Steen Rasmussen

Effect of Prepregnancy Maternal Overweight and Obesity on Pregnancy Outcome

OBJECTIVE: To estimate the association between maternal overweight and obesity on complications during pregnancy and delivery in Denmark. METHODS: A population-based study on a cohort consisting of all Danish women giving birth to a singleton from 2004 through June 30, 2010 (N=403,092) was undertaken. Women were identified from the Danish Medical Birth Registry, which contains data on 99.8% of all deliveries in Denmark. Maternal complications during pregnancy and delivery and fetal complications were classified according to the International Classification of Diseases, 10th Revision. RESULTS: The final study population consisted of 369,347 women, 20.9% being overweight (body mass index [BMI] 25–29.9), 7.7% obese (BMI 30–35), and 4% severely obese (BMI higher than 35). Overweight, obese, and severely obese women had more complications than did normal weight women. Adjusted odds ratios (ORs) were significantly increased as follows: for gestational diabetes mellitus, 3.5, 7.7, and 11.0 for each BMI category; for preeclampsia 1.9, 3, and 4.4. Planned and especially emergency cesarean delivery was significantly increased with increasing BMI (OR ranging from 1.2 to 2.1). The risk of giving birth to a macrosomic neonate (greater than 4,500 g) increased significantly with increasing BMI (1.6, 2.2, and 2.7), as did the risks of having a neonate with a low Apgar score (1.3, 1.4, and 1.9) and having a stillborn fetus (1.4, 1.6, and 1.9). For shoulder dystocia the risk was significantly increased in the unadjusted analysis, but the significance disappeared in the adjusted analysis. No statistically significance was seen for hemorrhage and thrombosis. CONCLUSION: This study shows a significant increased risk of a wide variety of pregnancy, birth, and neonatal complications in overweight, obese, and severely obese women. LEVEL OF EVIDENCE: II

Infant outcome of 957 singletons born after frozen embryo replacement: The Danish National Cohort Study 1995–2006

OBJECTIVE To examine infant outcome of singletons born after cryopreservation of embryos (Cryo). DESIGN National population-based controlled follow-up study. SETTING Denmark, 1995-2007. PATIENT(S) The study population was 957 Cryo singletons (Cryo-IVF, n=660; Cryo-ICSI, n=244; Cryo-IVF/-ICSI, n=53). The first control group was all singletons born after fresh IVF or intracytoplasmic sperm injection (ICSI) during the same period (IVF, n=6904; ICSI, n=3425). The second control group comprised a random sample of non-assisted reproductive technology (ART) singletons (n=4800). INTERVENTION(S) All observations were obtained from national registers. MAIN OUTCOME MEASURE(S) Low birth weight (LBW; <2500 g), preterm birth (PTB; <37 weeks), congenital malformations, mortality, and morbidity. RESULT(S) Birth weight was higher in Cryo (mean=3578 g, SD=625) versus fresh (mean=3373 g, SD=648) and in Cryo versus non-ART (mean=3537 g, SD=572), and this was also the case for first birth only. Lower adjusted risk of LBW (odds ratio [OR]=0.63; 95% confidence interval [CI], 0.45-0.87) and PTB (OR=0.70; 95% CI, 0.53-0.92) was observed in Cryo versus fresh. Similar LBW and PTB rates were observed when comparing Cryo with non-ART, but the perinatal mortality rate was doubled in Cryo (1.6%) compared with non-ART (0.8%) singletons, and the adjusted risks of very preterm birth (<34 weeks) and neonatal admittance were also significantly increased. No significant differences in the prevalence rates of birth defects, neurological sequelae, malignancies, and imprinting-related diseases were observed between the Cryo and the two control groups. However higher malformation and cerebral palsy rates were observed in the total Fresh vs. non-ART group. CONCLUSION(S) Cryo singletons have better neonatal outcome than offspring after fresh ET but poorer compared with non-ART singletons.

Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study

STUDY QUESTION Does neonatal outcome including congenital malformations in children born after ICSI with epididymal and testicular sperm [testicular sperm extraction (TESE)/percutaneous epididymal sperm aspiration (PESA)/testicular sperm aspiration (TESA) (TPT)] differ from neonatal outcome in children born after ICSI with ejaculated sperm, IVF and natural conception (NC)? SUMMARY ANSWER Children born after TPT have similar neonatal outcome, including total malformation rates, as have children born after ICSI and IVF with ejaculated sperm. Testing for variance over the four groups may indicate smaller differences in specific malformation rates with TPT as the highest risk group. WHAT IS KNOWN ALREADY Regarding neonatal outcome as well as congenital malformations in children born after TPT, studies are few, with limited sample size, heterogeneous and often performed without relevant control groups. STUDY DESIGN, SIZE, DURATION Population-based cohort study including all Danish children born after TPT and fresh embryo transfer in Denmark from 1995 to 2009. Children born after transfer of frozen-thawed embryos were excluded. Control groups of children conceived by ICSI with ejaculated sperm, IVF and NC were identified by cross-linkage of the Danish IVF Register, Medical Birth Register (MBR) and National Hospital Discharge Register (HDR). PARTICIPANTS/MATERIALS, SETTING The study group consisted of 466 children born after TPT, while the control groups consisted of 8967 (ICSI with ejaculated sperm), 17 592 (IVF) and 63 854 (NC) children. Neonatal outcomes and congenital malformations were analysed for singletons and twins separately. Risk estimates for low birthweight (LBW, <2500 g) and preterm birth (PTB, <37 gestational weeks) were adjusted for maternal age, parity, child gender and year of childbirth. The study group was identified from the Danish national database on children born after TPT. Control groups were obtained from the IVF register and the MBR. All information included in the study was retrieved from the national registers. MAIN RESULTS AND THE ROLE OF CHANCE Considering singletons and twins as one group, the sex ratio (♂/♀) was significantly lower for children born after TPT (0.89) compared with conventional IVF (1.11; P = 0.017) but did not differ significantly when compared with ICSI with ejaculated sperm (0.94) and NC (1.05). The mean birthweight (BW) for singletons did not differ significantly between groups when including only first-born children. The mean gestational age (GA) in the TPT singletons (279 ± 12 days) was significantly higher compared with IVF (276 ± 18 days; P = 0.02), but similar to ICSI with ejaculated sperm and NC singletons when including only first-born children (277 ± 16 days and 279 ± 14 days, respectively). Rate of stillbirths, perinatal and neonatal mortality in the group of TPT singletons did not differ significantly from any of the control groups. Comparable results were found for the TPT twin group, except for perinatal mortality, which was significantly lower in the TPT group compared with naturally conceived twins. The adjusted risk of LBW was significantly higher for TPT versus NC singletons [adjusted odds ratio (AOR) = 0.67 (0.48-0.93)]; however AOR for PTB was similar in the two groups. Regarding twins, similar adjusted risks were observed for PTB and LBW between the TPT and all three control groups. Significantly more Caesarean sections were performed after IVF (27.3% for singletons) and ICSI (25.1% for singletons) with ejaculated sperm compared with the TPT group (16.4% for singletons). The total rate of congenital malformations in the TPT group was 7.7% and did not differ significantly from any of the control groups. However, singleton TPT boys showed an increased rate of cardiac malformations (3.6%) compared with singleton boys after IVF (1.4%; P = 0.04) and NC (1.1%; P = 0.02). Considering the level of male infertility as a continuum over the four groups, tests for variance in the rate of cardiac malformations in singleton boys, and undescended testicles for singleton as well as twin boys were each significantly increased from NC to IVF to ICSI to TPT (P < 0.001). The rate of hypospadias showed the same pattern, but the TPT group did not differ significantly compared with the control groups. LIMITATIONS, REASONS FOR CAUTION One of the limitations is that the TPT group could not be classified according to testicular or epididymal sperm, as these data were not available in the IVF register. Another limitation is that registry-based studies are encumbered with the risk of reporting or coding errors or missing data due to insufficient coding. However, the quality of data on congenital malformations in HDR has, in other studies, been validated and found acceptable for epidemiological research, and furthermore, recordings on study and control groups are performed similarly. WIDER IMPLICATIONS OF THE FINDINGS Accumulating data show that TPT treatment is equally safe as conventional ICSI and IVF treatment and as NC with regard to neonatal outcome including congenital malformation. STUDY FUNDING/POTENTIAL COMPETING INTERESTS This study is supported by Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital. No competing interests declared.

