Mordechai Dulitzky

Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis

Abstract.Acute exacerbations may complicate the course of pregnancy and the postpartum period in patients with relapsing-remitting multiple sclerosis (RRMS). To evaluate relapse rate and the effect of immunomodulatory treatment with intravenous immunoglobulin (IVIg) during pregnancy and the postpartum period we retrospectively analysed the data of 108 pregnant RRMS patients. Group I patients were not treated, Group II patients were treated with IVIg 0.4 g/kg body weight/day for 5 consecutive days within the first week after delivery with additional booster doses of 0.4 g/kg body weight/day at 6 and 12 weeks postpartum (defined as 12 weeks after labor), and Group III patients were treated continuously with IVIg during gestation and the postpartum period (0.4 g/kg body weight/day for 5 consecutive days within the 6–8 weeks of gestation with additional booster doses of 0.4 g/kg body weight/day once every 6 weeks until 12 weeks postpartum). All patients underwent antenatal care and fetal ultrasonographic surveillance examinations. Relapse rate per woman per year during the pregnancy and the postpartum period as well as neonatal outcome data and IVIg related adverse events were analysed.Relapse rate per woman per year for patients treated with IVIg for the whole pregnancy and postpartum period (Group III, N = 28) compared with the untreated Group I patients (N = 39) were as follows: first trimester 0.43 vs. 0.72, second trimester 0.15 vs. 0.61, third trimester 0.0 vs. 0.41, and postpartum period 0.28 vs.1.33 (p < 0.05). Patients treated with IVIg only during the postpartum period (Group II, N = 41) also showed a decrease in relapse rate compared with untreated Group I patients, 0.58 vs. 1.33 (p = 0.012). The mean maternal age, disease duration, gestational age at delivery and fetal delivery weight did not significantly differ between the three groups. Mode of delivery, obstetrical complications, the use of epidural analgesia and breast-feeding, did not affect postpartum relapse rate. No severe adverse events were associated with IVIg treatment either during the pregnancy or postpartum period for the patients and newborns.We conclude that in RRMS patients IVIg treatment could be considered as an optional treatment to reduce the incidence of pregnancy and postpartum-related relapses. Further randomized double-blind studies are needed to confirm our findings.

Maternal and neonatal outcomes of large for gestational age pregnancies.

Objective. To compare maternal and neonatal outcomes of term large for gestational age (LGA) pregnancies and adequate for gestational age (AGA) pregnancies. Design. Retrospective analysis. Setting. Large university research medical center. Population. All term singleton LGA (birthweight ≥90th percentile) and AGA pregnancies (birthweight 10.1–89.9th percentile) delivering between 2004 and 2008. Methods. Data collected included maternal age, gestational age at delivery, mode of delivery, birthweight, fetal sex, and maternal and neonatal complications. Birthweight percentiles were determined according to locally derived gender‐specific birthweight tables. Main outcome measures. Comparisons between LGA and AGA pregnancies and between LGA 90–94.9th, 95–98.9th and ≥99th percentile. Results. The study population comprised 34 685 pregnancies; 3900 neonates matched the definition of term LGA. Maternal age and gestational age at delivery were significantly higher for LGA neonates. Significantly more LGA neonates were born by cesarean section, and significantly more LGA pregnancies were complicated by postpartum hemorrhage (PPH), shoulder dystocia or neonatal hypoglycemia, and had a longer hospitalization period. Maternal and neonatal risks increased as birthweight increased from the 90–94.9th to 95–98.9th to ≥99th percentile. Specifically, the risks of shoulder dystocia (odds ratio 2.61, 3.35 and 5.11, respectively), PPH (odds ratio 1.81, 2.12 and 3.92, respectively) and neonatal hypoglycemia (odds ratio 2.53, 3.8 and 5.19, respectively) all increased linearly with birthweight percentile. Conclusions. Large for gestational age pregnancies are associated with an increased rate of cesarean section, PPH, shoulder dystocia and neonatal hypoglycemia, as well as longer hospitalization. These risks increase as the birth percentile rises. These risks need to be emphasized in pre‐delivery counseling.

Intravenous immunoglobulin treatment in the prevention of childbirth-associated acute exacerbations in multiple sclerosis — A pilot study

Acute exacerbations frequently occur after childbirth in patients with relapsing-remitting multiple sclerosis (MS). The present pilot study was initiated in an attempt to reduce the number of childbirth-associated acute exacerbations in the postpartum period. We treated nine MS patients with a history of 12 childbirth-associated acute exacerbations that had occurred 2–9 weeks after previous deliveries. The patients were administered intravenous immunoglobulin (IVIg) at a dose of 0.4 g/kg per day for 5 consecutive days during the 1st week after childbirth and at 6 and 12 weeks there after. None of the treated patients relapsed during the 6-month period after delivery. However, three patients had a remote relapse, two at 8 months and one at 10 months after childbirth, but these probably represented the natural course of disease and were not associated with childbirth. We conclude that IVIg treatment may prevent acute childbirth-associated exacerbations in relapsing-remitting MS patients.

