary adrenal (HPA) axis activity may play a sex-specific role in the development of PNA. As PNA is most likely of a multifactorial origin, it would be interesting to examine other factors possibly involved in the etiology of PNA in future studies, such as (epi) genetics.

Antidepressants during pregnancy and postpartum hemorrhage: a systematic review.

The use of antidepressants in pregnancy is increasing. Concerns have risen about the use of antidepressants during pregnancy and the risk of postpartum hemorrhage (PPH). The aim of this systematic review is to summarize evidence on the association between use of antidepressants during pregnancy and the risk of PPH. An Embase and Pubmed search was conducted. English and Dutch language studies reporting original data regarding bleeding after delivery associated with exposure to antidepressants during pregnancy were selected. Quality appraisal was conducted using the Newcastle Ottawa Scale (NOS). Out of 81 citations, 4 studies were included. Based on the NOS, 3 were considered of good quality and 1 was considered of satisfactory quality. Two studies reported an increased incidence of PPH in women who used antidepressants during pregnancy. The other two studies identified no overall increased risk of PPH among pregnant women exposed to antidepressants. The existing evidence remains inconclusive whether use of antidepressants during pregnancy is associated with an increased risk of postpartum hemorrhage. If there is such an association the absolute increased risk will be low and the clinical relevance needs to be further examined.

Adapted Finnegan scoring list for observation of anti-depressant exposed infants.

OBJECTIVE: The Finnegan scoring list (FSL) is widely used to screen for poor neonatal adaptation in infants exposed to anti-depressants in utero. However, the large number of FSL-items and differential weighing of each item is time consuming. The aim of this study was to shorten and simplify the FSL yet preserving its clinimetric properties. METHODS: This observational study examined infants exposed to an anti-depressant during pregnancy admitted for at least 72 h on a maternity ward. Trained nurses completed the FSL three times daily. Items for the adapted FSL were selected through forward analysis whereby the number of selected items was based on the area under the curve (AUC). Internal validity was assessed by cross-validation. RESULTS: 183 infants met the inclusion criteria. By forward analysis eight equally-weighed items resulted in an AUC of 0.91. In cross-validation, the mean AUC was 0.89 for 8 items. This adapted FSL had a sensitivity of 97.7% and specificity of 37.0% and a sensitivity of 41.9% and specificity of 86.2% regarding a cut-off of, respectively, 1 and 2. CONCLUSIONS: An adapted FSL with eight equally-weighed items has acceptable clinimetric properties and can serve as an easy to apply screening tool in infants exposed to anti-depressants during pregnancy.

[A medical-psychiatric unit in a general hospital: effective combined somatic and psychiatric care?]. / Medisch-psychiatrische unit in algemeen ziekenhuis: effectieve gecombineerde somatische en psychiatrische zorg?

OBJECTIVE: To study the effectiveness of combined integral somatic and psychiatric treatment in a medical-psychiatric unit (MPU). DESIGN: Retrospective case-note study. METHOD: The case notes of all patients admitted to the MPU at the VU Medical Center, Amsterdam, in 2011 were analysed. Data on reasons for referral and somatic and psychiatric diagnoses were collected. Using a global clinical assessment scale and the Health of the Nations Outcome Scales (HoNOS), data on psychiatric symptomology and limitations, behavioural problems, social problems and limitations associated with physical health problems were collected on both admission and discharge. In this way the effect of the admission period on various problems was determined. RESULTS: In 2011 there were 139 admissions to the MPU with a wide variation of somatic and psychiatric diagnoses. The average admission period was 9 days. Global clinical evaluation of the treatment goals set for somatic and psychiatric conditions showed that more than 90% and 85% of the treatment goals, respectively, were completely achieved. HoNOS scores showed a reduction in severity of both psychiatric and somatic problems. The total HoNOS-core was significantly reduced by nearly 3.5 points - a large effect size. CONCLUSION: The MPU has succeeded in its goal to deliver integral care to a very diverse group of patients with somatic and psychiatric co-morbidities. It is able to offer care to a vulnerable patient group in which it can be presumed that treatment on a non-integrated unit could not have been delivered or not delivered adequately, due to the complexity of their somatic and behavioural problems.

The use of psychotropic medication during pregnancy: how about the newborn?

Infants are at risk of developing symptoms of Poor Neonatal Adaptation (PNA) after exposure to psychotropic drugs in utero. Such symptoms are largely similar after exposure to antidepressants, antipsychotics and benzodiazepines and consist of mostly mild neurologic, autonomic, respirator and gastro-intestinal abnormalities. Most symptoms develop within 48 hours after birth and last for 2-6 days. After exposure to Selective Serotonin Reuptake Inhibitors (SSRIs), mirtazapine or venlafaxine in utero, breastfeeding is presumably protective for development of PNA. The dosage of antidepressants does not seem to be related to the risk of PNA. In order to objectify possible symptoms of PNA, observation of mother and child at the maternity ward is advisable. If PNA symptoms do not occur, an observation period of 48-72 hours is sufficient. This applies to all types of psychotropic drugs. When PNA symptoms are present it is advisable to observe the infant until the symptoms are fully resolved. Observation can be performed by trained nurses using the Finnegan scoring list. This observation list should be administered every 8 hours. Interpretation of the scores should be carried out by a paediatrician. In most cases symptoms are non-specific. Therefore other diagnoses, such as infection or neurologic problems, have to be excluded. When there is any doubt on possible intoxications during pregnancy, toxicological urine screening is indicated. Most cases of PNA are mild, of short duration and self-limiting without need for treatment. Supporting measures such as frequent small feedings, swaddling and increase of skin to skin contact with the mother is usually sufficient. In case of severe PNA it is advised to admit the infant to the Neonatal Care Unit (NCU). Phenobarbital is a safe therapeutic option. There seem to be no major long term effects; however, additional studies are necessary in order to draw definite conclusions.

[Withdrawal in newborns after exposure to psychotropic medications during pregnancy]. / Ontwenning bij de pasgeborene na blootstelling aan psychofarmaca tijdens de zwangerschap.

The use of psychotropic medications during pregnancy causes withdrawal symptoms in 20-30% of the newborns. The literature on withdrawal symptoms is not unanimous concerning their recognition and treatment. A search of PubMed and Embase revealed 198 articles in which potential withdrawal symptoms in newborns were described following exposure to psychotropic medications during pregnancy. Commonly occurring withdrawal symptoms are mostly mild, including restlessness and sleeping and feeding difficulties. Severe symptoms such as convulsions are rare. It can sometimes be difficult to differentiate between symptoms of intoxication and symptoms of withdrawal. The Finnegan scale is widely used to recognise withdrawal from psychotropic medication. An observation period of at least 48 h post-partum is advised. Recognition of withdrawal is important to prevent needless additional tests. In withdrawal symptoms supportive measures such as feeding on demand and swaddling are usually sufficient. If withdrawal symptoms are severe, phenobarbital is a therapeutic option.