The main finding of our study is that HG requiring hospitalisation was not associated with increased risks for PTB, LBW or SGA. Pregnancies complicated with HG had a slightly shorter gestational length. There was no difference in birth weight according to maternal HG-status. Time-point for hospitalisation did not influence birthweight or gestational age. Moreover, HG was associated with lower risk for having Apgar score < 7 after 1 minute, whereas there was no difference in risks for Apgar < 7 score after 5 minutes. The clinical relevance of these findings is, however, limited.
Strengths and limitations
The major strength of our study is that it has data on the main exposure and confounders from a large, nationwide pregnancy cohort. Furthermore, previous research has proven that the validity of the data in MoBa to be high [
22‐
24]. Information on pregnancy outcomes were obtained from MBRN comprising data validity earlier described as sufficient for large scale epidemiologic research [
25,
26]. Altogether, the two different sets of data provide a unique opportunity to study possible effects of HG on pregnancy outcomes. To some extent MoBa suffers from selection bias as the women included are older, have more education, smoke less and are less likely to be immigrants compared to the Norwegian population at large [
27]. Nilsen et al. reported in a study on MoBa and selection bias that the prevalence of conditions could be affected by selection bias, but that there was no evidence that the selection bias affected the associations studied [
27]. If the validity of the observed association between HG and pregnancy outcomes should be affected by selection bias, it would require differential selection of participants related to both HG and pregnancy outcomes studied, something not considered in this study. Thus it is inconceivable that data on pregnancy outcomes from MBRN, compulsory obtained after recruitment, could be directly associated with selection to the study. Since all citizens of Norway have access to hospitals free of charge, there should be little selection to in-patient care based on economic resources of the single patient. Furthermore, as HG is associated with ethnicity, it is unfortunate that we did not have information on maternal country of birth in MoBa. However, only 5.6% of the participants reported not to have Norwegian as mother tongue. Adjustment for mother tongue did not influence our estimates.
Comparison with other studies
Unlike the previously mentioned meta-analysis including more than 50% case–control studies, we did not find HG to be associated with an increased risk of PTB, LBW and SGA [
13]. The heterogeneity described in the meta-analysis is, however, a consequence of methodological as well as clinical differences between the studies. The clinical heterogeneity was mainly related to difficulties in defining HG. The use of different diagnostic criteria may reflect that so far there is no universally accepted definition of HG, indicating that other pregnancy related conditions may have been confused with HG. Some studies had used hospital admission as a criterion, others the 8th or 9th version of the International Classification of Disease (ICD) or Fairweather’s diagnostic criteria from 1968 that included dehydration, electrolyte disturbances, ketonuria and more than 5% weight loss compared to prepregnancy weight [
4,
9,
28]. Due to the structure of MoBa’s questionnaires, HG was in our study defined as long-lasting nausea and vomiting in pregnancy starting before the 25th gestational week which required hospitalisation. In line with previous studies, more than 70% of the women with HG in MoBa were hospitalised during the first 12 weeks [
18,
19]. In contrast to the recent Swedish publication, time-point for hospitalisation did not influence the estimates in our study [
19]. In Norway, only women with HG and metabolic disturbances are being hospitalised, indicating that our sample includes severe HG only (or ICD 10 code O21.1). This assumption suggests that our sample was not diluted with other pregnancy related conditions, such as the more common “nausea and vomiting in pregnancy” (NVP), which up to 90% of all pregnant women suffer from [
29]. However, dilution may have been a problem in the large study based on the Dutch Perinatal Registry, describing that 34% was having HG diagnoses set by midwifes in the absence of hospitalisation [
14]. The prevalence of HG in the Dutch study was 0.2%, which is lower than in other European studies. The authors questioned the quality of their own dataset, suggesting an underreporting of the disease. Also; HG was associated with near to 40% increase in risk for PTB, and about 10% increase in risk for SGA [
14]. When maternal characteristics, such as age, parity, ethnicity, socio-economic status and concomitant diseases were adjusted for, only PTB remained associated with HG. However, several relevant confounders, such as BMI and smoking, were not adjusted for. Another study based on Swedish births between 1973 and 1982 reported a HG prevalence of 0.3% [
30]. These women were more likely to give birth before 38 gestational weeks and to deliver children with LBW. The abovementioned American cohort study among more than 500,000 live births found a HG prevalence of 0.5%, where HG was associated with SGA and LBW [
11]. The two latter studies reported univariate analyses only.