Increased prevalence of thrombophilia among women with severe ovarian hyperstimulation syndrome

OBJECTIVE To determine the prevalence of markers of thrombophilia in women hospitalized for severe OHSS. DESIGN Prospective study. SETTING Academic research center. PATIENT(S) Women undergoing induction of ovulation complicated by severe OHSS (n = 20) and women undergoing induction of ovulation without development of severe OHSS (n = 41). INTERVENTION(S) Blood samples to test for markers of thrombophilia were obtained during the luteal phase of the treatment cycle. MAIN OUTCOME MEASURE(S) Blood samples were analyzed for markers of thrombophilia, such as plasma levels of antithrombin, protein S and protein C, antiphospholipid antibodies, the factor V Leiden mutation, and 677T polymorphism in the 5,10 methyltetrahydrofolate reductase (MTHFR 677T) gene. RESULT(S) Seventeen of 20 patients with severe OHSS (85%) and 11 of 41 controls (26.8%) had one or more positive markers of thrombophilia. Of the women with severe OHSS, 6 had a decreased antithrombin level, 8 had decreased levels of protein S, 7 were homozygous for the MTHFR 677T mutation, 1 was heterozygous for the factor V Leiden mutation, and 5 had antiphospholipid antibodies. Eight women with OHSS and no controls had more than one positive marker of thrombophilia. CONCLUSION(S) The prevalence of thrombophilia is increased in women with severe OHSS. These findings suggest that prophylactic screening for this disorder and possible use of heparin prophylaxis for thromboembolic phenomena should be considered in these patients.

Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events

The objective of this study was to assess the safety of induction of ovulation and oocyte retrieval in patients at risk of thrombosis, necessitating treatment with anticoagulants. Twenty-four patients considered as high risk for a thromboembolic event underwent 73 IVF cycles and 68 oocyte retrieval procedures, and were treated concomitantly with anticoagulation therapy (low molecular weight heparin; LMWH). A subgroup of five patients considered at especially high risk for thrombosis was isolated. These patients were prepared for oocyte retrieval using a controlled spontaneous cycle. All these patients were programmed exclusively for surrogacy. Nineteen women underwent 49 cycles of ovulation induction with gonadotrophins. The average peak oestradiol concentration was 1791 +/- 1420 pg/ml with an average of 13.5 +/- 8.4 oocytes retrieved in each cycle. The five patients from the very high risk group underwent 24 cycles: the average peak oestradiol concentration was 163 +/- 98 pg/ml. In 18, an egg was retrieved and in 14, fertilization was achieved. No bleeding or thromboembolic complications were noted during treatment of both groups of patients. It is concluded that during induction of ovulation in patients at risk for thrombosis, the introduction of LMWH as a cycle protective treatment was not associated with any medical complication. The use of a controlled spontaneous cycle with LMWH is suggested in very high risk patients.

Maternal and neonatal outcomes of macrosomic pregnancies

Summary Background To compare maternal and neonatal outcomes of term macrosomic and adequate for gestational age (AGA) pregnancies. Material/Methods A retrospective analysis was performed on all term singleton macrosomic (birth weight ≥4000 g) and AGA (birth weight >10th percentile and <4000 g) pregnancies delivered at our hospital between 2004 and 2008. Data collected included maternal age, gestational age at delivery, mode of delivery, birth weight, fetal gender, maternal and neonatal complications. Comparisons were made between macrosomic and AGA pregnancies and between different severities of macrosomia (4000–4250 g, 4250–4500 g and ≥4500 g). Results The study population comprised of 34,685 pregnancies. 2077 neonates had birth weight ≥4000 g. Maternal age and gestational age at delivery were significantly higher for macrosomic neonates. Significantly more macrosomic neonates were born by cesarean section, and were complicated with shoulder dystocia, neonatal hypoglycemia, and had longer hospitalization period (both in vaginal and cesarean deliveries). Specifically, the odds ratio (OR) relative to AGA pregnancies for each macrosomic category (4000–4250 g, 4250–4500 g and ≥4500 g) of shoulder dystocia was 2.37, 2.24, 7.61, respectively, and for neonatal hypoglycemia 4.24, 4.41, 4.15, respectively. The risk of post partum hemorrhage was statistically increased when birth weight was >4500 g (OR=5.23) but not for birth weight between 4000–4500 g. No differences were found in the rates of extensive perineal lacerations between AGA and the different macrosomic groups. Conclusions Macrosomia is associated with increased rate of cesarean section, shoulder dystocia, neonatal hypoglycemia, and longer hospitalization, but not associated with excessive perineal tears. Increased risk of PPH was found in the >4500g group.

