Adam C. Urato

Preterm Birth and Antidepressant Medication Use during Pregnancy: A Systematic Review and Meta-Analysis

Introduction Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. Methods We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. Results Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40–1.66) for antidepressant use at any time and 1.96 (1.62–2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92–1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. Discussion Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out.

The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond

STUDY QUESTION What is the current literature on the safety and efficacy of selective serotonin reuptake inhibitor (SSRI) use in infertile women? SUMMARY ANSWER There is little evidence that infertile women benefit from taking an SSRI, therefore they should be counseled appropriately about the risks and be advised to consider alternate safer treatments to treat depressive symptoms. WHAT IS KNOWN ALREADY SSRI use is associated with possible reduced infertility treatment efficacy as well as higher rates of pregnancy loss, preterm birth, pregnancy complications, neonatal issues and long-term neurobehavioral abnormalities in offspring. STUDY DESIGN, SIZE, DURATION Review of existing literature. PARTICIPANTS/MATERIALS, SETTING, METHODS We conducted a review of all published studies that evaluate females with depressive symptoms who are taking antidepressant medications and who are experiencing infertility. MAIN RESULTS AND THE ROLE OF CHANCE Antidepressant use during pregnancy is associated with increased risks of miscarriage, birth defects, preterm birth, newborn behavioral syndrome, persistent pulmonary hypertension of the newborn and possible longer term neurobehavioral effects. There is no evidence of improved pregnancy outcomes with antidepressant use. There is some evidence that psychotherapy, including cognitive-behavioral therapy as well as physical exercise, is associated with significant decreases in depressive symptoms in the general population; research indicates that some forms of counseling are effective in treating depressive symptoms in infertile women. LIMITATIONS, REASONS FOR CAUTION Our findings are limited by the availability of published studies in the field, which are often retrospective and of small size. WIDER IMPLICATIONS OF THE FINDINGS Practitioners who care for infertility patients should have a thorough understanding of the published literature so that they can adequately counsel their patients. STUDY FUNDING/COMPETING INTEREST(S) None.

Time of delivery and neonatal morbidity and mortality

OBJECTIVE The objective of the study was to examine the association between time of delivery and neonatal outcomes in term deliveries. STUDY DESIGN We conducted a retrospective cohort study of all term pregnancies delivered at an academic institution with 24-hour in-house obstetric and anesthesia coverage. Time of delivery was categorized as day (7 am to 6 pm), evening (6 pm to 12 midnight), and late night (12 midnight to 7 am). Outcomes included 5-minute Apgar less than 7, umbilical artery pH less than 7.0, base excess less than -12, admission to the neonatal intensive care unit (NICU), and neonatal death. We excluded patients delivered via cesarean delivery not in labor. We had greater than 80% power to detect a 25% difference in Apgar score, base excess, and admission to the NICU and 80% power to detect a 50% difference in umbilical artery pH less than 7.0. RESULTS Among the 34,424 deliveries meeting inclusion criteria, 15,664 were during the day, 8495 were during the evening, and 10,265 were during the night. In univariate comparisons, there were no statistically significant differences in neonatal outcomes. For example, the rate of pH less than 7.0 was 0.7% during the day, 1.0% in the evening, and 0.6% at night (P = .12). Admissions to the NICU were 3.6% during the day, 3.7% in the evening, and 3.5% at night (P = .81). When we controlled for obstetric history, demographic factors, and labor characteristics, there were still no differences in rates of either neonatal morbidity or mortality by time of delivery. CONCLUSION At our institution, we could not demonstrate any significant differences in neonatal morbidity or mortality by time of day among neonates delivered at term. These data can be used to counsel patients and families concerned about differences in time of delivery and potential impact on their infants health. Future research should include time of delivery in relation to maternal and neonatal outcomes in various types of inpatient settings.

May-Hegglin anomaly: a case of vaginal delivery when both mother and fetus are affected.