Perinatal outcomes in 375 children born after oocyte donation: a Danish national cohort study

OBJECTIVE To describe perinatal outcomes in children born after oocyte donation (OD) compared with in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and spontaneous conception (SC). DESIGN National cohort study. SETTING Fertility clinics. PATIENT(S) Three hundred seventy-five children born after OD during the period 1995-2010. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Mean birth weight, mean gestational age, risks of low birth weight (LBW), preterm birth (PTB), congenital malformations, cesarean delivery, preeclampsia, and admittance to neonatal intensive care unit. RESULT(S) We found an increased risk of PTB in OD pregnancies. The adjusted odds ratio (AOR) of PTB in OD singletons was 1.8 (95% CI, 1.2-2.69), 2.5 (95% CI, 1.7-3.6), and 3.4 (95% CI, 2.3-4.9) compared with IVF, ICSI, and SC, respectively. The risk of LBW was also increased. The AOR of LBW was 1.4 (95% CI, 0.9-2.2), 1.8 (95% CI, 1.2-2.8), and 2.6 (95% CI, 1.7-4.0) compared with IVF, ICSI, and SC. The risk of preeclampsia was increased in OD pregnancies with an AOR of 2.9 (95% CI, 1.8-4.6), 2.8 (95% CI, 1.7-4.5), and 3.1 (95% CI, 1.9-4.9) compared with IVF, ICSI, and SC. After additional adjustment for preeclampsia, perinatal outcome improved. Among the twins, the difference between the groups was less pronounced. CONCLUSION(S) Pregnancies after OD have a poorer perinatal outcome than those after standard IVF and ICSI mainly because of the high prevalence of preeclampsia.

Maternal and neonatal outcomes in pregnancies complicated by gestational diabetes. a nation-wide study

Abstract Objective: To estimate the association between gestational diabetes mellitus (GDM) and adverse pregnancy and neonatal outcomes in Denmark. Methods: A population-based cohort study including all singleton pregnancies in Denmark from 2004 to 2010 (n = 403 092). Maternal complications during pregnancy and delivery and fetal complications were classified according to the International Classification of Diseases 10th Revision. Results: The final study population consisted of 398 623 women. Of these, 9014 (2.3%) had GDM. Data were adjusted for maternal age, parity, smoking, gestational age, birth weight, BMI, gender of the fetus and calendar year. The risk of preeclampsia, caesarean section (both planned and emergency) and shoulder dystocia was increased in women with GDM. In the unadjusted analysis, the risk of thrombosis was increased by a factor 2 in the GDM patients, but in the adjusted analysis this association disappeared. Post-partum hemorrhage was similar in the two groups. The GDM women had an increased risk of giving birth to a macrosomic neonate although the unadjusted analysis did not show any difference between the two groups. Low Apgar score was increased in the GDM, but this association disappeared in the adjusted analysis. Stillbirth was comparable in the two groups. Conclusions: Women with GDM still have increased incidence of obstetric and neonatal complications, which could imply that treatment of women with GDM should be tightened.

Treatment for Retinopathy of Prematurity in Denmark in a Ten-Year Period (1996–2005): Is the Incidence Increasing?

OBJECTIVE. The objective of this study was to analyze the population incidence of retinopathy of prematurity treatment in Denmark in the 10-year period from 1996 to 2005. METHODS. Patient charts of infants treated for retinopathy of prematurity and the national birth registry provide information about neonatal parameters. These parameters, along with birth in the latter half of the period (2001–2005), were analyzed as risk factors for retinopathy of prematurity. The national registry for blind and visually impaired children was accessed to obtain information about visual impairment attributable to retinopathy of prematurity in both treated and untreated infants. RESULTS. The study population consisted of 5467 Danish preterm infants born in 1996 to 2005, with a gestational age of <32 weeks, who survived for ≥5 postnatal weeks; 2616 were born in 1996 to 2000, and 2851 were born in 2001 to 2005. The incidence of treated retinopathy of prematurity cases increased significantly from 1.3% in 1996 to 2000 to 3.5% in 2001 to 2005. Significant risk factors for retinopathy of prematurity treatment were low gestational age, small for gestational age, male gender, and multiple birth. Other, yet unknown factors contributed to the increased incidence in the latter half of the period. Of the study population, 0.6% were registered as visually impaired because of retinopathy of prematurity within 2 years after birth (early-detected visual impairment). The incidences were not significantly different between 1996 to 2000 and 2001 to 2005. Of all of the early-detected, visually impaired children, 16% had not been treated for retinopathy of prematurity and were considered screening failures. CONCLUSIONS. The incidence of retinopathy of prematurity treatment in Denmark has more than doubled during the past half-decade. This increase could not be fully explained by increased survival rates for the infants or by changes in the investigated neonatal risk factors.