In contrast, a Canadian historical birth cohort study of 156,000 pregnancies, using hospital admission before the 24th gestational week as a diagnostic criterion for HG, found a prevalence of HG of 1.0%, which is similar to our study [
9]. The HG diagnosis was based on Fairweather’s diagnostic criteria, and information on most relevant confounders was available. Unlike our study, HG was found to be associated with an increased risk of PTB, LBW, SGA and Apgar score < 7 after 5 minutes, but only for women with maternal weight gain during pregnancy < 7 kg. The relative risks were 3.0, 2.8, 1.5 and 5.0, respectively. In MoBa 25% of the women in our study had missing data on maternal weight gain. Since these women had significantly higher risk of adverse pregnancy outcomes, we adjusted for maternal weight gain instead of stratifying similar to the Canadian study. Additional sub-analysis, where women with missing data on weight gain were excluded and the remaining sample was stratified according to whether the women gained less than 7 kilos or 7 kilos and more, did not change our estimates.
Maternal weight gain and body composition have, regardless of maternal HG-status, been thoroughly investigated as possible predictors for gestational age and birth weight [
31,
32]. A recent metanalysis of 55 studies, 37 cohort and 18 case–control including 3.5 million women, reported that low total gestational weight gain was associated with increased risks for PTB, LBW and intrauterine growth retardation (IUGR) and lower mean birth weight [
31]. In this perspective, the associations between HG and adverse pregnancy outcomes reported in previous research may be explained by poor maternal weight gain rather than the mother suffering from HG [
9,
12]. Moreover, an American case–control study found women with HG to gain on average 4.6 kg less during pregnancy, and to deliver babies who weighed on average 291 grams less compared to those born from healthy women [
10]. In MoBa women with HG gained on average 2.2 kg less than women without HG, but their babies did not have lower birth weight. However, they were born on average one day earlier. In contrast, a Norwegian institution-based case–control study reported that the 175 women hospitalised with HG gained on average 5.1 kg less than women without HG, their babies to be born 0.5 day earlier and weigh on average 138 grams less [
33]. Birthweight was positively associated with maternal weight in early pregnancy, weight gain during pregnancy and parity, but not HG. This is partly in line with our study, where stepwise regression showed that differences in birth weight between babies born to women with and without HG disappeared when maternal weight gain was adjusted for. In the other study, almost 50% of the cases and more than 20% of controls had non-Norwegian names, which is different from MoBa [
33]. Immigrant women in Norway are more likely to develop HG and have higher risks of adverse pregnancy outcomes such as IUGR and perinatal death [
3,
34,
35]. It is not yet known if immigrant women with HG have more severe symptoms and gain less weight during pregnancy compared to ethnic Norwegians. Differences in results between the studies might be explained by differences in ethnic background among the women included. The results of our study may therefore not be generalisable for the total population of Norway. Since HG is not found associated with adverse pregnancy outcomes, our results might reflect good antenatal care and treatment of women hospitalised with HG participating in MoBa.
Whereas the 1 minute Apgar score reflects the immediate need for resuscitation, the 5 minute Apgar score has more a prognostic value [
36]. Most studies therefore report Apgar score after 5 minutes, since this information is reckoned to be of higher clinical importance [
37,
38]. In our study, the children of women with HG had about 40% lower risk of Apgar score < 7 after 1 minute, but there was no difference in risk for Apgar score < 7 after 5 minutes. It is highly unlikely that this is an effect of corticosteroids administered to relieve symptoms in women with refractory HG during the first or second trimester [
29,
39]. Corticosteroids administered before 23rd gestational week is not known to have any effect on the fetal lung [
40]. Accordingly, the 40% reduction of Apgar score in our study might reflect underlying mechanisms for HG rather than consequence of treatment. The clinical importance of this statistical significant finding, however, is considered limited.
Although HG in our study did not have any negative short-term consequences for the offspring, the possibility for long-term consequences have barely been studied. Previous research has shown that metabolic changes in women with HG might resemble those resulting from starvation [
41]. Given the fact that fetal undernutrion during first trimester is associated with cardiovascular disease, diabetes and schizophrenia in later life, HG may also influence disease patterns [
41,
42].