May-Hegglin anomaly is a rare, autosomal dominant disorder characterized by thrombocytopenia and a variable bleeding tendency. In almost all the case reports in the recent literature, platelet transfusion and cesarean section were performed to avoid maternal and neonatal bleeding. We present a case of a woman with May-Hegglin anomaly who had no history of a bleeding tendency. She had a vaginal delivery and a platelet count of 16,000/mm3; the neonates platelet count was 35,000/mm3. There were no complications. We advocate a reappraisal of basing platelet transfusion and mode of delivery on the platelet count in patients with May-Hegglin anomaly.

Smoking in pregnancy is associated with increased total maternal serum cell‐free DNA levels

Cell‐free DNA is a marker of cellular apoptosis and necrosis. We wished to determine if maternal smoking affects maternal and fetal serum cell‐free DNA levels.

A guide towards pre-pregnancy management of defective implantation and placentation.

Pregnancy complications such as pre-eclampsia, placental abruption and growth restriction were once thought to represent end-of-pregnancy issues. Currently, the cause of such complications are being increasingly recognised as defective implantation and placentation. The molecular mechanisms responsible for normal and abnormal implantation are an area of active investigation. Screening tests, such as Doppler ultrasound of the maternal uterine arteries and evaluation of markers in the maternal serum, are being assessed to determine if such tests might allow for better recognition and, perhaps, prevention of many pregnancy complications related to abnormal placentation. Many techniques during pregnancy have been used to prevent pregnancy complications such as pre-eclampsia. Most have been unsuccessful. Ultimately, the solution may reside in pre-pregnancy approaches to improve implantation and placentation. Such approaches are actively being investigated and have promise.

Admission uric acid levels and length of expectant management in preterm preeclampsia

Objective:Uric acid is known to be elevated in preeclampsia. We sought to determine if uric acid levels on admission correlate with the length of expectant management in preterm patients with preeclampsia.Study Design:A retrospective chart review was conducted on singleton preeclamptic pregnancies delivered between 24 0/7 and 37 0/7 weeks’ gestation at Tufts Medical Center between January 2005 and December 2007. Patients with a multiple gestation and those transferred or discharged before delivery were excluded. Data regarding signs and symptoms of preeclampsia, laboratory values, pregnancy complications and outcome were abstracted from the medical records. Correlation between admission uric acid level and days of expectant management was assessed. The relative risk (RR) was used to estimate the effect of uric acid levels on expectant management length >7 days. Mantel–Haenszel χ 2 values were used to construct 95% confidence intervals (CIs) around the RR.Result:Four hundred seventy-one charts were reviewed. Of these, 190 met inclusion criteria. In all, 55 patients (28.9%) were managed expectantly for >1 week. Admission uric acid level correlated with days of expectant management (P<0.0001). Uric acid levels at admission were categorized as ⩽4.0 mg dl–1 (low uric acid level), 4.1 to 6.0 mg dl–1 (medium) and ⩾6.1 mg dl–1 (high). Relative to women with high uric acid levels at admission, we observed a sevenfold higher rate of extending expectant management for >1 week among women with low uric acid level (7.0; 95% CI: 3.34 to 14.68). Women with medium uric acid levels at admission also had a higher likelihood of prolonging pregnancy relative to women with high uric acid levels (RR: 2.81; 95% CI: 1.32 to 5.96) (P-value for trend <0.0001).Conclusion:Admission uric acid levels correlate with the length of expectant management in preterm patients with preeclampsia. Pregnancy prolongation for >1 week is significantly more likely in patients with low and medium uric acid levels at the time of admission. Uric acid levels may be helpful in assessing disease severity and counseling preeclamptic patients regarding likelihood of extended expectant management.

Relationships between cell-free DNA and serum analytes in the first and second trimesters of pregnancy.

