Women of reproductive age living in the North of the Netherlands: Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort.

The specific focus of the Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort is on the role of reproduction-related determinants of health and disease. Lifelines-ROAHD cohort contains information regarding a broad range of determinants such as the progress and outcomes of pregnancies, birth experiences and health outcomes of mothers and children. The Lifelines-ROAHD cohort aims to facilitate research into the importance of early life development, starting before conception, as first described by Barker and more recently conceptualised by ‘The first 1000 days’. 1 2 Lifelines-ROAHD is a cohort embedded in the original Lifelines cohort. Lifelines is a large representative population-based cohort study and a biobank in the Northern provinces of the Netherlands with the aim to investigate risk factors for multifactorial diseases. 3–5 Recruitment for the Lifelines Cohort study was performed between 2006 and 2013 and includes data over 167 000 individuals over multiple generations in the Northern parts of the Netherlands. 3–5 The Lifelines cohort study collects data longitudinally: every 1.5 years participants complete an online or postal questionnaire and once every 5 years participants visit a Lifelines location where biomaterials (eg, urine, blood) are collected and several measures are obtained (eg, pulmonary function, blood pressure). 3–6 Due to the imbedding of Lifelines-ROAHD cohort in the original Lifelines cohort, the women will be longitudinally followed. By creating Lifelines-ROAHD cohort, women of reproductive age retrospectively completed an online questionnaire, allowing the identification of determinants associated with menstrual cycle, fertility treatments, progress and outcomes of pregnancies (eg, complications), childbirth and health outcomes of mothers and children. This extensive data collection encompasses all experienced pregnancies and births including all different outcomes. By combining Lifelines-ROAHD cohort data with the extensive phenotyping performed in the context of the Lifelines cohort, a unique detailed dataset is created, allowing investigation into the determinants of reproductive health as well as the influence of reproductive events on future health and disease of mother and child(ren). The women included in Lifelines-ROAHD cohort will cover the whole range of maternity care in the North of the Netherlands (ie, primary and secondary care). Data from Lifelines-ROAHD cohort provide more in-depth information about reproductive determinants, but also about early life determinants of future health which will be further assessed in future papers addressing the research questions below: Which factors (eg, biological, lifestyle and exposures) are associated with cycle irregularities, time to pregnancy, conception and progress and outcomes of pregnancies? What is the impact of the progress and outcomes of pregnancies including mode of birth (eg, spontaneous, induction, pain management, episiotomy, augmentation of labour, medication during labour and mode of birth) on women’s and children’s health? What is the impact of weight gain during the reproductive lifespan, on cycle irregularities, fertility, progress and outcomes of pregnancies and birth interventions (eg, induction, pain management, episiotomy and caesarean section)?

Women of reproductive age (range 20–45 years) were asked to participate in Lifelines-ROAHD cohort and completed an online questionnaire in 2017–2018. They completed items in an online questionnaire on topics of women’s health, reproductive health, and, if applicable, the progress and outcomes of their pregnancies, childbirth experiences and health outcomes for mothers and any children. The first part of the questionnaire comprised items on women’s health. Detailed data were gathered on menstrual cycle characteristics (cycle patterns, age at menarche, duration and pattern), menopause (eg, onset, pharmacological treatment) and contraceptive use (eg, contraceptive medications, intrauterine device with/without hormones). The second part of the online questionnaire was related to reproductive health and comprised items on fertility problems and assisted reproduction treatments including cycles of intrauterine insemination (IUI)) in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). 