Bay, B., Boie, S., & Kesmodel, U. S. (2019). Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study. BJOG : an international journal of obstetrics and gynaecology, 126(2), 253-260. https://doi.org/10.1111/1471-0528.15509
Bay B, Boie S, Kesmodel US. Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study. BJOG : an international journal of obstetrics and gynaecology. 2019;126(2):253-260. doi:10.1111/1471-0528.15509
Bay, B., et al. "Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study." BJOG : an international journal of obstetrics and gynaecology, vol. 126, no. 2, 2019, pp. 253-260.
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Abstract
Objective
To assess the risk of stillbirth in low-risk in vitro fertilisation (IVF) pregnancies.
Design
Register-based national cohort study.
Setting
Denmark 2003-2013.
Population
Cohort of 425 732 singleton pregnancies including 10 235 conceived following IVF/intracytoplasmic sperm injection (ICSI), 4521 conceived following intrauterine insemination (IUI), and 410 976 spontaneously conceived.
Methods
Information on pregnancy, obstetrical risk factors, stillbirth, and fertility treatment was obtained from the Danish national health registers for all pregnancies after gestational week 21+6 . We estimated the overall and gestational age-specific risk of stillbirth in low-risk term pregnancies following IVF, ICSI, and IUI. Further, we estimated the association between stillbirth and IVF and ICSI respectively as well as fresh or frozen-thawed embryo transfer.
Main Outcome Measures
Risk of stillbirth.
Results
The number of stillbirths in spontaneously conceived and IVF/ICSI low-risk term pregnancies was 525 (0.1%) and 35 (0.3%), respectively. In multivariate analysis, the risk of stillbirth in pregnancies following IVF/ICSI was increased (odds ratio 2.1, 95% CI 1.4-3.1). The risk of stillbirth was correspondingly increased in time-to-event analyses taking risk time for each fetus into account from gestational week 37 and onwards (hazard ratio 2.4, 95% CI 1.6-3.6). In sub-analyses, the risk of stillbirth was increased for pregnancies following ICSI (odds ratio 2.2, 95% CI 1.2-3.1), but not IVF (odds ratio 1.7, 95% CI 0.9-3.1).
Conclusion
We found a systematically increased risk of stillbirth in low-risk term pregnancies following IVF/ICSI. Whether the risk was related to the treatment or to underlying subfertility is uncertain. The results may indicate a need for obstetrical surveillance for these pregnancies when reaching term.
Tweetable Abstract
Increased risk of stillbirth in low-risk term pregnancies following fresh cycle IVF/ICSI.
Michaelsen MP et al., 2025·BJOG: An International Journal of Obstetrics and Gynaecology·Free full text on PubMed Central
To study the association between previous use of levonorgestrel intrauterine system (LNG-IUS) and endometrial thickness (EMT) in women undergoing in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Multicentre historical cohort study. Eight Danish public and private fertility clinics. 12786 women aged 18-46 years contributing with an EMT measurement from 22 464 different IVF/ICSI treatment cycles between 2000 and 2021. Exposure was previous use of LNG-IUS, combined oral contraceptive pills (OCPs), progestogen-only pills (POPs), no/other contraception or combined, cumulated use of contraception when more contraceptives had been used during the inclusion period. LNG-IUS use was categorised into 0-3 years, >3-6 years, >6-9 years and >9 years. Mixed effect logistic regression adjusted for age, BMI, smoking, educational level, total FSH dose and fertility clinic was used. EMT (< 7 mm vs >= 7 mm). Statistically significantly higher odds of EMT >= 7 mm were found for OCPs [OR 3.53 (95% CI 1.29-9.65)], POPs [OR 6.43 (95% CI 1.45-28.63)] and no/other contraception [OR 6.67 (95% CI 2.37-18.74)] relative to LNG-IUS in IVF/ICSI cycles. All duration categories of ever use of LNG-IUS were associated with significantly lower odds of EMT >= 7 mm compared to no/other contraception. Previous use of LNG-IUS was associated with decreased endometrial growth in women undergoing IVF/ICSI.
