Microphthalmos results from incomplete invagination of the optic vesicle or closure of the embryonic fissure. We present three patients with unilateral congenital microphthalmia with cyst. None of them had vision in the affected eye since birth. There was gradually increasing left eye orbital mass encroaching towards lower fornix and lower eyelid ectropion. On examination and investigations, patients had large orbital cyst with microphthalmia pushing the eyeball superiorly and posteriorly in affected orbit. Microphthalmic globe with cyst was surgically excised and histopathologically studied. Orbital cavity was big enough to occupy the conformer and the prosthetic eye after 6 weeks. Diagnosis was confirmed as large communicating orbital cyst with microphthalmia without systemic association in all the patients. None of the mothers of patients had regular antenatal check up. All the parents had consanguineous marriage. Antenatal check up with ultrasound at 14 to16 weeks of pregnancy is important for genetic counselling. Targeted abdominal ultrasound examination of pregnant women focused on the orbital region of foetus is recommended, in mothers who have children with congenital eye anomalies. About 150 cases have been reported and only one-third of them were bilateral. It may be genetic or non-genetic, unilateral or bilateral, and isolated or as a component of syndrome. Extra-ocular malformations are more frequently associated with bilateral cases.We present three patients, two male and one female within age range of 3-24 years diagnosed as unilateral congenital microphthalmia with cyst involving right eye (RE) in one patient and left eye (LE) in two that was surgically removed and histopathologically studied.A 3 years old male presented with gradually increasing mass in LE since birth. On examination of his LE, the mass was extending to lower fornix but detailed anatomy could not be distinguished. There was no perception of light (NPL) in his LE. Mass was soft, cystic under cover of conjunctiva, trans- illumination test was positive. His palpebral fissure could not be opened fully. Palpebral fissure height was 6mm in LE. There was absence of both upper and lower fornix. Eyelashes were present normally in both upper and lower eyelids in LE. There was mild ectropion of left lower lid. His vision in right eye was 6/6. Both anterior and posterior segments were normal in right eye (RE). There was history of consanguineous marriage in parents. Age of mother was 26. The child was delivered by normal vaginal delivery with irregular ANC visit. The patient's parents do not give history of abdominal ultrasound during antenatal period.Contrast enhanced computed tomography (CECT) scan revealed large well defined hypodense cystic lesion measuring 2.7x2.1cm in left orbit causing compression and displacement of orbital nerve, bony orbit laterally leading to atrophic left globe postero superiorly located with calcification. There was no CNS involvement. Total excision of the cyst with communicating microphthalmic globe was done and sent for histopathological examination (HPE). The large orbital cyst in this patient has played an import^^rae in socket expansion thus the socket was big enough to accommodate a conformer.The gross and HPE showed an eye ball with deformed looking structure measuring 2.9x3x1.2cm with corneal tissue 0.7mm in diameter, lined by stratified squamous epithelium, the sub-epithelial stroma reveal scattered few congested vascular channels along with some mixed chronic inflammatory cells. There was presence of degenerate layer of retina, iris  and acellular fibro collagenous choroid-like layers. Sections from cystic structure attached with the small eyeball shows acellular fibro collagenous tissue mimicking the oedematous choroidal layer along with presence of focal mixed chronic inflammatory cells infiltrate. That confirmed it to be microphthalmia with communicating cyst.A 17 years old female had similar presentations as the first patient with mass in LE since birth. On examination of her LE her anatomy could not be distinguished. There was no perception of light in her LE. Mass was soft, cystic under cover of conjunctiva, trans-illumination test was positive. Her palpebral fissure could not be opened fully. Palpebral fissure height was 4mm in left eye. There was absence of both upper and lower fornix. Eyelashes were present normally in both upper and lower eyelids in LE. There was ectropion of left lower eyelid. Her vision in right eye was 6/6. Both anterior and posterior segments were normal in RE. There was history of consanguineous marriage in parents.CECT scan revealed small left globe with a focal calcification at its optic disc, thin optic nerve, extra ocular muscles and 36x31x27 mm non-enhancing extra- conal hypodense cystic mass . The HPE showed it to be consistent with microphthalmia with cyst.All three patients were advised with oral and systemic antibiotic, NSAID. Post operatively patient was advised for ocular prosthesis.5Patients with microphthalmia presents with spectrum of visual impairment from mild impairment to complete blindness. Patients can suffer from intellectual disability, if the anomaly presents as part of a syndrome. Prognosis is varied and patients usually require the support of a multidisciplinary team to manage the vision, for plastic surgery, intellectual and psychological aspects.6 Sometimes, the congenital colobomatous microphthalmos with orbital cyst may not communicate with the eye or the central nervous system. Microphthalmia with cyst is non-hereditary, but has been described in siblings and with syndromes. Genetic disorders responsible for microphthalmos with cyst include autosomal recessive, autosomal dominant, and X linked syndromes. Once the condition has been identified, genetic counselling has to be given to the family.The differential diagnosis for cystic anomalies include microphthalmia with cyst, congenital cystic eye, microphthalmia with cystic teratoma, ectopic brain tissue and meningo-encephalocele. Microphthalmos with cyst is distinguished on the basis of a small globe with a communicating channel between it and cyst.9 The previously presented cases of bilateral microphthalmia with cyst, the cysts had made contact with the eyes. Removal of both eye with cyst is the most frequent therapy.10 Congenital microphthalmos with cyst is defined in three categories, a relatively normal eye with a small cyst, clinically not apparent, an obvious cyst associated with a grossly deformed eye, lastly a large cyst which has pushed the globe backwards so that it is not visible clinically.11 Severe microphthalmia according to the anatomic appearance and severity of the reduction of the globe refers to a globe with a corneal diameter less than 4 mm and a total axial length less than 10 mm at birth.12Two unilateral cases  and one bilateral case (Ehlers 1966) have previously been published.3 Congenital micropthalmos with cyst can be isolated or associated with other ocular or systemic abnormalities. Congenital heart defects, central nervous system diseases, cleft lip/palate, pulmonary aplasia and renal agenesis was reported to be associated.14 Although systemic abnormalities associated with microphthalmos were not common in cases with bilateral cysts compared to cases with unilateral cysts in some reports.4 Regular antenatal checkup along with ultrasound is recommended in every pregnant women. Mashiach et al. described how transvaginal sonography at 14-16 weeks was helpful in detecting the eye abnormality in five cases in which at least one previous child in the family had the same congenital anomaly of eye.15 Searle A et al, advised to use a curvilinear transducer (2-9 MHz) and imaging orbits in both axial and coronal planes.16 This can be aided by using a trans vaginal probe in selected cases if it is difficult to visualize structures by the trans abdominal method. Three-dimensional reverse-face imaging should be obtained in suspected cases of anophthalmia or microphthalmia.Presentation symptoms are generally congenital mass with increasing lower lid protrusion.In all our cases, the cyst was grade 3 according to Elder classification as the large cyst had pushed the globe backwards so that it was not visible clinically. Excision of cyst along with the microphthalmic eye was done.2. Surgery is usually recommended before school age for cosmetic appearance, since 90% orbital bone maturation was already completed until school age.17Management is not standard for every case and principally depends on visual potential, cyst size and orbital volume. Simple small cysts with normal ranged orbital volume should be observed while others treated surgically18 However, sparing the micropthalmic eye implies repeated follow-up consultations because cysts may recur and neoplasia may develop.19Excision of the cyst alone may be performed if there is no contact with the eye or intracranially. Cystectomy has been performed in a limited number of cases.JNMA Case Report Consent Form was signed by the patient and the original is attached with the patient's chart.None.