7 Next, women completed items on sexually transmittable diseases (eg, chlamydia, herpes) and family planning (eg, start or extension of family). If applicable, women completed the third part of the online questionnaire for each experienced pregnancy. Women completed items on conception (natural or with assisted reproduction treatments, (un)planned or (un)wanted pregnancy, time to pregnancy), medication use during pregnancy (folic acid use, over-the-counter-medication and prescribed medication), lifestyle (smoking during pregnancy, secondhand smoking, alcohol use and weight gain), progress of pregnancy (maternal complications, foetal complications) and pregnancy outcomes (eg, miscarriage, abortion). If women had given birth they completed the fourth part of the online questionnaire. For each experienced birth (≥25 weeks of gestation), women completed the following items: onset of delivery (spontaneous, induction of labour), pain relief treatment (pharmacological pain medication), mode of birth (vaginal birth, instrumental vaginal birth, elective caesarean section and emergency caesarean section), birth outcomes (live birth, preterm births, stillbirth and neonatal death), health outcomes for mothers (episiotomy, manual placenta removal, blood transfusion, hospitalisation within 6 weeks postpartum) and infant health problems (congenital anomalies, adverse physical or developmental health). For all born children, women completed items on gestational age, birth weight, skin-to-skin contact between mother and infant within 1 hour after birth, breastfeeding and hospitalisation shortly after birth. In the final part of the online questionnaire, we requested women to complete items related to their most recent pregnancy. Women completed items on work characteristics for example, working schedule, exposures to chemicals, radiation, extreme temperatures or noise, contact with human bodily fluids, raw meat and waste. 8 9 Next, women completed items on their physical health (eg, pelvic complaints, uterus prolapse), adverse psychological health (eg, anxiety, depression, post-traumatic stress disorder), diminished sexual health (eg, pain or numbness during intercourse) 1 year postpartum. Finally, women completed the validated Dutch version of the Childbirth Experience Questionnaire 2.0. 10 11 This measure contains 22 items and assesses women’s experiences regarding their childbirth, with an overall weighted mean score and weighted mean scores across four subdomains, that is, own capacity (eight items), perceived safety (six items), professional support (five items) and participation (three items). Nineteen items were scored on a 4-point Likert scale ranging from 1 (completely disagree) to 4 (completely agree) and three items were scored with a visual analogue scale. The scoring of the Dutch version of the CEQ2.0 is the following: the item ratings per subscale are aggregated to scale scores by summing the coded values of the Items in each scale and dividing by the number of items in that subscale. 11 The weighted mean CEQ2.0 score can be calculated by adding all subscale scores (own capacity, perceived safety, professional support and participation) and dividing by four. 11 The theoretical range is from 1 to 4, a higher score indicates more positive experiences. 11 Women or the public were not involved in the design, conduct, reporting, or dissemination plans of our cohort.

In total, 30 712 women of reproductive age (range 20–45 years) were eligible to participate in the Lifelines cohort and were eligible to participate in Lifelines-ROAHD cohort and received the online questionnaire. In total, 5933 (19.3%) women have (partly) completed the questionnaire in the period September 2017 until March 2018. In total, 310 women were excluded since they did not complete the essential parts of the online questionnaire regarding women’s health, women’s reproductive health, pregnancy and birth. In addition, 132 women with multiple pregnancies (eg, twins, triplets) were excluded since their data on experienced pregnancies and births had too many missing values. Finally, 79 women were excluded since the year of birth of their children was unknown. In total, we included 5412 women in the Lifelines-ROAHD cohort. Of the included population, 2604 women (48.1%) had not been pregnant and 2808 women (51.9%) had experienced 6158 pregnancies and 5068 births ( figure 1 : flowchart). Comparison of the characteristics of the included women in Lifelines-ROAHD cohort with women participating in the regular Lifelines cohort showed that the Lifelines-ROAHD participants were younger in age, had obtained a higher level of education and received a higher monthly income, whereas they showed similar proportions on migration background and urbanisation grade ( table 1 ). When comparing marital status and ethnic background of the Lifelines-ROAHD participants with women of reproductive age living in the North of the Netherlands, we found that the Lifelines-ROAHD women more often had a partner/spouse (52% vs 47%) and were more often from a Dutch native background (92% vs 88%), although differences were small. 