Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study

Nijsten K; Dean C; van der Minnen LM; Bais JMJ; Ris-Stalpers C; van Eekelen R; Bremer HA; David P van der Ham; Heidema WM; Anjoke Huisjes; Gunilla Kleiverda; Simone M. Kuppens; Judith O E H van Laar; Langenveld J; van der Made F; Dimitri Papatsonis; Marie J Pelinck; Pernet PJ; van Rheenen-Flach L; Rijnders RJ; Scheepers HCJ; Vogelvang T; Ben W Mol; Roseboom TJ; Koot MH; Grooten IJ; Painter RC

doi:10.1111/aogs.14197

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study

Nijsten K, Dean C, van der Minnen LM, Bais JMJ, Ris-Stalpers C, van Eekelen R, Bremer HA, van der Ham DP, Heidema WM, Huisjes A, Kleiverda G, Kuppens SM, van Laar JOEH, Langenveld J, van der Made F, Papatsonis D, Pelinck MJ, Pernet PJ, van Rheenen-Flach L, Rijnders RJ, Scheepers HCJ, Vogelvang T, Mol BW, Roseboom TJ, Koot MH, Grooten IJ, Painter RC

Published September 2021 Acta obstetricia et gynecologica Scandinavica, 100(9), 1636-1643

DOI 10.1111/aogs.14197 PMID 34033123 PMC PMC8457209

Abstract

Introduction

Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies.

Materials and Methods

We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies.

Results

Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03).

Conclusions

High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.

By this author

Hormonal Agents · Progesterone and Progestins

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis

Melo P et al., 2023 BJOG Free to read

Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. Search Strategy: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. Selection Criteria: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. Data Collection and Analysis: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I(2) = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I(2) = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I(2) = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I(2) = 0%; low-certainty evidence). Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

Outcomes and Effectiveness · Live Birth Rates

Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

Wessel JA et al., 2022 Fertility & Reproduction Free to read

Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model. Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial

Landman AJEMC et al., 2022 PLoS Med Free full text on PubMed Central

Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. Findings: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Pregnancy outcomes from a restorative infertility treatment model: a single centre case series

James G et al., 2021 medRxiv Free to read

Infertility is a significant problem with multiple causes and a corresponding array of therapeutic options. In an era of increasing assisted reproductive treatments, few studies examine the role of conventional non-assisted reproductive treatments to address underlying behavioural, lifestyle and medical issues. To assess outcomes from a conventional or non-assisted reproductive treatment approach. Retrospective case series of 162 couples that attended an Australian, hospital-based, multidisciplinary fertility clinic between 2005 and 2010. There were 58 live births for all couples giving a crude live birth rate of 35.4% over a 24-month analysis period. When adjusted by Kaplan-Meier method, a 57.4% cumulative live birth rate (CLBR) was achieved. Couples had a median 33.9 months duration of infertility and the median female age was 33.7. For the 74 couples with an unexplained infertility diagnosis, 32 achieved a live birth at a crude rate of 43.2% or 71.2% CLBR when adjusted by Kaplan-Meier method. This observational data indicates that reproductive medicine should have a personalized approach in which alternatives for immediate IVF are considered.

Related research

Prescribing Safety · Medication Safety in Pregnancy

Nausea and vomiting of pregnancy and hyperemesis gravidarum

Fejzo MS et al., 2019 Nature reviews. Disease primers

Nausea and vomiting of pregnancy (NVP) is a common condition that affects as many as 70% of pregnant women. Although no consensus definition is available for hyperemesis gravidarum (HG), it is typically viewed as the severe form of NVP and has been reported to occur in 0.3-10.8% of pregnant women. HG can be associated with poor maternal, fetal and child outcomes. The majority of women with NVP can be managed with dietary and lifestyle changes, but more than one-third of patients experience clinically relevant symptoms that may require fluid and vitamin supplementation and/or antiemetic therapy such as, for example, combined doxylamine/pyridoxine, which is not teratogenic and may be effective in treating NVP. Ondansetron is commonly used to treat HG, but studies are urgently needed to determine whether it is safer and more effective than using first-line antiemetics. Thiamine (vitamin B1) should be introduced following protocols to prevent refeeding syndrome and Wernicke encephalopathy. Recent advances in the genetic study of NVP and HG suggest a placental component to the aetiology by implicating common variants in genes encoding placental proteins (namely GDF15 and IGFBP7) and hormone receptors (namely GFRAL and PGR). New studies on aetiology, diagnosis, management and treatment are under way. In the next decade, progress in these areas may improve maternal quality of life and limit the adverse outcomes associated with HG.