Boie S et al., 2021·BMJ (Clinical research ed.)·Free full text on PubMed Central
To determine whether discontinuing oxytocin stimulation in the active phase of induced labour is associated with lower caesarean section rates. International multicentre, double blind, randomised controlled trial. Nine hospitals in Denmark and one in the Netherlands between 8 April 2016 and 30 June 2020. 1200 women stimulated with intravenous oxytocin infusion during the latent phase of induced labour. Women were randomly assigned to have their oxytocin stimulation discontinued or continued in the active phase of labour. Delivery by caesarean section. A total of 607 women were assigned to discontinuation and 593 to continuation of the oxytocin infusion. The rates of caesarean section were 16.6% (n=101) in the discontinued group and 14.2% (n=84) in the continued group (relative risk 1.17, 95% confidence interval 0.90 to 1.53). In 94 parous women with no previous caesarean section, the caesarean section rate was 7.5% (11/147) in the discontinued group and 0.6% (1/155)in the continued group (relative risk 11.6, 1.15 to 88.7). Discontinuation was associated with longer duration of labour (median from randomisation to delivery 282 v 201 min; P<0.001), a reduced risk of hyperstimulation (20/546 (3.7%) v 70/541 (12.9%); P<0.001), and a reduced risk of fetal heart rate abnormalities (153/548 (27.9%) v 219/537 (40.8%); P<0.001) but rates of other adverse maternal and neonatal outcomes were similar between groups. In a setting where monitoring of the fetal condition and the uterine contractions can be guaranteed, routine discontinuation of oxytocin stimulation may lead to a small increase in caesarean section rate but a significantly reduced risk of uterine hyperstimulation and abnormal fetal heart rate patterns. ClinicalTrials.gov NCT02553226.
Kettner LO et al., 2021·Human reproduction (Oxford, England)
Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy? Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood. Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus. This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016. Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression. A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53). The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis. The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment. Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work. N/A.
Wisborg K et al., 2010·Human reproduction (Oxford, England)
Previous studies have indicated that the risk of stillbirth is increased in singleton pregnancies achieved after assisted reproduction technology (ART). However, no previous study fully accounted for factors with potential influence on the risk of stillbirth. Further, whether fertility treatment, the possible reproductive pathology of the infertile couples or other characteristics related to being subfertile may explain a possible association with stillbirth remains unclear. This study compares the risk of stillbirth in women pregnant after fertility treatment (IVF/ICSI and non-IVF ART) and subfertile women with that in fertile women. We used prospectively collected data from the Aarhus Birth Cohort, Denmark and included information about 20 166 singleton pregnancies (1989-2006). Outcome measure was stillbirth. The risk of stillbirth in women who conceived after IVF/ICSI was 16.2 per thousand ( per thousand) and in women who conceived after non-IVF ART 2.3 per thousand. In fertile and subfertile women, the risk of stillbirth was 3.7 per thousand and 5.4 per thousand, respectively. Compared with fertile women, women who conceived after IVF/ICSI had more than four times the risk of stillbirth [odds ratio (OR): 4.44, 95% confidence interval (CI): 2.38-8.28], and adjustments for maternal age, BMI, education, smoking habits and alcohol and coffee intake during pregnancy had only minor impact on the findings (OR: 4.08; 95% CI: 2.11-7.93). The risk of stillbirth in women who conceived after non-IVF ART and in women who conceived spontaneously with a waiting time to pregnancy of a year or more was not significantly different from the risk in women with a shorter time to pregnancy. Compared with fertile women, women who conceived by IVF/ICSI had an increased risk of stillbirth that was not explained by confounding. Our results indicate that the increased risk of stillbirth seen after fertility treatment is a result of the fertility treatment or unknown factors pertaining to couples who undergo IVF/ICSI.
