Study population and data sources

The Committee of Nordic ART and Safety (CoNARTaS) study population comprises all deliveries in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1985–2015). Data were obtained from the nationwide Medical Birth Registries (MBRs) in each country, where detailed information on maternal, fetal, and neonatal health for all deliveries is recorded. Individual-level data from MBRs can be linked to other data sources through the unique national identity number assigned to all residents in the Nordic countries. ART conception was determined through direct reporting to MBRs (Finland 1990–2014, Norway 1984–2015, and Sweden 1985–2006), in separate notifications of all ART pregnancies at gestational week 6-7 (Norway 1984–2015) or through linkage with cycle-based ART registries (Denmark 1994–2014 and Sweden 2007–2015).

From the MBRs we obtained information on birth year, plurality, birthweight, gestational age, offspring sex, parity, maternal age, smoking status in pregnancy and body mass index (BMI, measured prepregnancy or in first trimester). For SC pregnancies, gestational age was estimated based on ultrasound examination or on last menstrual period if information from ultrasound examination was unavailable. For ART pregnancies, gestational age was estimated based on ultrasound examination or on date of embryo transfer and culture duration, according to clinical practice in each country.

Information on pregnancy complications was obtained directly from MBRs in Finland (2004–2014), Norway (1984–2015), and Sweden (1985–2015) and from data linkage with national patient registries (NPRs) in Denmark (1994–2014) and Finland (1989–2014). In the MBRs, complications are reported at delivery with limited information on gestational age at diagnosis. In Norway, the MBR revised the notification form in 1998, changing the reporting of pregnancy complications from free text to checkboxes. For NPR data, diagnoses from each prenatal visit, delivery and postpartum controls were linked to each pregnancy using maternal identity and date of delivery. The Danish NPR comprised data from hospital admissions and outpatient visits in public specialist health care during the entire study period, and from private specialist health care since 2003. The Finnish NPR expanded its data collection in 1998 from hospital admissions only to include also hospital outpatient visits.

Because there were very few ART deliveries during the first years of registration, and among women of young or high reproductive ages, we restricted the study to 1988–2015 and deliveries with maternal age 22–44 years. Thus, a total of 6,830,578 deliveries among 4,160,402 women were eligible.

We excluded 120,628 deliveries with missing information on one or more study variables and 12,944 deliveries with gestational age <22 or ≥45 weeks, birthweight <300 g or ≥6000 g and birthweight for gestational age ≥+6 standard deviations. Multiple pregnancies were excluded when at least one child met the exclusion criteria. Our main analysis sample included 146,998 deliveries after ART and 6,683,580 deliveries of SC pregnancies. Selection of the study population and subsamples for sensitivity analyses are described in Figure 1 .

Selection of the study population and subsamples for sensitivity analyses

Solid-line arrows pointing to the right indicate exclusions, and dashed-line arrows pointing to the right indicate subsample selection. ^a Using z-scores from Marsal et al where the authors developed growth curves based on ultrasonography from Swedish centers and made exclusive curves according to offspring sex. ^b Deliveries among parous women whose first delivery was included in the main analysis sample and thus had information on delivery mode in all previous deliveries. ^c Data from Denmark (2011–2014), Norway (2011–2015), and Sweden (2006–2015). ^d Data from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015).

ART , assisted reproductive technology, BMI , body mass index; SC , spontaneous conception.

Petersen et al. Time trends in placenta-mediated pregnancy complications after assisted reproductive technology in the Nordic countries. Am J Obstet Gynecol 2020.

Outcome variables

Pregnancy complications were registered according to national adaptations of the International Classification of Diseases and related Health Problems classification as outlined in Supplemental Table 1 . We considered HDP as a combined outcome including preeclampsia, eclampsia, gestational hypertension, and chronic hypertension with superimposed preeclampsia. We did not consider chronic hypertension as a hypertensive disorder in pregnancy because prepregnancy conditions cannot be a consequence of ART. For MBR data, any reporting of relevant International Classification of Diseases and related Health Problems codes was considered as events, whereas the following diagnoses were included from NPRs: Diagnoses of HDP registered after 20 weeks gestation, any diagnosis of placental abruption, and any diagnosis of placenta previa in the third trimester or within one month before delivery.

