Volume 41, Issue 5

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 μg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6 S )-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B 12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

Objective: Preeclampsia (PE) can be sub-divided into early- and late-onset phenotypes. The pathogenesis of these two phenotypes has not been elucidated. To gain insight into the mechanisms of disease, the transcriptional profiles of whole blood from women with early- and late-onset PE were examined. Methods: A cross-sectional study was conducted to include women with: i) early-onset PE (diagnosed prior to 34 weeks, n=25); ii) late-onset PE (after 34 weeks, n=47); and iii) uncomplicated pregnancy (n=61). Microarray analysis of mRNA expression in peripheral whole blood was undertaken using Affymetrix microarrays. Differential gene expression was evaluated using a moderated t -test (false discovery rate <0.1 and fold change >1.5), adjusting for maternal white blood cell count and gestational age. Validation by real-time qRT-PCR was performed in a larger sample size [early PE (n=31), late PE (n=72) and controls (n=99)] in all differentially expressed genes. Gene ontology analysis and pathway analysis were performed. Results: i) 43 and 28 genes were differentially expressed in early- and late-onset PE compared to the control group, respectively; ii) qRT-PCR confirmed the microarray results for early and late-onset PE in 77% (33/43) and 71% (20/28) of genes, respectively; iii) 20 genes that are involved in coagulation ( SERPINI2 ), immune regulation ( VSIG4, CD24 ), developmental process ( H19 ) and inflammation ( S100A10 ) were differentially expressed in early-onset PE alone. In contrast, only seven genes that encoded proteins involved in innate immunity ( LTF, ELANE ) and cell-to-cell recognition in the nervous system ( CNTNAP3 ) were differentially expressed in late-onset PE alone. Thirteen genes that encode proteins involved in host defense ( DEFA4, BPI , CTSG, LCN2 ), tight junctions in blood-brain barrier ( EMP1 ) and liver regeneration ( ECT2 ) were differentially expressed in both early- and late-onset PE. Conclusion: Early- and late-onset PE are characterized by a common signature in the transcriptional profile of whole blood. A small set of genes were differentially regulated in early- and late-onset PE. Future studies of the biological function, expression timetable and protein expression of these genes may provide insight into the pathophysiology of PE.

Aim: To determine the association, if any, between placental architecture findings assessed ultrasonographically at 22 and 36 weeks and placental histology. Methods: There was prospective recruitment of 1011 low-risk primigravids from the antenatal clinic at the Rotunda Hospital, Dublin, Ireland. Ultrasound of the placenta was performed at 22 and 36 weeks and histological assessment was made of the placenta of all participants. Results: Complete data pertaining to ultrasound and placental histology was available for 810 women (80%). Placental calcification on ultrasound in the third trimester was associated with a higher incidence of placental infarction identified following placental histology (80.0% vs. 21.5%; P=0.009: r=0.115). The placental thickness on ultrasound in the second trimester was less in cases complicated by chorioamnionitis (2.62 cm vs. 3.07 cm; P=0.039: r=–0.176). Chronic villitis was associated with a statistically significant increased incidence of antenatal placental infarction identified on ultrasound in the third trimester (10.7% vs. 1.9%; P=0.020: r=0.113). Intervillous thrombi occurred more frequently in cases with reduced placental thickness on ultrasound in the second trimester (3.0 cm vs. 3.3 cm; P=0.035: r=–0.171). Conclusions: Antenatal ultrasound of the placenta may aid detection of placental disease, particularly in the identification of placental infarction.