12 Flowchart of the included participants in the Lifelines-ROAHD cohort. Lifelines-ROAHD, Lifelines Reproductive Origins of Adult Health and Disease. Demographic characteristics of Dutch women of reproductive age participating in Lifelines (N=30 712) and in Lifelines-ROAHD (N=5412) *Migration background was calorised as Dutch versus non-Dutch, which was defined as the women or one of the women’s parents being born in the, for example, Dutch Antilles, Aruba, background Suriname, Morocco, Turkey, Indonesia or other foreign country. †Education level was categorised as follows: low (ie, primary school, first 3 years of secondary school or lower level of vocational training), middle (upper secondary school or medium level of vocational training or work-based learning pathways) or high (higher vocational education and university education). ‡Urbanisation was based on postcode and afterwards categorised into very high, (ie, ≥2500 addresses/km 2 ), high (ie, 1500–2499 addresses/km 2 ), moderate (ie, 1000–1499 addresses/km 2 ), low (ie, 500–999 addresses/km 2 ) and rural (ie, <500 addresses/km 2 ). Lifelines-ROAHD, Lifelines Reproductive Origins of Adult Health and Disease. The characteristics of the women participating in the original Lifelines and Lifelines-ROAHD were reported by using descriptive statistics. Regarding women’s last birth, the valid measure Childbirth Experience Questionnaire 2.0 was completed and afterwards a weighted means with SD were calculated for the total score and domain scores, that is, own capacity, perceived safety, professional support and participation. 11 In total, 5412 women participated in Lifelines-ROAHD who were born between 1971 and 1995. The majority of women (77.4%) was above 30 years when completing the online questionnaire. Two thousand six hundred and four women (48.1%) had experienced no pregnancy whereas 2808 women (51.9%) experienced at least one pregnancy. Almost all included women were of Dutch origin and had a middle or high level of education. The monthly net family income showed that 22.0% had an income lower than €1500, which, in the Netherlands, is a minimum income. 13 Women lived in areas of various degrees of urbanisation across the Northern part of the Netherlands ( table 1 ). Regarding women’s health, 45.6% of the women indicated that they had a natural menstrual cycle, 30.9% had a menstrual cycle with hormonal contraceptives whereas 23.6% had no menstrual cycle due to various reasons. For the vast majority of the women (70.2%), their age at first menarche was between 12 and 14 years. Women who had a natural menstrual cycle (n=2466) indicated that the duration of their menstrual cycle was regular (76%) and they had a menstrual cycle every 27–29 days (44.6%). In total, 191 women (3.5%) indicated that they had no menstruation due to (early) menopause or no menstruation due to operative procedures. Women who had no menstruation indicated that their last menstruation occurred when they were <35 years (17.8%), 35–39 years (35.1%) or ≥40 years (46.1%). A minority (13.6%) had been prescribed pharmacological treatment for menopause or osteoporosis. All women provided detailed information about the episodes in their lives when they used contraceptives. The majority of women had used condoms (81%), contraceptive injections, pills or patches (94.8%), contraceptive implants or NuvaRing (35.1%), were sterilised (2.7%) or indicated that their partner was sterilised (16.0%, table 2 ). Women’s health data on menstrual cycle, menopause and contraceptive use of Dutch women of reproductive age (N=5412) *Other reasons include no menstrual cycle due to breastfeeding, or a menstrual cycle had never started, or reasons unknown for not having a menstrual cycle. †Not reported due to numbers n≤10 or to ensure anonymity of the Lifelines respondents. ‡Calculated for women with a natural menstrual cycle for the total population (n=2466), women with no pregnancy (n=1201), women with at least one pregnancy (n=1265). §Calculated for women who had no menstruation due to (early) menopause or no menstruation due to operative procedures, for the total population (n=191), women with no pregnancy (n=104), women with at least one pregnancy (n=87). ¶Women may have used different contraceptives during their life courses. Regarding reproductive health, 908 women (16.8%) consulted a general practitioner or gynaecologist for infertility. They indicated various infertility problems such as anovulation (24.4%), male partner infertility problems (22.5%) or unexplained infertility (22.2%). These women underwent various consecutive assisted reproductive treatments, that is, ovulation induction (19.8%), IUI (26.9%), artificial insemination (5.4%), IVF (13.0%) and ICSI (16.4%). A minority of 5.3% had experienced at least one sexually transmittable disease. All women provided information regarding their family planning, 61.4% stated that they don’t intend to have another pregnancy, whereas 25.5% would like to start or extend their families and 13% did not make a decision yet regarding their family planning ( table 3 ). Reproductive health data on fertility and family planning of Dutch women of reproductive age (N=5412) *Fertility-related treatments and assisted reproductive treatments were calculated for women who visited their GP/gynaecologist for fertility problems, for the total population n=908, no pregnancy n=428, at least one pregnancy n=480. †Sexually transmitted disorders includes HIV, hepatitis B, syphilis and/or gonorrhoea. ‡Not reported due to number n≤10 or to ensure anonymity of the Lifelines respondents. GP, general practitioner. In total, 2808 women had experienced 6158 pregnancies (range 1–9). While 2629 women had a first pregnancy, 2115 