What is the long-term association of infant physical development and rapid growth with the timing of puberty onset in girls?z score at 12 months of age and rapid weight gain from birth to 24 months of age and birth to 3 months of age were associated with puberty onset.In this birth cohort of 294 adolescent girls in rural China, the infancy weight-for-age The findings suggest that weight-related indicators may serve as proxies of puberty onset among adolescent girls. Whether physical development and rapid growth during the first 2 years of life are associated with puberty onset in girls remains unclear.To examine the associations of infant physical development and rapid growth with the timing of puberty onset in girls.This prospective birth cohort study included girls whose mothers had participated in a randomized, double-blind cluster trial of micronutrient supplementation with a daily capsule of folic acid, iron and folic acid, or multiple micronutrients during pregnancy. A total of 547 singleton girls in rural western China who were born after 2004 were followed up at 3, 6, 12, and 24 months of age and were eligible for long-term follow-up. Of these, 294 adolescent girls (aged 10-12 years), representing 53.7% of the total sample, were included in the follow-up interview that was conducted from June 1 through December 31, 2016. Data analyses were conducted from November 1, 2019, to May 30, 2020.z score increase of greater than 0.67, was calculated during 5 periods: birth to 3 months, birth to 6 months, 6 to 12 months, 12 to 24 months, and birth to 24 months of age.Infant weight and length were assessed at birth and 3, 6, 12, and 24 months of age. Rapid growth, defined as a weight-for-age or length-for-age Puberty stage was assessed using the standardized Tanner staging system. Onset of puberty was defined as attaining Tanner stage 2 of breast development or pubic hair growth, and the corresponding age at follow-up was recorded.z score at 12 months of age  and rapid weight gain from birth to 24 months of age  and birth to 3 months of age . However, length-related indicators during early life were not associated with adolescent puberty onset.Of 294 girls included in the analysis , the median age of puberty onset was 11  years. A significant association with puberty onset was found for infancy weight-for-age z score and rapid weight gain during infancy, particularly from birth to 3 months of age, were associated with an increased likelihood of puberty onset in girls. These findings suggest that weight-related indicators may serve as proxies of puberty onset among adolescent girls.This study found that a higher weight-for-age  This birth cohort study examines the associations of infant physical development and rapid growth with the timing of puberty onset in girls in China. A systematic review based on cohort studies8 reported that small for gestational age (SGA) and low birth weight (LBW) were associated with earlier age at puberty onset in girls . Few studies have detailed measures of weight and height during childhood,9 and these studies lacked specific secular data during the first 2 years of life. Infant rapid growth, compensating for intrauterine growth restriction, is usually observed during the first 2 years after birth.10 Emerging evidence suggests that the timing of rapid growth (tempo) itself may play an independent role in modifying subsequent health outcomes.11 However, it is not clear which period of rapid growth during infancy results in earlier puberty. Few studies have examined the association of rapid weight gain in infancy with puberty, and limited assessments have been performed.13 The DONALD  Study from Germany12 assessed rapid weight gain with measurements at birth and at 24 months of age. Another birth cohort from South Africa focused on transient rapid weight gain from birth to 12 months of age.13 Thus, a study with multiple prospective measures of growth during the first 2 years of life is needed to determine the specific period associated with the timing of puberty.The literature to date has largely focused on secular increases in body mass index (BMI) in early childhood and their associations with the timing of puberty ,14 have mainly used the timing of menarche, a relatively late milestone of pubertal development, which may mask the true associations of infant growth in early life with puberty onset. In addition, growth during early life may interfere with the onset of puberty but not the subsequent stages or durations .12To assess puberty onset, previous studiesIn the present study, we aimed to investigate the associations of infant physical development and rapid growth during early life with puberty onset in girls. We used birth cohort data in rural western China, with physical development  assessed at birth and at 3, 6, 12, and 24 months of age and puberty assessment at early adolescence (10-12 years of age). Our results may help to identify the strongest indicator of physical development that is associated with puberty onset and its critical period within the first 2 years after birth.15 The parent trial is detailed elsewhere.16 Briefly, pregnant women in the designated villages were randomly allocated to daily supplementation with folic acid (400 μg [control group]), iron (60 mg) and folic acid (400 μg), or multiple micronutrients in accordance with the World Health Organization’s recommended allowance of 15 vitamins and minerals; supplements were used from enrollment to delivery.17 In the trial, 4604 singleton births occurred, but only 1400 births in 2004-2006 were enrolled in the long-term follow-up cohort. A total of 1388 births were followed up after excluding deaths (n = 3), children with birth defects (n = 7), and parents with disabilities (n = 2). Among them, 547 girls were eligible for long-term follow-up. Finally, we tracked 294 girls (53.7%) from birth through 3, 6, 12, and 24 months of age and into early adolescence (10-12 years of age). Follow-up data were collected from June 1 through December 31, 2016.The study design was a prospective birth cohort of participants whose mothers participated in a randomized, double-blind cluster trial of micronutrient supplementation in pregnancy.STROBE) reporting guideline.The follow-up evaluations were approved by the ethics committee of the Xi’an Jiaotong University Health Science Center in Xi’an, China. Parents or caregivers provided signed informed consent, and verbal assent was obtained from each child. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  or by township maternal and child health care staff within 72 hours for home deliveries (31 [10.5%]). Weight and length at 3, 6, 12, and 24 months of age at each follow-up visit were measured using standard World Health Organization procedures. Weight was measured to the nearest 10 g using an electronic scale  after removing heavy clothes. Length was measured to the nearest 1 mm using a portable measuring board with a fixed headpiece.z score (WAZ), length-for-age z score (LAZ), and BMI-for-age z score (BAZ) were calculated using the World Health Organization Child Growth Standards 2006.18 The birth WAZ and LAZ were accordingly calculated by International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) standards.19 Infant stunting was defined as an LAZ less than −2.00 SD; underweight, an WAZ less than −1.00 SD; and overweight, a BAZ greater than 2.00 SD.21Low birth weight was defined as less than 2500 g. Body mass index was calculated as weight in kilograms divided by the square of body height in meters. The infant weight-for-age z scores among infants were calculated using WAZ or LAZ at the end minus the scores at the beginning of every interval of interest, including birth to 3 months of age, birth to 6 months of age, 6 to 12 months of age, 12 to 24 months of age, and birth to 24 months of age. We defined rapid growth as a change in z score that was greater than 0.67.22Changes in 24 Among girls with a Tanner stage greater than 2 (68 [23.1%]), the age of puberty onset was determined by asking the following questions: (1) Have you noticed that your breasts/pubic hair have begun to grow? (2) If yes, how old were you when this began? As for other girls with a Tanner stage of 2 (173 [58.8%]), we used the chronological age at visit as the age of puberty onset.Trained public health postgraduate students (including Z.Z.) measured the staging of breast development using observation and palpation according to the Tanner staging system, which represents the 5 Tanner stages for breast size. Similarly, the development of pubic hair was staged by visual inspection. We defined the onset of puberty as attaining Tanner stage 2 of breast development or pubic hair growth.19 The household wealth index was constructed by assessing 17 different household assets or facilities  using the principal components method and was then categorized into tertiles indicating low, middle, and high levels of household wealth.Covariables were collected using a structured questionnaire at the enrollment of the parent trial, including sociodemographic characteristics, perinatal factors, and birth outcomes. Sociodemographic characteristics included parental occupation (farmer and others), age at enrollment, and educational attainment  and household wealth index. Perinatal factors—including maternal parity, self-reported age at menarche, and BMI during the first trimester with maternal weight and height—were measured at the clinic by trained maternal and child health staff, and participants were randomly assigned to a micronutrient regimen . Birth outcomes included SGA, which was defined as birth weight less than the 10th population percentile according to the INTERGROWTH-21st standard.2 tests or analysis of variance. Cox proportional hazard regression models were used to examine the associations of infant growth and rapid growth at specified periods with puberty onset with hazard ratios (HRs) and 95% CIs. Event times were defined as the age of puberty onset. The possible covariables we considered were parental age, parental educational level, parental occupation, household wealth index at enrollment, parity, SGA outcome at birth, maternal age at menarche, maternal BMI, and randomly assigned regimens. Statistical significance was set at a 2-sided P < .05. All analyses were conducted with STATA software, version 15 (StataCorp LLC).Data were analyzed from November 1, 2019, to May 30, 2020. Continuous variables were described using mean (SD) or median (interquartile range [IQR]); categorical variables, frequencies or proportions. Baseline characteristics by puberty onset were compared using χIn addition, we examined the associations of underweight, stunting, and overweight with adolescent puberty onset. Similarly, the results showed that adolescent girls who experienced malnutrition during infancy had lower likelihood of entering puberty , but the difference did not reach statistical significance in the multivariable analyses.A total of 109 of 254 infants (42.9%) showed rapid weight gain from birth to 24 months of age; 133 of 246 (54.1%), from birth to 3 months of age; 153 of 249 (61.4%), from birth to 6 months of age; 26 of 243 (10.7%), from 6 to 12 months of age; and 19 of 251 (7.6%), from 12 to 24 months of age. However, only rapid weight gain from birth to 24 months of age and birth to 3 months of age achieved a significant association with an increased likelihood of puberty onset among adolescent girls, with adjusted HRs of 1.40  and 1.39 , respectively .In addition, 53 of 253 infants (20.9%) showed rapid length gain from birth to 24 months of age; 49 of 245 (20.0%), from birth to 3 months of age; 48 of 247 (19.4), from birth to 6 months of age; 79 of 243 (32.5%), from 6 to 12 months of age; and 27 to 253 (10.7%), from 12 to 24 months of age. We did not find that rapid length gain during the aforementioned infancy periods was associated with adolescent puberty onset. Similar results were observed in unadjusted models .In this prospective birth cohort study of girls conducted in rural western China, we found that the median age of puberty onset was 11  years. A higher WAZ during infancy was associated with earlier puberty onset. Furthermore, rapid weight gain in infancy during the first 2 years of life, particularly from birth to 3 months of age, was associated with an increased likelihood of earlier puberty onset. However, we did not find that length-related indicators during early life were associated with adolescent puberty onset, such as LAZ, stunting, and rapid length gain. Similar null associations were observed for birth weight and LAZ.26 However, most of the study areas were located in metropolises such as Shanghai and Guangzhou and did not include rural western areas,25 where malnutrition is still relatively prevalent.27 In western China, only 1 study conducted in 2001-2002 in Shaanxi Province observed puberty onset and reported a mean age of 12.1 years,28 which was 1 year older than our result. This discrepancy was expected given the improvement of nutritional status among children in western China during the last decade.29 However, the earlier puberty onset observed in developed countries warrants other explanations beyond undernutrition. Crocker et al30 reported that the secular change in age at puberty onset parallels the increasing prevalence of overweight and obesity in the United States. Similar changes have been observed in Western Europe.7 Consequently, we examined the associations of infancy growth in early life with adolescent puberty onset in an attempt to understand the mechanism behind these links.In the present study, 241 girls (82.0%) experienced puberty onset at a median age of 11  years. Secular trend analyses showed that the median age at puberty onset in Chinese girls declined from 9.8 years in 1993 to 9.2 years in 2010.31 we did not find any associations between birth size and timing of puberty onset. Most studies,33 however, found that intrauterine growth restriction and lower birth weight were associated with earlier puberty onset. In contrast, some studies34 have reported that girls with higher birth weights tend to have earlier puberty onset. The divergent results may partly be explained by participants from different ethnicities and the different analytical approaches and birth weight measures used.Consistent with the Avon Longitudinal Study in British girls,35 we also found that infant rapid weight gain was associated with an increased likelihood of puberty onset. Although the biological mechanisms are not yet fully illustrated, studies speculate that rapid weight gain in early life has been linked to elevated insulinlike growth factor 1 concentrations and insulin resistance, adrenal androgen concentrations, and risk of obesity, all of which could promote the activity of the gonadotropin-releasing hormone pulse generator, consequently influencing the timing of puberty.14To the best of our knowledge, our study is the first to fully and comparatively assess the roles of infant WAZ, LAZ, and BAZ during the first 2 years of puberty onset. We found that higher WAZ was associated with earlier puberty onset, and girls who experienced underweight in early life were less likely to enter puberty. In line with prior studies, which used menarche to assess puberty onset,36 reported that the rapid weight gain from birth to 6 months of age was associated with earlier puberty onset. Similar results have been reported in other studies with longer intervals, from birth to 12 months of age in the Danish National Birth Cohort32 and from birth to 20 months of age in a British study.31 The lack of association in our study could be explained by the sample size and different ethnicities. Furthermore, in these 2 studies, the information on Tanner stage and weight was self-reported. Inconsistent with our null findings, a study conducted in North Carolina34 reported that girls with greater early weight gain from 6 to 12 months of age and from 12 to 24 months of age reached advanced Tanner stages at earlier ages, which may be due to the small sample size. Our results suggest for the first time that rapid weight gain within the first 3 months of age plays an independent role in subsequent pubertal development, and postnatal growth should be monitored closely as soon as possible after birth. In addition, some twin analyses have reported that weight gain is less likely to be influenced by genetic background during infancy than during childhood, suggesting a susceptible, modifiable window of infancy for long-term health outcomes.38 Interventions designed to reduce infant rapid weight gain through early nutrition management and maintain a healthy weight before, during, and after pregnancy may be feasible and practical.40In addition, our results  show tha41 The difference in findings suggests complex pathways that should be replicated in larger studies. We could not rule out the possibility that there is no association between length gain during infancy and puberty onset. Woo and colleagues42 reported that faster linear growth was associated with higher fat-free mass and lower percentage of body fat later in life, which may support our results, because body fat stores but not fat-free mass influence estradiol level. Thus, although linear growth in early life has been shown to be associated with many subsequent health outcomes, such as cognitive and motor development,43 puberty onset may not be one of them.We did not find that length gain was associated with puberty onset in the present study. We hypothesize that this null finding may be due to the small number of participants who experienced rapid length gain, ranging from 10.7% to 32.5%. However, a British cohort study reported that rapid height changes in infancy, particularly from 4 to 12 months of age, may be related to later age at menarche.44 This is particularly critical for girls who are in early puberty and are slightly overweight or obese, which may falsely suggest the presence of breast development with the staging of thelarche by visual inspection only.To our knowledge, our study is the first to investigate the influence of infancy growth on early puberty onset in girls in rural western China. The Tanner stages we used to determine the onset of puberty are considered the standard criteria by which prepubertal and pubertal girls can be reliably distinguished.The study has a few limitations. First, our study was conducted within the context of a trial of antenatal micronutrient supplementation, which may result in selection bias, limiting the generalizability of our results. In addition, 253 of 547 participants (46.3%) were lost to follow-up, although most of the baseline characteristics were balanced between participants who were lost to follow-up and those who were followed up. Third, age at puberty onset for girls with Tanner stages of greater than 2 was self-reported, which may involve the risk of recall bias. However, given the importance of puberty onset for girls and the short time after experiencing this milestone event, we considered the risk of recall bias to be acceptable. Interstaff variability in anthropometry measurements exists during different visits. Finally, we did not include all possible covariates, such as maternal smoking during pregnancy, the type of feeding, excessive gestational weight gain, and stressful life events experienced during pregnancy. Future studies with strict designs are warranted to investigate the causal association between weight gain in infancy and puberty onset.In this prospective cohort study, girls who experienced rapid weight gain and had higher WAZ during the first 2 years of life had a higher likelihood of early onset of puberty. We identified the period of the first 3 months after birth as a critical window for the correlative role of weight-related indicators in puberty onset, indicating the necessity of monitoring weight growth as soon as possible after birth. Further research is needed to investigate whether these associations are causal and whether weight growth in early life could be modified to lower subsequent disease risk.


Current evidence suggests that lipoprotein(a) [Lp(a)] level above 50 mg/dL is associated with increased cardiovascular risk. Our study aim was to determine the relationship of apolipoprotein(a) [apo(a)] phenotypes and Lp(a) concentration below and above 50 mg/dL with coronary atherosclerosis severity and myocardial infarction (MI).The study population consisted of 540 patients  who passed through coronary angiography. The number of diseased major coronary arteries assessed atherosclerosis severity. Lipids, glucose, Lp(a) levels and apo(a) phenotypes were determined in all patients. All patients were divided into four groups: with Lp(a) <50 mg/dL [ “normal” Lp(a)] or ≥50 mg/dL [hyperLp(a)], and with low-molecular (LMW) or high-molecular weight (HMW) apo(a) phenotypes.p < 0.005 for hyperLp(a) and 2.2; 1.0–4.9, p = 0.056 for normal Lp(a)], but not in the group with HMW apo(a) and hyperLp(a)  compared with the reference group with HMW apo(a) and normal Lp(a). Similarly, MI was observed more often in patients with LMW apo(a) phenotype and hyperLp(a) and normal Lp(a) than in groups with HMW apo(a) phenotype.Baseline clinical and biochemical characteristics were similar between the groups. In groups with LMW apo(a) phenotypes, the odds ratio  of multivessel disease was higher [10.1; 3.1–33.5, The LMW apo(a) phenotype is associated with the severity of coronary atherosclerosis and MI even when Lp(a) level is below 50 mg/dL. The combination of Lp(a) level above 50 mg/dL and LMW apo(a) phenotype increases the risk of severe coronary atherosclerosis, regardless of other risk factors. LPA gene (Lipoprotein(a) [Lp(a)] is the supramolecular complex consisting of low-density lipoprotein (LDL)-like particle and highly-glycosylated protein—apolipoprotein(a) [apo(a)]. Apo(a) is an unique one among the apolipoproteins family. First, the structure and primary sequence of apo(a) has high homology with the plasminogen and consists of the kringle domains that are specific for such blood coagulation factors as plasminogen, prothrombin, urokinase, and tissue-type plasminogen activator. Second, apo(a) is one of the most polymorphic proteins in blood plasma, having more than 40 isoforms, and third, apo(a) plasma level is controlled by the LPA gene .The relationship between Lp(a) level and polymorphism of apo(a) with cardiovascular diseases (CVD) have been studied for several decades. The association of the low molecule weight (LMW) apo(a) isoforms with a higher risk of CHD in various populations was shown in 1992 –5. Howevn = 257) admitted for initial examination and/or without CHD were statin naïve.In the single-center study, we included 540 consecutive patients  who passed through coronary angiography with subsequent angiogram analysis. The Institutional Review Board approved the study. All patients provided their informed consent for participation in the study. Main exclusion criteria were acute, inflammatory, or autoimmune diseases, significant thyroid, liver or kidney dysfunction, alcohol abuse, treatment with any hormones, PCSK9 inhibitors, and apheresis. In accordance with clinical indications, patients received different doses of statins and ezetimibe. However, some of them (n = 57), 1—one