Statistical analyses

We used logistic regression to estimate time trends in occurrence of pregnancy complications within the ART and SC populations. To facilitate interpretation, we used post-estimation commands to calculate absolute risks and risk differences (RDs) with 95% confidence intervals (CIs). We estimated trends over birth year categories (1988–1992, 1993–1997, 1998–2002, 2003–2007, 2008–2012, 2013–2015) and as linear trends across the study period (change per 5 years, continuous variable). We also compared risk of each complication in ART versus SC pregnancies within each period as a measure of whether risks in the 2 populations converged over time. Analyses were performed on the all pregnancies, and for singletons and twins, separately. We adjusted for parity, maternal age and country. To investigate whether time trends differed between countries, we repeated analyses for each country separately.

We performed several sensitivity analyses to investigate potential explanations for the observed trends: We repeated analyses for primiparous women. In subsamples with available information, we adjusted for maternal BMI and smoking. Within the ART population, we also adjusted for embryo cryopreservation (restricted to Denmark, Norway and Sweden) and culture duration (cleavage stage 2–3 days vs blastocyst stage 5–6 days, restricted to Denmark and Sweden). Next, we restricted diagnosis of placenta previa to pregnancies with delivery by cesarean section, which is required in cases of complete obstruction. Furthermore, to investigate the potential impact of a previous cesarean delivery, a known risk factor for placenta previa subjected to marked time trends, we adjusted for this in a subsample of deliveries among parous women whose first delivery was included in the study. Statistical analyses were performed using Stata/MP for Windows, Version 15.0 (StataCorp LLC, College Station, TX).

Ethical considerations and approvals

Approvals for data retrieval and linkage were obtained in each country. In Denmark and Finland, ethical approval is not required for research solely based on registry data. In Norway, ethical approval was given by the Regional Committee for Medical and Health Research Ethics (REC North, 2010/1909). In Sweden approval was obtained from the Ethical committee in Gothenburg, Dnr 214-12, T422-12, T516-15, T233-16, T300-17, T1144-17, T121-18.

Hypertensive disorders in pregnancy

Risk of HDP in SC pregnancies was 4.4% ( Table 2 ). For all pregnancies (ie, singletons and multiples combined), risk of HDP was greater in ART compared with SC pregnancies throughout the study period (odds ratio [OR], 1.25, 95% CI, 1.23–1.28, corresponding to a RD of 1.06 percentage points [ pp ]). In SC pregnancies, risk increased with 0.17 pp per 5 years (95% CI, 0.16–0.18). The increase was stronger in twin compared with singleton pregnancies (RD 0.75 and 0.16 pp per 5 years, respectively). When adjusting for maternal smoking and BMI in a subsample, time trends were reversed in SC singletons and substantially attenuated in SC twins ( Supplemental Table 2 ). For all ART pregnancies combined, there was no clear time trend. However, in separate analyses of singleton and twin pregnancies, development followed that in SC pregnancies ( Figure 2 A–B), with strongly increasing risk in twin pregnancies (RD 1.73 pp per 5 years, 95% CI, 1.35–2.11) in all countries. Adjustment for maternal smoking and BMI had little influence on trends in ART pregnancies, but adjustment for cryopreservation moderately attenuated trends in ART twin pregnancies ( Supplemental Table 2 ).

Time trends in risk of placenta-mediated pregnancy complications

Shown are time trends in risk of HDP, placental abruption, and placenta previa according to conception method, plurality, and country. ( A ) HDP in ART pregnancies. ( B ) HDP in SC pregnancies. ( C ) Placental abruption in ART pregnancies. ( D ) Placental abruption in SC pregnancies. ( E ) Placenta previa in ART pregnancies. ( F ) Placenta previa in SC pregnancies. Estimates are adjusted for parity and maternal age.

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