had a second pregnancy, 951 had a third pregnancy and 326 had a fourth pregnancy. Most pregnancies were conceived naturally (89.2%). Of the total pregnancies, 87% of the pregnancies were planned and wanted, however, this differed across the first, second, third and fourth pregnancies: the proportions were 85.7 %, 91%, 85.9% or 77.6%, respectively. Time to pregnancies of the total pregnancies were 0–3 months (47.7%), 4–12 months (24.7%), 13–24 months (5.9%) and ≥25 months (4.6%). A third of the women had used folic acid prior to or at the beginning of a pregnancy, 12.7% had used over-the-counter medication and 19.4% had used prescribed medications during their pregnancies. Of all pregnancies, 7.3% of the women smoked (partly or for the full duration of pregnancy) during pregnancy and 8.1% had a partner or family member that smoked. The proportions of smoking during pregnancy differed across the first, second, third and fourth pregnancies: the proportions were 9.2%, 6.3%, 4.2% and 4.9%, respectively. About 5.9% of the women consumed alcohol (partly or for the full duration of pregnancy) during their pregnancies. The outcomes of all pregnancies before 25 weeks of gestation were miscarriage (14.3%), ectopic pregnancy (0.9%) or termination of pregnancy or medical abortion (2.0 %). The proportions of miscarriage differed across the first, second, third and fourth pregnancies: the proportions were 13.9%, 13.1%, 14.3% and 19.9% ( table 4 ). Data on conception, medication use, lifestyle and pregnancy outcomes of 6158 experienced pregnancies *Assisted reproductive treatment includes ovulation induction, intra-uterine insemination, artificial insemination partner, artificial insemination donor, in vitro fertilisation, intracytoplasmic sperm injection. †Women reported the number of months it took to get pregnant. ‡Not reported due to numbers n≤10 or to ensure anonymity of the Lifelines respondents. In total, 2808 women had experienced 5068 births. Maternal complications were reported, for example, hypertension (11.2%), urine tract infections (4.9%), pre-term blood loss in first trimester (4.4%), preeclampsia/hemolysis, elevated liver enzymes and low platelets (HELLP) (3.3%) and diabetes gravidarum (2.6%). Women also reported foetal complications as intrauterine growth restriction (2.7%), and meconium stained amniotic fluid (8.5%). The majority of all births started spontaneously (73.6%), and the proportions for spontaneous start at onset of labour fluctuated for first, second, third and fourth births: 73.6%, 74.3%, 73.1% and 68.4%, respectively. In total, 28.4% of the births were at home, 11.6% were in the hospital with primary care midwives, 59.8% were in the hospital with obstetricians/clinical midwives. The modes of births were vaginal births (74.9%), instrumental vaginal births (11.9%), elective caesarean section (3.9%) and emergency caesarean section (9.3%). If women had more births, it showed that the proportions of emergency caesarean section decreased whereas the elective caesarean sections increased. During or after all experienced births, women had several adverse health outcomes that is, episiotomy (40.1%), manual placenta removal (6.3%), blood transfusions (3.5%) and hospitalisation within 6 weeks after birth (3.6%). The outcomes for all births were born alive at term (93.6%), born alive (very) pre-term (5.8%), stillbirth (0.316%) and neonatal death (0.197%). Regarding infant health problems, a minority had congenital abnormality (3.7%), adverse future physical health (1.2%) or adverse developmental health (1.2%). Most infants (83.5%) had a birth weight of ≥3000 grams and 86.9% had skin-to-skin contact with their mothers and 71.5% started breastfeeding within 1 hour after birth. In total, 11.1% of the children were hospitalised immediately after birth, 2.7% were hospitalised within 1 week after birth and 6.6% had a hospital admission after 1 week after birth ( table 5 ). Data on progress and outcomes of pregnancies, birth characteristics, adverse maternal outcomes, birth outcomes and infant characteristics of 5068 births *Not reported due to numbers n≤10 or to ensure anonymity of the Lifelines respondents. †Pharmacological pain medication includes sleep medication, sterile water injections, morphine, pethidine, remifentanil, nitrous oxide, epidural or general anaesthesia. ‡Non-pharmacological pain medication (ie, back massage, warm bath or shower, pressure points massage, transcutaneous electrical nerve stimulation (TENS), acupuncture, yoga, (self)hypnosis). §Episiotomy was calculated for vaginal births for the total population (n=4399), and for first birth (n=1809), second birth (n=1576), third birth (n=704), fourth birth (n=226). CS, caesarean section. Additional data about 2660 most recent experienced pregnancies were collected. Regarding work characteristics, 84.8% of women worked during their most recent pregnancy. About 19.9% had irregular working hours and were exposed to chemical use (5.6%), radiation (3.2%), extreme temperatures (1.3%) or noise (2.7%) during working hours. At work, some women had contact with human bodily fluids (20.5%–24.5%) and waste (5%). One year postpartum, 0.5%–12.5% of the women experienced adverse physical health, 0.7%–1.6% had adverse psychological health issues whereas 1.6% experienced diminished sexual health ( table 6 ). Data on work characteristics and adverse maternal health postpartum of 2660 most recent experienced pregnancies *Not reported due to numbers n≤10 or to ensure anonymity of the Lifelines respondents. In total, 1742 women completed all items of the CEQ2.0 and the weighted mean score (SD) was 3.2 (0.5) which is similar to a previously reported score in a Dutch population. 