Aims: Preeclampsia (PE) is considered a uniformly progressive disease, however, it shows a different pattern of clinical progression in patients with early (<34 weeks) or late (≥34 weeks) onset of the disease. Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) are closely related to the clinical course of PE. We evaluated sFlt-1 and PlGF levels in the clinical course of PE in women admitted with a diagnosis of PE at different gestational ages. Methods: This retrospective study included 34 patients with PE, of which 11 patients had HELLP syndrome (over a period of 3 years). Serial measurements of sFlt-1 and PlGF were completed from admission until delivery. Values are presented as mean±standard deviation. Results: Mean gestational age of admission among women with early onset PE was significantly lower, at 29±3 weeks compared to 37±1 weeks among patients with late onset disease. Mean prolongation of pregnancy was 6 days, which was similar within the two groups. Compared to women with late onset PE, women with early-onset PE had a greater increase in sFlt-1 (11% vs. 3% per day, P<0.05), greater decrease in PlGF levels (21% vs. 10% per day, P=0.30), resulting in a much higher increase in sFlt-1/PlGF ratio (23% vs. 8% per day, P<0.05). Patients with HELLP syndrome showed comparable progression patterns. Conclusion: In a similar way to the progressively worsening clinical course observed in women with early onset PE, there were changes in the angiogenic profile that leads to a more anti-angiogenic state in these women with each passing day. These findings may have implications in identification of the women for appropriate patient management and possible future therapies based on the reduction of sFlt-1 levels.

To determine whether the effectiveness of oxytocin treatment of arrest of dilatation differed in obese compared to lean women, we did a retrospective analysis of 118 subjects in spontaneous labor whose arrest of dilatation was treated with oxytocin. Cases were stratified by maternal body mass index (BMI): Group A, <25 kg/m 2 ; Group B, 25.0–29.9 kg/m 2 ; Group C, 30.0–34.9 kg/m 2 ; and Group D, ≥35 kg/m 2 . Groups were comparable in maternal age, parity, gestational age, birth weight, and the frequency of infection. Full dilatation was reached in about 90% of Group A and B, 72% of Group C, and 39% of Group D, the most obese women (P<0.001). The cesarean rate was directly related to maternal BMI, 11.4%, 22.9%, 34.3%, and 69.6% in Groups A through D, respectively (P<0.001). Significantly more oxytocin was used in group D than in the other groups during the first 3h of infusion in attempting to overcome the arrest (P=0.003). We conclude that oxytocin treatment of arrest of dilatation was less effective in obese than in lean women. This effect was most prominent in women with a BMI >35 kg/m 2 , who were, despite having received more oxytocin than those in the leaner groups, less than half as likely to attain full dilatation and more than twice as likely to deliver by cesarean.

Objective: The aim of the study was to examine the perinatal outcomes in gestational diabetes in women with body mass index (BMI)-adjusted gestational weight gain (GWG) according to the Institute of Medicine (IOM) 2009 recommendations. Material and methods: The clinic’s database was used to analyze 675 singleton GDM pregnancy outcomes. GWG for the entire pregnancy was compared to IOM recommendations and adjusted for prepregnancy BMI categories: underweight <18.5; normal 18.5–24.9; overweight 25–29.9; and obese >30. The study group was divided into three categories: below IOM limits, within IOM limits and above IOM limits. Results: Only 37% of women achieved the proper weight gain (n=256). Almost 30% of women with GDM (n=196) had an excessive weight gain. GWG above limits was associated with a significantly higher neonatal measurements and a higher rate of large-for-gestational-age neonates. In underweight and normal-prepregnancy-weight women, no relation between GWG and birth-weight percentile was noted. For the overweight and obese women, a positive significant correlation between GWG until GDM diagnosis and birth-weight percentile was noted (P=0.002), which was not present when GWG until delivery was considered. Conclusions: Limited weight gain in overweight and obese women with gestational diabetes mellitus results in favourable pregnancy outcomes.