Meteorological factors in hypertensive disorders, vaginal bleeding and premature rupture of membranes during pregnancy

In order to determine whether there is a correlation between meteorological factors and the occurrence of hypertensive disorders, vaginal bleeding during pregnancy and premature rupture of the fetal membranes, we stratified all the patients hospitalized with such complications between the years 1984 and 1988 by the months of occurrence, weather, humidity and heat. During this period, there were 276 women hospitalized with exacerbation of hypertension and toxemia, 349 because of vaginal bleeding during pregnancy and 35 women following premature rupture of the fetal membrane between 30 and 33 weeks of gestation. The occurrence of pre-eclampsia and exacerbation of pregnancy-induced hypertension was significantly increased in the winter months (p less than 0.001).

Progression of labor in twin versus singleton gestations

OBJECTIVE The aim of this study was to investigate whether labor curves of twin gestations differ from those of singleton gestations. STUDY DESIGN Among 1821 twin deliveries at our institution (1984-1996), we found 69 nulliparous and 94 multiparous women who were delivered at term (>/=37 weeks) of a vertex twin A with a birth weight of >/=2500 g. We excluded women who had any of the following: induction of labor, oxytocin augmentation, cervical dilatation >6 cm on admission, tocolysis during the previous 14 days, height <150 cm, hypertension, and diabetes. Women with singleton gestations (n = 163) who met the same exclusion criteria were matched for parity and maternal age (+/-3 years). Stage 1 of labor was defined as the interval between 4 and 10 cm cervical dilatation. Kaplan-Meier survival analysis was used for comparison between the groups. RESULTS The study and control groups were similar in mean maternal height; however, women with twins were significantly heavier than were those with singletons (79.3 +/- 11.2 kg vs 73.2 +/- 10.8 kg, P <.001), had a higher frequency of epidural anesthesia (82% vs 62%), and had a significantly lower birth weight of the presenting fetus (2779.1 +/- 242.5 g vs 3301.4 +/- 429.2 g, P <.001). The cervical effacements and vertex stations on admission were similar in the 2 groups. On admission the cervical dilatation of women delivered of twins was smaller than that of the control group. Twin gestations had a significantly shorter first stage of labor than did their matched singleton control gestations (3.0 +/- 1.5 hours vs 4.0 +/- 2. 6 hours, P <.0001). This difference was apparent only in nulliparous women. No statistical difference was noted in the mean length of the second stage of labor (0.8 +/- 0.5 hour for twins and 0.7 +/- 0.6 hour for singletons). CONCLUSION Twin gestations have a significantly shorter first stage of labor than do singleton gestations. This difference may be the result of the birth weight of the presenting twin being lower than that of its singleton counterpart or to differences in uterine contractility in twin and singleton gestations. Different labor curves should be considered for managing twin deliveries.

Currently recommended oral regimens for ritodrine tocolysis result in extremely low plasma levels

OBJECTIVE Our aim was to compare plasma drug levels in patients receiving ritodrine intravenously with those in patients receiving ritodrine orally at recommended dosages. STUDY DESIGN Plasma samples from 20 pregnant patients treated with intravenous ritodrine (50 to 300 micrograms/min), 9 patients treated with oral ritodrine only (60 to 120 mg per 24 hours), and 9 patients treated first with intravenous and subsequently with oral ritodrine were analyzed for ritodrine concentration with the use of high-performance liquid chromatography. RESULTS Average plasma ritodrine levels of patients receiving different intravenous dosages ranged from 27.8 +/- 3.5 to 113.3 +/- 38.8 ng/ml. Levels during oral therapy ranged between 9.8 +/- 3.2 and 13.8 +/- 4.4 ng/ml. In both modes of drug delivery, concentrations were significantly correlated with doses. In patients treated first with intravenous ritodrine and subsequently with the oral form, plasma concentrations during oral therapy averaged 27.7% +/- 18.8% of those obtained during intravenous infusion. CONCLUSION Subtherapeutic plasma concentrations might be responsible for the failure to demonstrate clinical benefits of oral ritodrine in prevention of recurrent preterm labor. A twofold to threefold increase in the maximum recommended oral dosage of ritodrine should be considered, especially for patients who had previously required relatively high intravenous infusion rates (> 100 micrograms/min).

Oxytocin or saline injected intra-umbilically did not influence the third stage of labor.

The injection of varying volumes of normal saline solution, alone or with oxytocin, into the umbilical vein immediately after delivery was studied in 125 normal women delivered at term. Thirty seconds after cord clamping, either 20 ml (group 1, n = 25 women), 30 ml (group 2, n = 25) or 40 ml (group 3, n = 25) of normal saline solution alone, or oxytocin 10 units in 20 ml saline solution (group 4, n = 25) or ozytoxin 10 units in 40 ml saline solution (group 5, n = 25) were injected into the umbilical vein 1 cm from the introitus just proximal to the umbilical clamp. The mean (± SD) duration of placental expulsion was similar in the five study groups. We conclude that neither the volume of the solution nor the oxytocin injected intra‐mumbilically has any effect on the duration of the third stage of normal labor.