vessel (n = 127), two- and three-vessel disease (n = 356). Coronary heart disease (CHD) was diagnosed in those with diseased coronary arteries (n = 483). CHD manifestation should be confirmed by history of MI, and/or typical angina pectoris with subsequent angiography confirmation. Discharge summaries had to be provided by subjects.The quantitative analysis of coronary artery lesions was conducted with an integrated computer system . Stenosis of more than 50% in a magistral artery or its major branches was considered significant. Patients were classified in accordance with the number of affected main coronary arteries: 0—no lesions  level, and apo(a) phenotypes were determined in all patients. Total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) were measured in blood serum. LDL-cholesterol (LDL-C) was estimated by the Friedewald equation for patients with TG levels <4.5 mmol/L: LDL-C = TC – HDL-C – TG/2.2 (mmol/L). The level of LDL-C corrected (LDL-Ccorr) for Lp(a)-cholesterol was estimated with the modified Friedewald formula: LDL-Ccorr (mmol/L) = LDL-C – 0.3 × Lp(a) mass (mg/dL)/38.7 . Lp(a) ct-tests and Mann–Whitney test. To compare the frequency data in the groups, the Chi-squared criterion or Fisher's exact test was used. Spearman's correlation analysis and the multiple logistic regression method were used to assess the association of risk factors with the severity of coronary atherosclerosis. The odds ratio (OR) with 95% confidential interval (CI) in different patients‘ groups was calculated to assess the relationship of Lp(a) concentration and apo(a) phenotype with coronary atherosclerosis severity or MI. P-values for all tests were two-tailed, and differences were significant at the p level below 0.05. An independent investigator double-checked all measurement calculations and database entries. All statistical analyses were performed with MedCalc 20.022 software .For continuous variables with an approximately normal distribution, data were presented as means ± standard deviation (SD). For parameters with non-Gaussian distribution, data were expressed as median and interquartile intervals. In univariate analysis, variables were compared by We included 540 patients  subjected to coronary angiography in the Institute of Clinical Cardiology. We observed a wide distribution of Lp(a) concentrations, most pronounced for LMW apo(a) .p < 0.01). CHD manifestation before the age of 49 years was observed in patients with LMW apo(a) phenotype more frequently, than HMW apo(a) phenotype (p = 0.026).All patients were divided into four groups: in accordance with Lp(a) concentration ] or ≥50 mg/dL [hyperLp(a)]), and apolipoprotein(a) phenotypes: low-molecular weight (LMW) or high-molecular weight (HMW) . There nhenotype . The prer = 0.14, p = 0.0006) was an independent predictor of severity of coronary atherosclerosis, as well as sex , and hyperlipidemia . The level of Lp(a) ≥50 mg/dl as a categorical binary variable or the presence of the LMW apo(a) phenotype were associated with the number of affected coronary arteries  concentration .The proportion of patients with more severe atherosclerosis increased steadily in groups stratified by apo(a) phenotype and Lp(a) concentration and reached 98% in group 4. There was a trend to association between the presence of LMW apo(a) and coronary atherosclerosis in patients with Lp(a) level below 50 mg/dL. For patients with LMW apo(a) and Lp(a) ≥50 mg/dL (group 4) the CHD probability increased by nine-fold . The probability of MI in patients from group 3 was comparable with those from group 4  patients had MI, the proportion of patients with MI were comparable in groups of patients with HMW apo(a) phenotype and different Lp(a) levels (56 and 55% for Lp(a) <50 mg/dL and Lp(a) ≥50 mg/dL, correspondingly). In group 3 [LMW apo(a) and normal Lp(a)] MI was registered in 72%, that was more frequent than in group 1  phenotype and Lp(a) concentration in the range from 30 to 49 mg/dl, 36 (86%) had MI, and this accounted for 11% of all patients with MI. LMW apo(a) phenotype was associated with MI in 360 patients with Lp(a) <50 mg/dL .We have analyzed the relationship between apo(a) phenotypes and atherosclerosis severity in the subgroup of 74 patients with Lp(a) level between 30 and 49 mg/dL. Multivessel disease was detected in 31 out of 42 patients (74%) with the LMW apo(a) phenotype and in 17 out of 32 (53%) patients with the HMW apo(a) phenotype, Lp(a) concentration varies widely between individuals from <0.1 mg/dl to more than 300 mg/dl, while there is a minimum number of people who have not detectable levels of Lp(a) in plasma  mg/dL.Considering the results of a meta-analysis of the relationship between the Lp(a) level and development of CHD did not show significant differences in the relative risk in studies using methods sensitive and insensitive to the size of apo(a) isoforms  and highWe did not determine the number of KIV-2 kringles, but used a classification based on mobility of apo(a) isoforms in polyacrylamide gel electrophoresis and dichotomized all patients into those with LMW or HMW apo(a) phenotypes.The low-molecular phenotypes of apo(a) are associated with the severity of coronary atherosclerosis and myocardial infarction even when Lp(a) level is <50 mg/dL. The combination of elevated concentrations of Lp(a) and low molecular weight apo(a) phenotype potentiate the risk of atherosclerosis and MI, regardless of other risk factors.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Russian Cardiology Research and Production Center of Ministry of Healthcare of Russian Federation. The patients/participants provided their written informed consent to participate in this study.OA and ME: conceptualization and writing—original draft preparation. OR, NT, MA, and YM: methodology. SP and ME: validation. OA: formal analysis. OR, ME, and NT: investigation. SP: resources. ME and NT: data curation. OA, ME, and SP: writing—review and editing. YM: visualization. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Fear of childbirth (FOC) may contribute to postpartum depression, impaired maternal-infant relation, and preference for cesarean in future pregnancies. We aimed to investigate predictors of FOC and normal vaginal birth among postpartum women who had planned for a normal vaginal birth.This cross-sectional study was conducted in 2019 with postpartum women during the first 24 h after the birth. A sample of 662 women, selected using a convenient sampling method, filled out the questionnaire composed of socio-demographic and obstetric questions and the Wijma Delivery-Expectancy Questionnaire (W-DEQ). We used multiple logistic regression analyses to determine predictors of FOC and normal vaginal birth.The percentage of women with mild (score ≤ 37), moderate (38–65), high (66–84), severe (85–99), and intense FOC (score ≥ 100) were 7.9, 19.5, 40.9, 21.1, and 10.6% respectively. Predictors of intense FOC were age < 30, primiparity, low maternal satisfaction with pregnancy, and a low level of perceived marital satisfaction. Overall, 21.8% of women gave birth by cesarean. Predictors of normal vaginal birth were birth weight < 4 kg, spontaneous onset of labor pain, mother’s age < 30, term pregnancy, having a doula, multiparity, satisfaction with husband’s support, and overall satisfaction with pregnancy. A high level of perceived marital/sexual satisfaction was a risk factor for cesarean. Mode of birth was not a predictor of postpartum FOC.The rate of severe and intense FOC among this group of postpartum women is high. Our findings highlight modifiable factors for reducing FOC and increasing normal vaginal birth. In designing programs to increase the rate of normal vaginal birth, the following factors should be considered: limiting induced labor, encouraging women to recruit a doula to help them at labor, facilitate husband’s attendance throughout antenatal/intrapartum, and postnatal care to support his wife, and pay attention to women’s common misunderstandings about the effect of vaginal birth on marital/sexual relationship. Our findings indicate that seeking novel ways to promote marital/sexual satisfaction and helping women to have a smooth, hassle-free pregnancy may contribute to a reduction in the rate of the FOC.The online version contains supplementary material available at 10.1186/s12884-021-03790-w. Most pregnant women regard childbirth as an important and challenging event which may be accompanied by fears and worries. Fear of childbirth (FOC) is common among pregnant women in Western countries with a prevalence rate of eight to 27% . The preSeveral studies have found that a number of factors might increase FOC including advanced maternal age, high socio-economic status , insuffiIran is among the countries which have a high rate of cesarean birth. Between 1976 and 2010, the overall incidence of caesarean increased from 19.5 to 48% in Iran  which leThese findings from earlier studies suggest that it would be informative to investigate FOC among women who had planned for normal vaginal birth and who delivered via cesarean or normal vaginal birth after going into labor. Several questions are worth considering with regard to these women such as 1. Does severity of FOC differ between primiparous and multiparas? 2. Do primiparous and multiparas differ with respect to different dimensions of FOC like fear of loss of baby or loneliness? 3. Does severity of FOC differ between women who had a doula at birth and those who had not? 4. Is there a relationship between FOC and mode of birth? 5. What are predictors of FOC and normal vaginal birth in women who planned for a normal vaginal birth?In designing policies to reduce FOC and cesarean rate, it is important to identify predictors of FOC and normal vaginal birth among postpartum women. Most of the previous studies about FOC have focused on evaluating antenatal FOC by investigate women’s expectations towards childbirth. In contrast, we aimed to investigate FOC in early postpartum to explore women’s actual experience of childbirth among those who had planned for normal vaginal birth.. The study population was postpartum women. Mothers hospitalized in the postpartum wards of Mobini Hospital, affiliated with Sabzevar University of Medical Sciences, Sabzevar, Iran were recruited during the first 24 h after birth using a convenience sampling method. Recruitment for this study began in July and ended in September 2019. Before the COVID-19 pandemic, there were on average 6000 births in this hospital annually.This study was conducted using data previously collected for a descriptive cross-sectional study on the validity of the Persian Birth Satisfaction Scale-Revised (the Persian BSS-R) . The EthThe inclusion criteria for the validity study of the questionnaire were having a pregnancy with a healthy single baby, ability to read and write, being physically able to fill out the questionnaires and giving consent to participate in the study. Exclusion criteria included mental illness requiring medication and having postpartum complications such as fever, severe hemorrhage, high blood pressure, or any other complications that may have compromised the accuracy of responses to the items of Wijma scale. For the present analysis, we excluded women who planned elective cesarean as well as those with vaginal birth after cesarean (VBAC) and instrumental birth.We instructed two graduate midwives on data collection. After obtaining verbal consent from participants in the study, the midwives extracted obstetrical information from the patients’ files, distributed the written consent forms and the questionnaires among all postpartum women, and instructed them on