Objective: We sought to investigate the incidence, maternal risk factors, and perinatal outcomes of women with complete and partial placental retention in a tertiary care teaching hospital in Southwestern Germany. Study design: We performed an unmatched case-control study with cases occurring between July 2000 and June 2007. Women were included into the study if they completed at least the 24th week of gestation and were diagnosed with placental retention requiring surgical intervention. We selected two controls per case and performed univariate and multivariate logistic regression analyses to identify risk factors for complete and partial placental retention. Results: A total of 161 cases (2.02%) were identified out of 7978 deliveries. The 1-year prevalence of all types of placental retention continuously increased during the 6-year study period from 0.93% to 3.26%. A significant independent risk factor for all types of placental retention in the multivariate logistic regression model was a previous retention of the placenta [odds ratio (OR)=21.723, 95% confidence interval (CI) 6.07–77.7]. Independent protective factors against all types of placental retention were a non-anterior and non-posterior placenta location (OR=0.561, 95% CI 0.35–0.91), and a cesarean delivery with (OR=0.193, 95% CI 0.09–0.40) and without labor (OR=0.482, 95% CI 0.27–0.86). Women without partial placental retention delivered neonates with better 5-min APGAR scores (OR=0.78, 95% CI 0.65–0.95). Conclusion: A thorough medical history and a vigilant prepartum ultrasound help in identifying women at risk for placental retention.

Aim: To present an experience with twin pregnancies underlining the impact of magnetic resonance imaging (MRI) on diagnosis and management. Methods: There were 17 cases of twin pregnancies: nine monochorionic [including four monochorionic diamniotic and five monochorionic monoamniotic (conjoined twins)] and eight dichorionic. The MRI examinations were performed between 19 and 39 weeks of gestational age in two centers using 1.5 T scanners (GE Signa Excite and GE Signa HDxt; GE Healthcare, Waukesha, WI, USA), always after ultrasound (US). In the first period of our activity, SSFSE sequence in T2-weighted images (SSFSE/T2WI) was the main diagnostic tool supported by TSE or GRE T1-weighted images (T1WI). After upgrading the scanners, diffusion-weighted imaging (DWI), steady-state free precession (FIESTA), and echoplanar GRE imaging (EPIGRE) became available. Results: In 11 cases (64.7%), MRI was superior to US and supplied additional information, including two cases in which pathology of the second twin suspected on US was ruled out on the basis of MRI. In six cases (35.3%) MRI confirmed US diagnosis and brought no new data. Conclusion: MRI offers more detailed assessment of fetal pathology in cases of twin pregnancies, including conjoined twins, in which sonographic evaluation is more difficult than in single cases.

Objective: To evaluate obstetric outcome after stillbirth according to placental and prothrombotic risk factors. Methods: Obstetric outcomes of women with prior stillbirth and subsequent pregnancies were reviewed. Data on the immediate subsequent pregnancy included fetal loss, stillbirth, obstetric/medical complications, gestational age and birth weight at delivery, mode of delivery, thrombophilia, and prescribed medication. Placental stillbirth was defined as stillbirth associated with placental abruption, intrauterine growth restriction (IUGR), or histological evidence of placental infarcts. Controls were unselected women who gave birth at our center during a single calendar year. Factors influencing recurrence risks were estimated. Results: Seventy-three subsequent pregnancies were identified. Five out of 73 (6.8%) women had a repeat stillbirth, significantly higher than controls (relative risk 22.2, 95% confidence interval 8.9–55.4). Four out of five repeat stillbirth cases occurred <37 weeks gestation. Hypertensive complications, diabetes and abruption were higher, while gestational age and birth weight at delivery were significantly lower than controls. Prior placental stillbirth was associated with a 10.5 times higher risk of IUGR in the subsequent pregnancy compared with non-placental stillbirth. All five repeat stillbirth cases occurred in thrombophilic women. Conclusion: Women with prior stillbirth face an increased risk of pregnancy complications and stillbirth recurrence, especially with concurrent thrombophilia. Most repeat stillbirth cases occur preterm.