Nausea and vomiting during pregnancy: A prospective study of its frequency, intensity, and patterns of change

Lacroix R et al., 2000 Am J Obstet Gynecol

Our purpose was to provide a detailed description of patterns of nausea and vomiting of pregnancy. A prospective study was performed with 160 women who provided daily recordings of frequency, duration, and severity of nausea and vomiting. Seventy-four percent of women reported nausea lasting a mean of 34.6 days. "Morning sickness" occurred in only 1.8% of women, whereas 80% reported nausea lasting all day. Only 50% of women were relieved by 14 weeks' gestation; 90% had relief by week 22. Data based on the McGill Nausea Questionnaire indicate that the nausea experienced by pregnant women is similar in character and intensity to the nausea experienced by patients undergoing cancer chemotherapy. Traditional teachings about nausea and vomiting of pregnancy are contradicted by our findings. Standardized tools for measuring the distribution, duration, and intensity of nausea are applicable to the study of nausea and vomiting of pregnancy and could be used in clinical trials to assess palliative measures.

Infections · Vaginal and Cervical Infections

Helicobacter pylori Infection Is Associated with an Increased Risk of Hyperemesis Gravidarum: A Meta-Analysis

Li L et al., 2015 Gastroenterol Res Pract Free full text on PubMed Central

Background. Several studies have shown a possible involvement of Helicobacter pylori (H. pylori) infection in individuals with hyperemesis gravidarum (HG), but the relationship remains controversial. This meta-analysis was performed to validate and strengthen the association between HG and H. pylori infection. Methods. PubMed, Embase, and Web of Science databases up to March 20, 2014, were searched to select studies on the prevalence of H. pylori infection between pregnant women with HG and the normal pregnant control subjects. Results. Of the HG cases, 1289 (69.6%) were H. pylori-positive; however, 1045 (46.2%) were H. pylori-positive in control group. Compared to the non-HG normal pregnant controls, infection rate of H. pylori was significantly higher in pregnant women with HG (OR = 3.34, 95% CI: 2.32-4.81, P < 0.001). Subgroup analysis indicated that H. pylori infection was a risk factor of HG in Asia, Africa, and Oceania, especially in Africa (OR = 12.38, 95% CI: 7.12-21.54, P < 0.001). Conclusions. H. pylori should be considered one of the risk factors of HG, especially in the developing countries. H. pylori eradication could be considered to relieve the symptoms of HG in some intractable cases.

Preterm Birth · Prediction

Implications of idiopathic preterm delivery for previous and subsequent pregnancies

Kristensen J et al., 1995 Obstet Gynecol

To describe the relationship between pregnancy complications and fetal outcome in first and second pregnancies, focusing on idiopathic and indicated preterm birth of singleton infants in either pregnancy. Included in the study were 13,967 women in Denmark who gave birth to their first singleton infant in 1982 and a second infant in 1982-1987. Information on pregnancy and birth was obtained by linking the National Medical Birth Register and the National Register of Hospital Discharges, based on personal identification numbers. The risk of a preterm second birth in women with idiopathic and indicated preterm first birth did not differ significantly (15.2 and 12.8%, respectively). However, women with idiopathic preterm birth in the first pregnancy tended to repeat idiopathic preterm birth twice as often as women with indicated preterm birth repeated indicated preterm birth (11.3 versus 6.4%). Adjustment by logistic regression analysis for other risk factors for preterm birth did not influence the relative risk (6.0 before 32 weeks and 4.8 for 32-36 weeks) of a second preterm birth after a first preterm birth. Women with idiopathic preterm delivery in their first and second pregnancies gave birth to infants with lower birth weight than in previous or subsequent pregnancies. Emergency cesarean delivery in a first term pregnancy was a risk factor for subsequent idiopathic preterm birth. Idiopathic preterm birth is associated with emergency cesarean delivery at term in previous pregnancies and infants with lower birth weight in previous and subsequent pregnancies.

David P van der Ham, Gunilla Kleiverda, Judith O E H van Laar, Marie J Pelinck, Ben W Mol

Dave Ham, D Ham, G Kleiverda, J Laar, M Pelinck, Benjamin Mol, B Mol

PMID 34033123 34033123 DOI 10.1111/aogs.14197 10.1111/aogs.14197 Nijsten et al. 2021, Nijsten 2021

Cite this article

Nijsten, K., Dean, C., van der Minnen, L. M., Bais, J. M. J., Ris-Stalpers, C., van Eekelen, R., Bremer, H. A., van der Ham, D. P., Heidema, W. M., Huisjes, A., Kleiverda, G., Kuppens, S. M., van Laar, J. O. E. H., Langenveld, J., van der Made, F., Papatsonis, D., Pelinck, M. J., Pernet, P. J., van Rheenen-Flach, L., Rijnders, R. J., Scheepers, H. C. J., Vogelvang, T., Mol, B. W., Roseboom, T. J., Koot, M. H., Grooten, I. J., & Painter, R. C. (2021). Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study. Acta obstetricia et gynecologica Scandinavica, 100(9), 1636-1643. https://doi.org/10.1111/aogs.14197

Keywords

hyperemesis gravidarum, induced abortion, pregnancy outcome, recurrence, reproductive behavior, risk assessment, risk factors, secondary prevention