how to fill out the anonymous questionnaires.The women were interviewed at the postpartum and an interview form was completed. It consisted of three sections containing questions on socio-demographic characteristics , obstetrical information , and psychosocial factors . We instructed the women to rate their level of satisfaction with pregnancy, husband’s support, and marital/sexual relationship on a five-point Likert scale ranging from one (not satisfied) to five (very satisfied). With regard to this issues, we asked the following questions: 1. To what extend are you satisfied with your pregnancy, given the health problems you encountered during your pregnancy?, 2. To what extent are you satisfied with your husband’s emotional/financial support during pregnancy?, and 3. To what extent are you satisfied with your marital/sexual relationship during the pregnancy? We asked women to rate their satisfaction with monthly household income on a three-point Likert scale ranging from 1 indicating a low level of satisfaction, 2 indicating satisfaction, and 3 indicating a high level of satisfaction the .The Wijma Delivery Expectancy/Experience Questionnaires (W-DEQ) was developed to investigate postpartum FOC . The W-Dp-value < 0.25 in simple logistic regression analysis were entered into the multiple logistic regression analysis.SPSS version 18 was used to analyze the data. Descriptive statistics were used to define the sample characteristics. Normal distribution of the Wijma scores was confirmed using skewness or kurtosis. The women were classified into two groups according to parity and the mean scores of W-DEQ for the two groups were compared using t-test. We investigated the relationship between having a doula and FOC in cesarean and vaginal birth using two t-test, one in the normal vaginal birth group and the other in the cesarean group. Multiple logistic regression analyses by backward-LR method was used to determine independent variables predicting the mode of birth and FOC. All variables with a n = 101), VBAC, and instrumental vaginal birth (n = 21); so, the sample size for the present study is 662. The mode of birth for 21.8% of women was emergency cesarean; the corresponding percentages among primiparous and multiparous were 24 and 20.1%, respectively. The percentage of primiparous and multiparous who had a doula at birth were 31.1 and 25.6%, respectively. Participants’ demographic and obstetric characteristics is presented in Table Of the 784 participants who were recruited for the validity study, we removed cases who had chosen elective cesarean n = 01, VBAC,p <  0.05). There was a significant relationship between parity and levels of FOC (p <  0.008).The means of the W-DEQ total scores and the mean scores of all its six factors for primiparous and multiparous women are presented in Table p = 0.047). We found no significant relationship between severe FOC (W-DEQ > 85) and mode of birth (p = 0.092) (Table There was a significant relationship between severe FOC (W-DEQ ≥ 85) and having a doula at childbirth (2) Table .Table 3Correlates of severe FOC (Wijma score ≥ 85) include low satisfaction with household income, not having a doula at birth, low level of satisfaction with pregnancy, low level of marital/sexual satisfaction, and low level of satisfaction with husband’s support. We conducted multiple logistic regression analysis on Wijma scores to determine socio-demographic/obstetric and psychological predictors of severe FOC (Wijma score ≥ 85). Age < 30, low level of satisfaction with marital/sexual relationship and low level of satisfaction with pregnancy predicted severe FOC (Table Correlates of intense FOC (Wijma score ≥ 100) include age < 30, primiparity, low level of satisfaction with pregnancy, and low perceived quality of marital/sexual relationship. We conducted multiple logistic regression analysis on Wijma scores to determine predictors of intense FOC (score ≥ 100). Age < 30, primiparity, low level of satisfaction with pregnancy, and low level of perceived marital/sexual satisfaction predicted intense FOC Table .Table 4p < 0.001). In the cesarean group, we found no significant difference between the mean scores of W-DEQ in women who had a doula at birth and those who had not (p = 0.117)  Table .Table 5p = 0.015, OR = .374, CI ]. We entered 10 variables with p-value < 0.25 into a multiple logistic regression analysis. Nine variables remained in the model , severe (85–99), and intense FOC (score ≥ 100) were 40.9 and 21.1%, and 10.6%, respectively. The above percentages are higher compared to those obtained in our previous study on pregnant women indicating that FOC is more prevalent in early postpartum. In that study, the prevalence of severe and intense antepartum FOC were 19.6 and 6.1%, respectively . The preThe rates of prevalence of high and severe FOC in our study are generally higher than those reported in western countries . In a stPredictors of intense FOC were mothers’ age < 30, primiparity, low level of satisfaction with pregnancy, and low level of perceived marital/sexual satisfaction. Primiparity has been found to be associated with antenatal FOC in several studies , 28, 29;Satisfaction with husband’s support was a correlate of FOC in our study. Some studies investigated the association of different sources of support and FOC. Women’s satisfaction with husband’s support , family Our results show that having a doula at birth could reduce FOC in women who gave birth by normal vaginal birth. This result is in agreement with a previous study which found that doula support reduced anxiety and tension and had a positive impact on maternal emotional wellbeing . In contOur results indicate that there is no association between mode of birth and FOC. This may be because our sample consisted of women who planned to have normal birth. Women with high or severe fear of childbirth might opt for an elective cesarean. Also, we excluded instrumental births which numbered only 21. This group’s experience of childbirth is painful and difficult and so it may provoke severe fear. In contrast to this, in Fenwick et al. study, cesarean increased levels of postpartum fear .Overall, 78.2% of women in our study experienced a normal vaginal birth. According to our results, demographic and obstetric predictors of normal vaginal birth were birth weight < 4 kg, spontaneous onset of labor pain, mother’s age < 30, term pregnancy, having a doula, and multiparity. According to a study on 284 Nigerian nulliparous women in which 74.8% of the parturient gave birth by vaginal birth, normal infant birth weight was a factor associated with vaginal birth . In the There were also two psychological predictors of normal vaginal birth, namely satisfaction with husband’s support and satisfaction with pregnancy. This implies that women with a hassle free pregnancy and those with a supportive husband are more likely to give birth normally. Satisfaction with marital/sexual relationship was a protective factor for vaginal birth. This means that women who were satisfied with their marital/sexual relationships were more likely to give birth by cesarean than those with a low level of marital/sexual satisfaction. It is a common belief that vaginal birth may affect sexual pleasure/function and consequently marital relationship. The results of a recent qualitative study in Iran indicates that fear of irreversible damage to urogenital organs and sexual function and husbands’ concerns about sexual function were among the reasons for requesting cesarean .The high cesarean rates during recent decades in Iran are both a symptom and a cause of changes in community norms resulting in maternal requests for cesarean. Affluent women usually opt for elective cesarean in luxury hospitals. Some women want their baby to be born on a particular day and some are concerned about the function of their urogenital organs and sexual satisfaction after vaginal birth, and there are women who believe that elective cesarean is safer for the fetus . Other rThis study has a number of limitations. First, sampling was performed in a maternity hospital during the first 24 h after birth. In early postpartum, mothers may still feel uncomfortable and it can cause false negative/positive results. The second limitation was that we had to exclude women who had instrumental birth because we could not compare this small group with the normal vaginal birth group.One of the strengths of this study is that we recruited a relatively large sample of women who planned to have normal birth. Also, we used the W-DEQ version B to measure the severity of postpartum FOC. The W-DEQ provides information on different domains of the fear. One of the disadvantages of this study was that we did not use validated scales to measure the levels of husband’s support, perceived marital/sexual satisfaction, and mothers’ satisfaction with pregnancy. Because all these factors have significant association with FOC and also with vaginal birth, we recommend that further research be conducted on postpartum FOC using valid scales to measure these variables. Also, further studies are needed to investigate women’s concerns about the negative effects of vaginal birth on marital/sexual relation and its association with FOC.In this study, we tested both cut-off points for Wijma scores and obtained quite similar results with regard to predictors of FOC. The use of cut-off point ≥85 compared with cut-off point ≥100 yielded more variables that were correlated with severe FOC.Intense FOC is more prevalent among primiparous than multiparas. Inspection of factors likely to influence FOC showed that the mode of birth did not have a significant effect on FOC. In contrast, psychological variables such as mother’s satisfaction with pregnancy or her satisfaction with marital/sexual relationship could predict FOC. So, in designing programs for reducing FOC, researchers and policy makers in Iran should pay more attention to psychological factors.The prevalence of high, severe, and intense FOC cases in our study are higher in comparison with those reported in western countries. We also found that postpartum FOC was not influenced by the mode of birth. Therefore, to reduce FOC health policymakers should learn from the experience of countries with low levels of FOC and adopt measures such as improving birth conditions, offering more choice to women with respect to labor and birth, avoiding unnecessary interventions during childbirth, promoting normal physiologic birth and respectful maternity care. Within the framework of the HTP, more emphasis should be placed on respectful maternity care and humanizing maternity services.According to our results, two psychological variables could predict normal vaginal birth namely satisfaction with husband’s support and women’s satisfaction with pregnancy. This means that these variables could be manipulated to reduce cesarean. We also found that satisfaction with marital/sexual relationship was a protective factor for vaginal birth. Therefore, we recommend that interventional studies to reduce the rate of cesarean pay attention to women’s common misunderstandings about the effects of vaginal birth on sexual/marital relationship.Our findings highlight factors which could be modified to increase normal birth. Limiting induced labor, encouraging women to have a doula to help them at labor, facilitating husbands’ attendance throughout antenatal/intrapartum and postnatal care to support their wives, consultation with couples to increase husband’s support, and attempts to make pregnancy safe and hassle-free should be considered in programs to increase the rate of normal vaginal birth.Additional file 1.