Aim: The present study attempts to understand the role of methylenetetrahydrofolate reductase C677T ( MTHFR C677T) in recurrent pregnancy losses in North Indian women because of hyperhomocysteinemia in light of serum folate and vitamin B 12 . Methods: One hundred and seven women with three or more consecutive unexplained recurrent pregnancy losses and 343 women with two or more successful and uncomplicated pregnancies were recruited. Plasma homocysteine, serum folate and vitamin B 12 were analyzed using chemiluminescence. MTHFR C677T detection was completed in all subjects. Results: MTHFR genotypic distribution among cases and controls showed no significant difference (P=0.409). However, MTHFR C677T polymorphism was found to be significantly associated with increased homocysteine in the case group (P=0.031). Hyperhomocysteinemia and vitamin B 12 deficiency were found to be significant risk factors for recurrent pregnancy loss (RPL) (OR=7.02 and 16.39, respectively). Folate deficiency was more common in controls (63.47%) as compared to the case group (2.56%). Conclusion: Low vitamin B 12 increases homocysteine, specifically among T allele carrying case mothers, suggesting T allele is detrimental with B 12 deficiency. The study emphasizes the importance of vitamin B 12 in the prevention of RPL in North Indian women.

Aims: To evaluate the efficacy of acupuncture, and sweeping of the fetal membranes, as methods for induction of labor. Methods: Four hundred and seven pregnant women with normal singleton pregnancies and cephalic presentations were randomized at three delivery wards in Denmark at day 290 of gestation into groups of acupuncture, sweeping, acupuncture and sweeping and controls. The primary objective was to compare the proportion of women going into labor before induction of labor at 294 days in the four groups. The secondary objective was to compare the combined groups: with and without acupuncture, and with and without sweeping of the fetal membranes. The midwives, completing the forms for the trial at labor or induction, were blinded to group assessments. Results: Four hundred and seventeen women were randomized. Ten were excluded after randomization. One hundred and four women were randomized to acupuncture, 103 to sweeping of the membranes, 100 to both acupuncture and sweeping, and 100 were randomized to the control group. Comparison of the four groups demonstrated no significant difference in the number of women achieving spontaneous labor before planned induction. No difference was demonstrated by comparing the combined groups treated with acupuncture with the groups not treated with acupuncture (P=0.76). However, significantly more women went into labor before planned induction (P=0.02) in the combined groups receiving sweeping, compared with the groups not treated with sweeping. Conclusions: Acupuncture at 41+ weeks of gestation did not reduce the need for induction. The study was of a sufficient size to demonstrate, in parallel, that sweeping of the fetal membranes significantly reduced the need of induction, sparing about 15% for formal induction of labor.

Aims: To determine first trimester maternal serum placental protein 13 (PP13) in singletons vs. twins with and without severe preeclampsia (PE). Methods: Serum samples were prospectively collected at 8–14 weeks of gestation. PP13 was determined by solid-phase immunoassay. Patients were recruited in community clinics throughout the country, and from the twin antenatal assessment clinic in Assaf Harofeh Medical Center, Zerifin, Israel. Demographics, medical, and pregnancy history were obtained at enrollment. Pregnancy outcome was collected after delivery. PP13 was compared by the Wilcoxon rank sum test. Results: In singletons, PP13 declined with maternal weight and was lower in in vitro fertilization. Levels were converted into multiples of the median (MoMs) accordingly. In twins, the median was 1.74 MoM (n=76) vs. 1.00 in singletons (n=676, P<0.0001). Among twins with severe PE (n=10), the median was 1.53 MoM vs. 1.74 in unaffected twins (P=0.10), and 2.26 (n=6) for mild PE (P=0.30). Among singletons with severe PE, the median was 0.44 MoM (n=26, P<0.0001), and for mild PE 0.62 (n=17, P<0.001). Conclusion: PP13 is higher in twins than singletons, corresponding to the larger placental mass. Among singletons with severe PE, levels were significantly reduced, however, among twins, only a non-significant tendency for a reduction was recorded, and warrants further investigation in a larger series.