11 Compared with women with a recent second, third or fourth births, the childbirth experiences of women with first births revealed lower scores on the subscales own capacity, perceived safety, professional support and participation ( table 7 ). Weighted mean scores on the Childbirth Experience Questionnaire 2.0 of the most recently experienced births (n=1742)

The main strength of the Lifelines-ROAHD cohort is that detailed information was gathered concerning women’s (reproductive) health and, if applicable, the progress and outcomes of pregnancies with respective health outcomes for mothers and their child(ren). We analysed data for the total number of experienced pregnancies and births, and also stratified these by subsequent pregnancies and births (range 1–4). With valid measures, data were gathered about infertility treatments, exposures during pregnancies and maternal childbirth experiences. Moreover, prior to their participation in Lifelines-ROAHD, women were already extensively characterised according to Lifelines data collection protocols. This included data on physical measurements such as blood pressure, lung function and clinical laboratory tests, as well as a wide range of completed self-reported questionnaires about general health, well-being and nutrition. A third strength is that women participating in Lifelines-ROAHD also provided detailed information regarding their most recent pregnancies and provided additional information about exposures during pregnancy (work characteristics) and postpartum physical, psychological and sexual health. A limitation of Lifelines-ROAHD is that the data were retrospectively collected which could have caused recall bias for some of the items. Another limitation is the response to the questionnaires. About 19.3% of the eligible women who participated in Lifelines completed the online questionnaires for Lifelines-ROAHD, since not all women indicated that they were willing to complete questionnaires online. However, by comparing the characteristics of the women with the general population living in the North, no major differences were observed supporting generalisability of the results. Women who participated in Lifelines completed baseline measurements and additional questionnaires for second (2011–2015), third (2013–2016) and fourth (2014–2019) waves. Questionnaire data of the fifth wave started in 2016 and will be running until 2023. The questionnaire data for Lifelines-ROAHD have been collected from 2017 to 2018. Since the Lifelines-ROAHD data concerned previously experienced pregnancies and births, the data relate to pregnancies that could have occurred between July 1988 and January 2018 ( figure 2 ). Children were born from 1988 to 2005 (35%), 2006–2009 (24%), 2010–2013 (22%) and 2014–2018 (19%). Regarding firstborn children, the youngest mother was 16 years of age, and the oldest mother 45 years of age. Time periods of inclusion of women participating in Lifelines-ROAHD cohort. Lifelines-ROAHD, Lifelines-ROAHD, Lifelines Reproductive Origins of Adult Health and Disease. In 2023–2024, we aim to collect additional data of the included women in Lifelines-ROAHD (n=5412). In this second online questionnaire, we aim to complete women’s reproductive histories, by collecting data about potential first and subsequent pregnancies conceived after the date of completion of baseline Lifelines-ROAHD data collection in 2017–2018. Women will be requested to complete items regarding conception (including fertility treatments), medication use and lifestyle during pregnancy, progress of pregnancy, birth characteristics and maternal outcomes after birth. Regarding all children, we will collect data about their development, healthcare utilisation and children’s health. In Lifelines-ROAHD, we had missing values on demographic characteristics ranging from 3.3% to 30%. We will try to complement information regarding items with missing values more than 5% (eg, marital status, monthly income).

Lifelines data, including Lifelines-ROAHD, are open to researchers worldwide and provide easy access to data and samples ( www.lifelines.nl/researcher ). Data can be linked with other registries like CBS (Statistics Netherlands), IADB (Dutch prescription medication database), PALGA (Dutch pathology/anatomy archive) and Netherlands Cancer Registry. It is also possible to collect additional data or samples in (part of) the participants. Please contact us for all possibilities ([email protected]).