ABSTRACT IMPACT: This work provides context from the patient perspective on the impact of hospital policies on their birthing experiencing during the first peak of the pandemic. OBJECTIVES/GOALS: The goal of this study was to report the intrapartum care experiences from people giving birth during the COVID-19 pandemic in the United States. Place of birth included hospital, birth center and home births. METHODS/STUDY POPULATION: Studies that involved patient-related data collection are hindered by pandemic-related changes in clinical practices and research policies. Our aim was to assess patient experience during a pandemic, we explored data collection via a large online community of pregnant women. We asked if women who birthed during COVID-19 changed their birth setting and if they experienced less respectful care, more pressure to undergo induction and/or cesarean birth and newborn separation. We also wanted to explore whether there were differences in the care experience depending on the race of the woman. Open ended questions on care experiences were included and content analysis conducted. Bivariate analysis was conducted comparing those from high versus less COVID-19 impacted areas and by race (White/Black self-identifying). RESULTS/ANTICIPATED RESULTS: The mean age was 31.5 years (SD = 5.0), 80.7% identified as White, 85.0% married, and 85.3% privately insured (N=388). Bivariate unadjusted analyses comparing high vs. low impact COVID-19 states, 22.3% considered changing their place of birth versus 12.7% in less impacted areas (p<.05): no difference pressure for induction/cesarean based on region. In bivariate unadjusted analysis comparing White and Black people, Black people had higher odds of pressure for cesarean or induction compared to White . Black people had lower respect scores vs. White (68.7 vs. 72.3 p<.01) and higher odds of preterm birth 3.7 . Content analysis themes were institutional policies, changes in care, hospital staff interactions, sub-par care, support during birth and mental health. DISCUSSION/SIGNIFICANCE OF FINDINGS: The analysis demonstrated differences among participants from highly versus less impacted COVID-19 states. Disparities persisted with Black women reporting lower respect, pressure for interventions and more preterm birth when compared to White participants. Limitations include use of a convenience sample and self-reported data.


In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM.It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01–2.77),  Although evidence from middle and low-income countries suggests that dietary supplementation with multiple micronutrients in pregnancy is beneficial in terms of reducing the prevalence of preterm births and low birth weight babies, as well as the numbers born small for their gestational age (SGA) , its valIron supplementation in pregnancy is common and indeed recommended in many countries . In the Following the previous studies linking dietary iron supplementation with GDM development ,9,10,11 The prospective longitudinal Cambridge Baby Growth Study (CBGS) recruited women from early pregnancy ultrasound clinics at the Rosie Maternity Hospital, Cambridge, UK, to the first phase between 2001 and 2009 . A totalAround week 28 of pregnancy, 1074 of the women underwent oral glucose tolerance testing (OGTTs) using 75 g glucose loads consumed orally after overnight fasting . The resEthical approval for the CBGS (00/325) was granted by the Cambridge Local Research Ethics Committee, Addenbrooke’s Hospital, Cambridge, UK. Women gave informed consent for both themselves and their babies. All procedures were followed according to the institutional guidelines.At recruitment, an extensive questionnaire was given to each of the participants. They were asked to complete it as the pregnancy progressed (with assistance from trained research nurses if required) ,17. The Birth weights were collected from hospital notes. Other new-born measurements were made as close to birth as possible (at a median (interquartile range) of 2–16 days) by trained paediatric nurses. These measurements included the baby’s length, head circumference, and skinfold thickness at four sites. They were all measured in triplicates and the mean was used in the analyses. Details of how the measurements were made have been presented previously [A simple but validated food frequency questionnaire to be filled in as the pregnancy progressed was also included in the full pregnancy questionnaire. Specific food intakes were converted into a frequency of consumption score as previously described . These wp < 0.05 was used to define statistical significance.This analysis follows a regrouping of data from pregnant women who were participants in the CBGS that were included in the previous multiple micronutrient and folic acid analyses ,3. The eSensitivity analyses were performed by repeating the association analyses in women who supplemented their diets with iron alone (rather than via multiple micronutrient supplementation) and by excluding those women who reported a diagnosis of anaemia in pregnancy. Effects of potential mediators that may underpin the significant associations (GDM and weight gain in pregnancy) were tested in women for whom these data were available by examining the effect of adjusting for those potential mediators on associations between iron supplementation and measures of size at birth. Similarly, iron supplementation was tested as a mediator of the significant associations between (1) multiple micronutrient supplementation and (2) maternal GDM risk, offspring birth size, and adiposity.There were few clinical disparities between the women whose data was included in this analysis and those that were excluded from it . Those tn = 582; 60.1%) and those that did not  (n = 524) amongst those that classified as taking iron took multiple micronutrient supplements. In fact, as all the multiple micronutrient preparations used contained iron, participants who supplemented with multiple micronutrients were all classified as taking iron . All the multiple micronutrient preparations also contained folic acid, supported by the fact that there was a higher proportion of those that took iron supplements than those that did not also supplement with folic acid. All but one of the women who reported experiencing anaemia during pregnancy (n = 27) took iron supplements . Although there were a wide range of start times, the modal time of when women started supplementing with iron was around conception  . Of thosnception  and manyn = 677; p = 0.048; p = 0.05). There were no differences between iron supplementation groups in the proportion of women that developed either gestational hypertension or pre-eclampsia, or in the proportion that gave birth to premature, SGA, or low birth weight babies.A higher proportion of women who took iron supplements developed GDM than the proportion of those that did not (RR 1.67 (1.01–2.77); p = 0.005), head circumference (p = 0.02), BMI (p = 0.01), and skinfold thicknesses in three of the four sites (p = 0.03–0.003) (the fourth having a borderline significance of p = 0.05) , the maternal iron supplementation was still associated with increased offspring subscapular skinfold thicknesses  . In the p = 0.045) and offspring size at birth (p = 0.02). When adjusted for iron supplementation, the significance of the association with multiple micronutrient supplementation in the same women was lost (RR 1.76 (0.64–4.81); p = 0.3). Adjusting for iron supplementation also attenuated associations between dietary supplementation with multiple micronutrients and offspring size at birth ; at birth . In 663 at birth .In 608 women for whom relevant data were available, adjusting for GDM attenuated the various associations between maternal iron supplementation in pregnancy and offspring size at birth . A smallIn this analysis, women who supplemented their diets with iron in pregnancy had an increased risk of developing GDM as well as increases in various measures of offspring size at birth . These findings are very similar to previously observed associations with pregnant women who supplemented their diets with multiple micronutrients . Unlike In addition to results suggesting that iron supplementation may have mediated previously observed associations with multiple micronutrient supplementation , this anWe found that GDM attenuated all the associations between iron supplementation in pregnancy and the various measures of size at birth. These assessments were conducted at a time when there was a temporal trend for a rising prevalence of GDM in this population , althougThe strengths of this study include the levels of detail available to us in relation to the assessment of size at birth and maternal GDM status in a relatively large number of newborns and women that were part of a well-characterised cohort. It also has a number of limitations, however. Firstly and most importantly, we analysed iron supplementation in pregnancy only as a dichotomous exposure; thus, there was no account of the stage of pregnancy when iron was supplemented, the doses of iron consumed, the dietary iron consumption, or maternal iron status. However, this approach had the advantage of increasing the numbers of participants available to us due to fewer exclusions resulting from missing iron-related data. Also, it has been shown by meta-analysis that the duration of iron use in pregnancy is not significantly associated with outcomes such as increases in birth weight . A seconIn conclusion, this analysis confirmed previous reported associations between iron supplementation in pregnancy and both maternal GDM and increased offspring birth weight. We extended this to other measures of size at birth and demonstrated that the principal reason for the increased weight seems to be increased adiposity. These associations appeared to be mediated by the increased risk of GDM. The main associations with iron supplementation reflected and attenuated those with multiple micronutrient supplementation in this cohort, suggesting that it may be the main mediator of such associations.