OBJECTIVE: To assess the relationship between first- and second-trimester cell-free DNA levels and maternal serum screening markers. METHODS: First- and second-trimester residual maternal serum samples from 50 women were obtained. First-trimester (pregnancy-associated plasma protein A and &bgr;-hCG) and second-trimester serum analytes (&bgr;-hCG, alpha-fetoprotein, unconjugated estriol, and inhibin A) had been measured at the time of sample receipt. All fetuses were male as confirmed by birth records. Cell-free DNA was extracted and measured by real-time quantitative polymerase chain reaction amplification using glyceraldehyde phosphate dehydrogenase and DYS1 as markers of total DNA and fetal DNA, respectively. Determination of linear associations between first- and second-trimester serum markers and cell-free DNA levels using Pearson correlations was performed. RESULTS: Statistically significant correlations between first-trimester pregnancy-associated plasma protein A multiples of the median and both total (r=0.36, P=.016) and fetal (r=0.41, P=.006) DNA in the first trimester were observed. There were no significant correlations between first-trimester serum human chorionic gonadotropin or any second-trimester serum marker with DNA levels. CONCLUSION: Correlation between serum pregnancy-associated plasma protein A and first-trimester circulating cell-free fetal and total DNA levels is a novel finding. Pregnancy-associated plasma protein A is a glycoprotein of placental origin, and its correlation to cell-free fetal DNA in maternal serum suggests a common tissue origin through apoptosis of placental cells. However, because pregnancy-associated plasma protein A and cell-free DNA were only marginally correlated and cell-free DNA can be reliably detected in the first trimester, the addition of cell-free DNA to serum screening strategies may be helpful in predicting adverse pregnancy outcome. LEVEL OF EVIDENCE: II

The isolated mildly enlarged cisterna magna in the third trimester: much ado about nothing?

ase—A 30-year-old woman, gravida 1, presents at 32 weeks for sonography to assess fetal growth. She is otherwise healthy, and her pregnancy has been uncomplicated. Her 18-week anatomy scan results were normal. Her serum screen for aneuploidy was low risk. On this sonographic examination, the fetus is found to have normal growth and fluid. The anatomic survey results are normal aside from a cisterna magna that measures 11 mm. The remainder of the intracranial anatomy is normal. How do you counsel her? With advances in fetal sonography, variations in fetal anatomy and structure are being identified. In particular, posterior fossa abnormalities pose a challenging diagnostic and management dilemma, as they are often difficult to interpret, and the neonatal outcome is difficult to accurately predict. Outcomes for neonates with posterior fossa abnormalities diagnosed antenatally can range from normal to severe developmental disabilities. The cisterna magna contains cerebrospinal fluid and is located behind the cerebellum in the posterior fossa of the brain. It communicates with the fourth ventricle via the foramina of Magendie and Luschka. Measurement of the anteroposterior diameter of the cisterna magna can be useful in diagnosing posterior fossa abnormalities. An enlarged cisterna magna has been defined as measuring greater than 10 mm.1 The optimal time to assess the posterior fossa for diagnosis of abnormalities has been debated in the literature. Embryologically, complete posterior fossa development is thought to occur between 18 and 22 weeks. Therefore, caution in making a diagnosis of cerebellar dysgenesis before 18 weeks is warranted.2 However, false-positive findings have also been reported at later gestational ages, and some authors have recommended that the diagnosis of the different forms of vermian hypoplasia should not be made before 24 weeks’ gestation.3 If a posterior fossa abnormality is suspected, further characterization by follow-up sonography is usuAsha J. Heard, MD Adam C. Urato, MD

Are the SSRI antidepressants safe in pregnancy? Understanding the debate.

BACKGROUND Rates of antidepressant use during pregnancy are rising worldwide. It is, therefore, essential to determine the effects of these medications in pregnancy and on the developing fetus. OBJECTIVE To review the two main explanatory models for understanding the effects of antidepressant use during pregnancy and compare the evidence to support them. METHODS Review, synthesis, and discussion of the available literature. RESULTS The preponderance of the basic science, animal data, and human studies supports the view that the Harmful Chemical Model is the best explanatory framework for understanding the effects of the SSRI antidepressants during pregnancy. They do not appear to be helpful medications that produce better outcomes for moms and babies. They are not like using insulin in pregnant diabetics. Their profile fits more with a harmful chemical exposure. CONCLUSIONS The totality of the scientific evidence convincingly suggests that the SSRI antidepressants are chemicals that do cause fetal harm and that the FDA should strongly consider changing the FDA Category from C to D for the entire class. This move would provide appropriate warning to the public while still allowing for use in selected cases.