Objective: To establish the frequency of post-cesarean relaparotomy, identify its risk factors, indications, and operative management. Methods: This study was a retrospective matched case control study. Records of all women who underwent a cesarean section (CS) from July 2006 to March 2012 were reviewed. We identified all women who had a relaparotomy within 1 month from their CS. For each woman, two women were matched. We analyzed data regarding obstetrical history, current gestation, surgical parameters, and outcome. Results: A total of 14,637 CS were performed during this period, of these, 58 cases required a relaparotomy (0.4%). In univariate analysis, female sex and duration of CS were associated with an increased risk for relaparotomy. In multivariate analysis, multiple pregnancies, general anesthesia, duration of operation, and female sex, independently increased the risk for relaparotomy. The leading indications for relaparotomy were hemodynamic shock and subcutaneous hematoma. The most common interventions during relaparotomy were cauterization of subcutaneous vessels, and ligation of large vessels. Overall, women requiring relaparotomy received, on average, 16 units of blood products. Conclusions: This study highlights risk factors associated with post-cesarean relaparotomy. Surgeons might use this important data to identify women at risk beforehand, and thus, reduce the morbidity associated with relaparotomy.

Objective: Ischemia modified albumin has been shown to increase in ischemic situations, and has also been shown to increase in fetal cord blood in deliveries by cesarean section. The aim of this study is to reveal whether anesthesia has an impact on maternal and fetal cord ischemia modified albumin levels. Methods: Seventy two women with uncomplicated term pregnancies were randomized to spinal (n=37) or general anesthesia (n=35) groups. The blood pressure, oxygen saturation, and pulse rate of the patients were recorded during the procedure. Maternal blood samples of ischemia modified albumin (IMA) were taken 10 min from the start of the procedure. The fetal cord blood samples of IMA were taken immediately after birth. Results: Maternal (0.99±0.19 vs. 0.80±0.27) and fetal (1.00±0.21 vs. 0.70±0.26) IMA levels were significantly higher in the general anesthesia group. Fetal IMA levels were positively correlated with maternal gravidity (r=0.31; P=0.008), parity (r=0.25; P=0.028), and fetal birth weight (r=0.23, P=0.045). Also, as time from incision to delivery lengthens, fetal IMA levels increase (r=0.29, P=0.012). Conclusion: Fetal cord ischemia modified albumin levels were higher in the general anesthesia group, therefore, it is proposed that regional anesthesia should be the preferred route of anesthesia for an elective cesarean section, at least until the impact of high fetal cord IMA levels are manifested.

Objective: The objective of this study was to determine whether maternal plasma concentrations of soluble α-klotho are different between women with microbial invasion of the intra-amniotic cavity (MIAC) and those without MIAC among preterm labor and intact membranes (PTL) or preterm prelabor rupture of membranes (pPROM). Methods : A cross-sectional study was conducted to include women in the following groups: i) PTL with MIAC (n=14); ii) PTL without MIAC (n=79); iii) pPROM with MIAC (n=30); and iv) pPROM without MIAC (n=33). MIAC was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas). Amniotic fluid samples were obtained within 48 h of maternal blood collection. Plasma concentration of soluble α-klotho was determined by ELISA. Results : i) The median plasma concentration (pg/mL) of soluble α-klotho was significantly lower in patients with MIAC than in those without MIAC (787.0 vs. 1117.8; P<0.001). ii) Among patients with PTL, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (787.0 vs. 1138.9; P=0.007). iii) Among patients with pPROM, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (766.4 vs. 1001.6; P=0.045). iv) There was no significant difference in the median plasma concentration of soluble α-klotho between PPROM without MIAC and PTL without MIAC (1001.6 pg/mL vs. 1138.9 pg/mL, respectively; P=0.5). v) After adjustment for potential confounders (maternal age, tobacco use, gestational age at venipuncture), soluble α-klotho remained significantly associated with MIAC (P=0.02); and vi) Among patients without MIAC, smoking was significantly associated with a lower median plasma concentration soluble α-klotho than in non-smokers (794.2 pg/mL vs. 1382.0 pg/mL, respectively; P<0.001); however, this difference was not observed in patients with MIAC. Conclusions : Intra-amniotic infection occurring at preterm gestations (regardless of membrane status) was associated with a decrease in maternal plasma concentrations of soluble α-klotho. Moreover, among patients without infection, the plasma concentration of α-klotho was lower in smokers.