Malnutrition was the main cause of death among children below 5 years in every state of India in 2017. Despite several flagship programmes and schemes implemented by the Government of India, the latest edition of the Global Nutrition Report 2018 addressed that India tops in the number of stunted children, which is a matter of concern. Thus, a micro-level study was designed to know the level of nutritional status and to study this by various disaggregate levels, as well as to examine the risk factors of stunting among pre-school children aged 36–59 months in Malda.A primary cross-sectional quantitative survey was conducted using structured questionnaires following a multi-stage, stratified simple random sampling procedure in 2018. A sum of 731 mothers with at least one eligible child aged 36–59 months were the study participants. Anthropometric measures of children were collected following the WHO child growth standard. Children were classified as stunted, wasted, and underweight if their HAZ, WHZ, and WAZ scores, respectively, were less than −2SD. The random intercept multilevel logistic regression model has been employed to estimate the effects of possible risk factors on childhood stunting.The prevalence of stunting in the study area is 40% among children aged 36–59 months, which is a very high prevalence as per the WHO’s cut-off values (≥40%) for public health significance. Results of the multilevel analysis revealed that preceding birth interval, low birth weight, duration of breastfeeding, mother’s age at birth, mother’s education, and occupation are the associated risk factors of stunting. Among them, low birth weight  and bidi worker as mothers’ occupation  are the most influencing factors of stunting. Further, about 14 and 86% variation in stunting lie at community and child/household level, respectively.Special attention needs to be placed on the modifiable risk factors of childhood stunting. Policy interventions should direct community health workers to encourage women as well as their male partners to increase birth interval using various family planning practices, provide extra care for low birth weight baby, that can help to reduce childhood stunting.The online version contains supplementary material available at 10.1186/s12889-021-11704-w. The latest edition of the Global Nutrition Report 2018 addressed that India tops in the number of stunted children (46.6 million), followed by Nigeria (13.9 million) and Pakistan (10.7 million). These three countries are home to almost half of the world’s stunted (47.2%) children  were taken from mother’s characteristics. Bidi, also spelt as beedi or biri, is a popular local mini-cigar or cigarette in India. It is filled with tobacco flake and wrapped by tendu leaf, made by women mostly in their homes. Bidi making is one of the main sources of livelihood in rural areas in the study region. Among household characteristics, religion , social groups or caste , wealth index  and the place of residence  were chosen. The wealth index was used as a proxy measure of income that has been constructed using the selected household’s amenities, facilities, and assets following the Demographic Health Survey (DHS) [A sum of 14 potential explanatory variables was chosen to examine the risk factors of stunting based on the findings of previous studies and the availability of the data in the present study. Among child’s characteristics, age of the child , sex of the child , birth order , low birth weight (dummy: no vs yes), preceding birth interval  and duration of breastfeeding  were selected. Low birth weight is defined by the World Health Organization as the weight of lower than 2500 g or 5.5 pounds at the time of birth . Mother’ey (DHS) . ChildreEthical approval was obtained from the IERB-JNU , New Delhi, IERB Ref. No.2019/Student/223. The purpose of the study was thoroughly explained to respondents, and written consents were obtained from the parents/guardians of the minors included (minors are considered anyone under the age of 16) before starting the survey. Also, the written consent information for all mothers and caregivers who participated in the study was obtained before starting the survey.Univariate descriptive statistics were carried out to describe the sample characteristics and to explore the pattern of the outcome variable. Since the dataset for the present study was hierarchically stratified, 731 children are nested within the 731 mothers/caregivers, mothers are nested within 731 households, and the households are nested within 42 Anganwadi Centres (AWCs) of the ICDS scheme. Thus, bearing in mind this hierarchical structure of the dataset, a random intercept multilevel logistic regression model was employed to estimate the effects of possible risk factors on childhood stunting. Also, multilevel modelling was used to estimate the variation in stunting at the lowest level of hierarchy to a higher one, is the advantaged over single-level model or simple logistic regression . Here, iA series of the models was employed in the multilevel modelling to look at the dynamics of effects of various possible risk factors of stunting among pre-school children, e.g., child, mother, and household-level characteristics to community-level characteristics, which were entered step by step in the models. The first model (Model 1) was a null model or unconditional model where no independent variables were included. In Model 2, the child’s characteristics were included, and in the later model (Model 3), the mother’s characteristics were added, while in Model 4, only ‘child attending AWC’ was added. In Model 5, household characteristics were incorporated, while in the subsequent model, Model 6 was a complete model, place of residence was included.Table Figure The bivariate estimations of childhood stunting by background characteristics of children in the Malda district are also presented in Table p-values of the log-likelihood ratio test (LR) versus logistic regression vary from 0.001 to 0.024, which also indicate that the variance in child stunting differs significantly by an individual child or household level and AWC or community level.Table Model 6 is a final and comprehensive model. After controlling for all the explanatory variables in this model, it is found that birth interval, low birth weight, duration of breastfeeding, mother’s age at birth, mother’s education, and occupation are the significant risk factors of stunting. Among them, low birth weight  and bidi worker  are the most influencing factors of stunting, which show a consistent effect throughout the models. Besides these, the mother’s age of > 25 years at birth  is also another important risk factor of stunting. Nevertheless, the proportion of stunted children among the mothers who are agricultural workers or manual labourers and children belonging to the ST community are extremely high, as shown by bivariate estimations, but these are not significant risk factors of stunting in the full regression model. On the other hand, the value of the community level ICC is 0.14, which indicates the correlation among the children within the same community is 0.14 in the case of child stunting. In other words, about 14% variation in stunting lies at AWC or community level, and the larger part of the variation in stunting lies at the child or household level, as shown in the random part of the model. Further, the highest degree of changes in the random part of the model is observed after including the mother’s characteristics in the third model.The prevalence of stunting in the study area is 40% among pre-school children aged 36–59 months, which is a very high prevalence as per the WHO’s cut-off values (≥40%) for public health significance . If the According to Arjan de Wagt, is the nutrition chief, UNICEF India, and his colleagues, 2019, huge potential interventions are still in the operations under the nutrition and health schemes and programmes, but the services of these programmes and schemes are not reaching the children and women at a satisfactory level. Therefore, implementation constrictions need to be appropriately addressed by that high-impact nutritional interventions can reach the maximum level, and that should be followed with the Coverage, Continuity, Intensity, and Quality (C2IQ) principle  in the sThe results of the multilevel analysis revealed that preceding birth interval, low birth weight, duration of breastfeeding, mother’s age at birth, mother’s education, and occupation are the only associated risk factors of stunting in this study. Low birth weight is the strongest predictor of stunting, followed by mothers’ occupation and mothers’ age at birth. Association between low birth weight and stunting has been shown by several studies , 19, 21.Mother’s age at birth is also another important risk factor of stunting, where children of higher maternal age are more likely to be stunted than their counterparts. A similar association is observed in another study based in India . DuratioAn attempt has been made in the present research to explore the level of nutritional status, to study this by disaggregate levels, and to examine the risk factors of stunting among pre-school children aged 36–59 months in Malda. Accordingly, a primary field survey was conducted to study the same in 2018. It was found that Malda district suffers from the burden of a high-level prevalence of child stunting. This district has already got priority from the policy-making body, and the Indian Government implemented a flagship program NNM  in the first phase (2017–18) to eradicate malnutrition in this district. Before that, another flagship program, ICDS was implemented by the Indian Government during the 1990s and still in operation. Nevertheless, the prevalence of child stunting is at an alarming level. All the public health machinery from the grassroots level to a higher level, e.g., the local governing body to the State Government and Central Government are requested to monitor the implementing process and effectiveness of the programmes if the target ‘Mission 25 by 2022’ for stunting, that is still to be achieved. Further, special attention needs to be placed on the modifiable risk factors of child stunting as this study has found that preceding birth interval, low birth weight, duration of breastfeeding, mother’s education, and occupation are the associated risk factors of stunting in this district. Policy interventions should direct community health workers, e.g., ASHA , AWW (Anganwadi Worker), and ANM (Auxiliary Nurse Midwife), to encourage women as well as their male partners to increase birth interval using various family planning practices, provide extra care for preterm birth or low birth weight baby following WHO’s recommendation 2015 , increasAdditional file 1.