To compare the risk of preterm delivery, low birth weight, and admission of the newborn to a neonatal intensive care unit (NICU) in women pregnant after fertility treatment and subfertile women with the risk in fertile women. Prospective follow-up study. Aarhus University Hospital, Skejby, Denmark, 1989-2006. PATIENT(S): A total of 20,080 liveborn singletons. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm delivery, low birth weight, and admission of the newborn to a NICU. RESULT(S): After adjustment we found a statistically significantly increased risk of preterm delivery and very preterm delivery in women who conceived after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) compared with fertile women. Compared with fertile women, the risk of preterm delivery and very preterm delivery was not statistically significantly different in women pregnant after non-IVF assisted reproductive treatment (non-IVF ART) or subfertile women. We found no association between IVF/ICSI and the risk of low birth weight at term or admittance to the NICU. CONCLUSION(S): The increased risk of preterm delivery after IVF/ICSI may be due to the fertility treatment or unknown characteristics in the couples who undergo IVF/ICSI.
Romundstad LB et al., 2008·Lancet (London, England)
Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.
Sanders JN et al., 2022·Reprod Health·Free full text on PubMed Central
In vitro fertilization (IVF) births contribute to a considerable proportion of preterm birth (PTB) each year. However, there is no formal surveillance of adverse perinatal outcomes for less invasive fertility treatments. The study objective was to describe associations between fertility treatment (in vitro fertilization, intrauterine insemination, usually with ovulation drugs (IUI), or ovulation drugs alone) and preterm birth, compared to no treatment in subfertile women. The Fertility Experiences Study (FES) is a retrospective cohort study conducted at the University of Utah between April 2010 and September 2012. Women with a history of primary subfertility self-reported treatment data via survey and interviews. Participant data were linked to birth certificates and fetal death records to asses for perinatal outcomes, particularly preterm birth. A total 487 birth certificates and 3 fetal death records were linked as first births for study participants who completed questionnaires. Among linked births, 19% had a PTB. After adjustment for maternal age, paternal age, maternal education, annual income, religious affiliation, female or male fertility diagnosis, and duration of subfertility, the odds ratios and 95% confidence intervals (CI) for PTB were 2.17 (CI 0.99, 4.75) for births conceived using ovulation drugs, 3.17 (CI 1.4, 7.19) for neonates conceived using IUI and 4.24 (CI 2.05, 8.77) for neonates conceived by IVF, compared to women with subfertility who used no treatment during the month of conception. A reported diagnosis of female factor infertility increased the adjusted odds of having a PTB 2.99 (CI 1.5, 5.97). Duration of pregnancy attempt was not independently associated with PTB. In restricting analyses to singleton gestation, odds ratios were not significant for any type of treatment. IVF, IUI, and ovulation drugs were all associated with a higher incidence of preterm birth and low birth weight, predominantly related to multiple gestation births.
Assisted Reproduction › Safety and Risks › Neonatal and Birth Outcomes · Pregnancy › Pregnancy Complications › Hypertensive Disorders · Birth and Delivery › Birth Outcomes › Maternal Morbidity
PMID 30341984 30341984 DOI 10.1111/1471-0528.15509 10.1111/1471-0528.15509 Bay et al. 2019, Bay 2019
Cite this article
Bay, B., Boie, S., & Kesmodel, U. S. (2019). Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study. BJOG : an international journal of obstetrics and gynaecology, 126(2), 253-260. https://doi.org/10.1111/1471-0528.15509
Bay B, Boie S, Kesmodel US. Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study. BJOG : an international journal of obstetrics and gynaecology. 2019;126(2):253-260. doi:10.1111/1471-0528.15509
Bay, B., et al. "Risk of stillbirth in low-risk singleton term pregnancies following fertility treatment: a national cohort study." BJOG : an international journal of obstetrics and gynaecology, vol. 126, no. 2, 2019, pp. 253-260.
Keywords
Fertility treatment, in vitro fertilisation, intracytoplasmic sperm injection, stillbirth