Consequences of the Term Breech Trial in Denmark

Objective. To analyze the consequences of the handling of breech presentation in Denmark after publication of the Term Breech Trial (TBT). Design. Population‐based retrospective cohort study. Settings. Data from the National Birth Registry and discharge letters from cases with perinatal death. Population. Singleton breech fetuses at term and alive at onset of labor delivered between 1997 and 2008 (n=23 789). Methods. Outcomes before and after publication of TBT were compared and analyzed by planned mode of delivery. Main outcome measures. Cesarean section, intrapartum or early neonatal mortality in infants without lethal congenital malformations, Apgar score ≤6 at five minutes and admittance to neonatal intensive care unit (NICU) for four days or more. Results. The rate of cesarean section increased from 79.6 to 94.2%. Intrapartum or early neonatal mortality was reduced from 0.13 to 0.05%[relative risk (RR) 0.38 (95% confidence intervals (CI) 0.15–0.98)]. The incidence of low Apgar scores declined from 1.0 to 0.6%[RR 0.83 (95%CI 0.73–0.95)] and admission to NICU from 4.2 to 3.2%[RR 0.92 (95%CI 0.87–0.97)]. Planned vaginal delivery was associated with an increased risk of mortality, low Apgar score and admission to NICU throughout the period. Conclusion. Reduction in the rate of vaginal delivery was correlated with a significant reduction in rates of intrapartum or early neonatal mortality and morbidity, but at a much lower level than reported in the Term Breech Trial. The lower rate of vaginal delivery, indicating a strict selection of women, did not reduce the relative risks of complications during a planned vaginal delivery.

Influence of chorionicity on perinatal outcome in a large cohort of Danish twin pregnancies.

To assess outcome in twin pregnancies according to chorionicity.

Waiting time to pregnancy according to maternal birthweight and prepregnancy BMI

BACKGROUND An association between a womans own birthweight and her fecundity has been suggested, but no empirical data have been published on the association between maternal birthweight and waiting time to pregnancy (TTP). METHODS In the Danish National Birth Cohort (1996-2002), which is an ongoing study of 92 274 women and their pregnancies, information about TTP and prepregnancy BMI was collected during pregnancy. At the 7-year follow-up of the children, 21 786 mothers reported their own birthweight and whether they were born at term or preterm. The association between maternal birthweight and TTP is presented as adjusted odds ratios with 95% confidence intervals. RESULTS Low maternal birthweight (< or =2500 g for term and < or =1500 g for preterm birth) was associated with an increased risk of TTP of >1 year [term: 1.2 (1.0-1.5); preterm: 1.8 (1.1-3.1)]. The latter association was strongest in women with a BMI < 25 kg/m(2) [2.6 (1.4-4.7)]. High maternal birthweight (>4500 g for term and >3500 g for preterm) was also associated with an increased risk of TTP of >1 year [1.5 (1.0-2.0) and 1.3 (0.7-2.4), respectively], especially in women with a BMI > or = 25 kg/m(2) [1.8 (1.1-3.1) and 2.5 (1.0-6.4), respectively]. CONCLUSIONS High or low maternal birthweight was associated with TTP > 1 year. Longer waiting times in women with very low birthweight may reflect an effect of being born very preterm. Subfecundity may partly be programmed in foetal life by factors that cause or correlate with foetal growth.

Parity and risk of diabetes in a Danish nationwide birth cohort

Diabet. Med. 28, 43–47 (2011)