Aim: Tissue culture studies indicate that bacterial products stimulate the production of proinflammatory cytokines by reproductive tissues. However, most of these studies have been performed under room air conditions, supplemented with 5% CO 2 . In this study, we tested whether O 2 tension affects bacteria-stimulated cytokine production by extra-placental fetal membranes. Methods: Cultures of full-thickness membranes, isolated choriodecidua, and isolated amnion were exposed to bacteria and incubated under 21% (room air) or 5% O 2 for 18 h. Cytokine concentrations in conditioned medium was quantified by immunoassay. Results: Culture under 5% O 2 increased production of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, but reduced IL-10 and IL-6 production by full membranes. Isolated choriodecidua responded to 5% O 2 with increased IL-1β production and reduced IL-6 production, but had no effect on TNF-α and IL-10 production was not detected. No effect of O 2 tension on IL-1β or IL-6 production by isolated amnion was detected, however, Escherichia coli -stimulated IL-10, TNF-α and IL-8 production was enhanced by culture under 5% O 2 . Conclusions: Increased oxygen tension reduces the pro-inflammatory responsiveness of cell cultures to E. coli and promotes an anti-inflammatory cytokine profile. Differential effects of O 2 tension on choriodecidua and amnion suggests a network of paracrine factors that regulate cytokine levels in response to changes in O 2 tension.

Aim: Fetal magnetography enables the recording of biomagnetic fetal signals, including fetal heart and fetal brain signals. These signals allow the determination of fetal behavioral states and functional brain signals with auditory evoked responses (AER). In the current study, we investigated how the behavioral state influences the AER and how stimulation affects fetal state. Methods: One hundred and four fetuses in three age groups (28–31 weeks, 32–35 weeks and 36–41 weeks) were recorded with and without auditory stimulation. Both sessions were scored for fetal states. The AER latency was determined for each state separately. Forty-five additional subjects were recorded with two sessions of 10 min without stimulation to investigate a possible time effect on state changes. Results: The state distribution was significantly different between stimulation and no stimulation conditions. The AER latencies were significantly shorter in active sleep (P=0.013) and active wakefulness (P=0.004) compared to quiet sleep. Conclusion: Auditory stimulation has an effect on fetal states. The state information should be taken into account for the analysis of AER latencies.

Objective: To evaluate skin temperature by using different positions with non-contact infrared thermography (IRT) in multiple body areas of preterm infants for detailed information about temperature regulation and distribution. Methods: The temperature of ten premature infants (median: 27 weeks; age 36 days; weight 1322 g) was determined via IRT (leg, back, arm, head, upper abdomen; diameter 1 cm, scale 0.00°C), and comparison was made with two conventional sensors. There were measurements of 10 min each: first incubator phase (I1), standardized skin-to-skin care (SSC) at the beginning (SSC1), after 90 min (SSC2), and then there was a second incubator phase (I2). Results: From I1 to SSC1, patients cooled down (max. 0.62°C; both methods). From SSC1 to SSC2 temperature on central areas (abdomen, back) was maintained but rose distinctively on the head and leg (P<0.05). In the incubator (I2), temperature niveau in all IRT-areas was significantly lower than before SSC. Conclusion: Via IRT, it is possible to detect fluctuations in temperature of premature infants. The cooling in I2 after SSC should be taken into account before routine daily care.

Aim: To determine whether infant gender influences the course of neonatal abstinence syndrome (NAS) following exposure to buprenorphine during pregnancy. Methods: A retrospective cohort study was performed in which maternal and infant data were collected for 46 male and 44 female infants. All infants were born to women enrolled in a buprenorphine treatment program from December 2007 until October 2012. Maternal and infant characteristics and outcomes were compared by infant gender. Results: Male infants had a significantly higher mean peak NAS score (10.04 vs. 7.98, P=0.028) and were more likely to require pharmacologic treatment for NAS (39.1% vs. 11.4%, P=0.005). Conclusions: These data indicate that, following exposure to buprenorphine during pregnancy, male infants experience a more severe withdrawal syndrome and are more likely to require pharmacologic treatment for NAS.