Supplemental Digital Content is available in the text. Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in utero exposure to antihypertensive treatment is conflicting, with many studies suffering from significant methodological issues, such as inappropriate study design, small sample sizes, and no untreated control group. We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010–2014 in Scotland to assess outcomes following in utero exposure to antihypertensive medication. We identified a cohort of 265 488 eligible children born over the study period; of which, 2350 were exposed to in utero antihypertensive medication, 4391 exposed to treated late-onset hypertension, and 7971 exposed to untreated hypertension during pregnancy. Untreated hypertension was associated with increased risk of preterm birth , low birth weight  and being small for gestational age , while in utero antihypertensive exposure was also associated with preterm birth , low birth weight , and being small for gestational age . Late-onset hypertension was also associated with preterm birth , low birth weight , and being small for gestational age . Our results suggest that hypertension is a key risk factor for low birth weight and preterm birth. Although preterm birth may be associated with antihypertensive medication exposure during pregnancy, these associations may reflect increasing hypertension severity necessitating treatment. Therefore, at present it is not clear whether there is a true association between adverse outcomes and antihypertensive use during pregnancy.Despite the widespread use of antihypertensive medication during pregnancy, the effects of medication on the fetus are unclear. Published literature is conflicting, with some reporting an increased incidence of preterm birth20 are followed regarding the treatment of hypertension in pregnant women. National Institute of Care and Excellence defines hypertension as a blood pressure of 140/90 mm Hg or higher, with a blood pressure of 160/110 mm Hg or higher classed as severe hypertension. Antihypertensive agents should be given when a measured blood pressure of 140/90 is exceeded.In the United Kingdom, strict guidelines set by The National Institute of Care and Excellence20Hypertension during pregnancy can fall into several categories: chronic hypertension, indicated by a diagnosis of hypertension or antihypertensive use before 20 weeks, or if unresolved following birth; gestational hypertension, indicated by new onset diagnosis of hypertension after 20 weeks gestation, without proteinuria; preeclampsia, indicated by hypertension occurring after 20 weeks gestation, with or without proteinuria; and preeclampsia superimposed on chronic hypertension, indicated by preeclampsia in the presence of previously diagnosed hypertension.The aim of this study was to assess the immediate birth outcomes for mother and child after in utero exposure to antihypertensive medication.https://www.isdscotland.org/.Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the Information Services Division at This study was approved by the National Health Service Scotland Public Benefit and Privacy Panel for Health and Social Care on the 18th April 2016: reference 1516-0363. Full ethical approval was given by the North West-Greater Manchester South Research Ethics Committee on the 20 April 2016: reference 16/NW/0313.Using the Community Health Index, a unique identifier given to all patients who use the National Health Service in Scotland, individual-level data from 4 Scottish healthcare databases, held by the Information Statistics Division, were linked. The linked databases used were the Scottish Morbidity Record 02 database, which collects data on maternal, obstetric, and child outcomes; the Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.Dispensed antihypertensive medication, excluding propranolol, were used as a surrogate for treated hypertension. Antihypertensive medication included any of the following British National Formulary codes: 2.2 diuretics, 2.4 beta-adrenoceptor blocking drugs, 2.5.2 centrally acting antihypertensive drugs, 2.5.5 drugs affecting the renin-angiotensin system, and 2.6.2 calcium channel blockers. To identify different hypertensive presentations during pregnancy, 4 study groups were defined.Exposure during pregnancy: All women who had a singleton live birth in Scotland between January 2010 and December 2014 and who were dispensed at least one prescription for an antihypertensive medication during the 300 days before birth.Late-onset hypertension: All women who had a singleton live birth in Scotland between January 2010 and December 2014 who were dispensed at least one prescription for an antihypertensive medication during the 60 days after birth, without any prior antihypertensive medication use. This group serves to identify those women who have had late-onset hypertension, or preeclampsia, that have not been treated throughout pregnancy. In the United Kingdom, women with preeclampsia will be started on antihypertensive therapy in secondary care, which is then continued in primary care after discharge. At present, unlike primary care prescribing, there is no national database of inpatient hospital prescriptions. A prescription for antihypertensive medication in the 60 days following birth was, therefore, used as a surrogate marker for preeclampsia or late-onset hypertension that has not resolved after delivery.International Classification of Diseases-Tenth Revision (ICD-10) code for one of the following: O10 chronic hypertension, O13 gestational hypertension, O14 preeclampsia, O15 eclampsia, O16 unspecified hypertension, and who were not dispensed antihypertensive medication at any stage during or 60 days after pregnancy (untreated hypertension).Untreated hypertensive group: All women who had a singleton birth during the same study period, who had an Unexposed comparison group: All women who had a singleton birth during the same study period who were not dispensed antihypertensive medication during or 60 days following pregnancy, and who did not have an ICD-10 code for one of the following: O10 chronic hypertension, O13 gestational hypertension, and O16 unspecified hypertension.Mother-child pairs with a duplicate or missing unique identifier, multiple births, pregnancies ending with abortion, miscarriage or stillbirth, and mothers recorded as younger than 14 years of age were excluded from the study. In the United Kingdom, propranolol is not routinely used in the treatment of hypertension during pregnancy and is not recommended by National Institute of Care and Excellence. The most common cause for prescription of propranolol is anxiety and migraine, which was reflected by the recorded dose range of 10 to 40 mg daily within our cohort. We, therefore, decided that women treated with propranolol should be excluded. Women who were prescribed an ACEi (angiotensin-converting enzyme inhibitor) or an ARB (angiotensin II receptor blocker) during pregnancy were also excluded.Four immediate birth outcomes for mother and child were studied: preterm birth, low birth weight , emergency caesarean section, and being small for gestational age. Preterm birth was defined as birth on or before 36 weeks gestation. Low birth weight was defined as a birth weight of <2500 g. Being small for gestational age was defined as having a birth weight below the 10th percentile of the population. Population percentiles were calculated from the complete cohort as this represents the full Scottish population born 2010 to 2014.21 and so were treated as potential confounders.The outcome measures were reported either as dichotomous variables , or as continuous variables . The Scottish Morbidity Record 02 data set provided data on the mother’s ethnicity, smoking status, alcohol and illicit drug use during pregnancy, previous stillbirth parity, maternal body mass index, maternal age, diabetes mellitus status, and Scottish Index of Multiple Deprivation quintile score, which was used as a marker of area socioeconomic deprivation. These variables were previously identified using a directed acyclic graphs processThe characteristics of mothers exposed to antihypertensive medication during pregnancy were described using appropriate summary statistics depending on the data type and distribution.22 The following variables were imputed: body mass index, Scottish Index of Multiple Deprivation, smoking, drug use, alcohol use, previous stillbirths, and parity. Body mass index was imputed by predictive mean matching with a K-nearest neighbors of 10, while the other variables were imputed by either multinomial, ordinal, or logistic regression. Rubin’s rules were used to combine the results of the imputed data sets to provide one overall estimate, with a CI adjusted for uncertainty.Where data were missing, multiple imputation chained equations were performed, using the MI impute function in STATA, to create 30 data sets.P value cutoff of 0.2. Models were adjusted for body mass index, Scottish Index of Multiple Deprivation, smoking, diabetes mellitus, previous stillbirths, parity, illicit drug use, recorded diagnosis of preeclampsia during the current pregnancy, maternal age, and interaction terms identified. All outcomes were modeled individually and are provided in Tables online-only Data Supplement. Univariate and multivariate regression are presented with risk ratios (RR), adjusted RRs (aRR), and 99% CI. Analysis of data was performed in STATA MP, version 14.1 (StataCorp).Poisson regressions with log links were performed for all dichotomous outcomes and linear regressions for continuous variables. Regressions were adjusted for relevant confounders as identified by directed acyclic graphs and then a stepwise model selection using the F test with a SMR 02 identified a total of 271 647 live births to 245 438 women during 2010 to 2014. Of these, 268 711 were singleton live births to 226 840 women aged >14 years: 39 949 women had ≥2 singleton deliveries over the period. After exclusion of 3223 mother-child pairs prescribed propranolol and 83 mother-child pairs prescribed an ACEI or ARB during pregnancy, 265 405 women-child pairs were eligible for inclusion in the study. Demographics of the study cohort are reported in the data S1, along with missing data totals.A total of 2350 offspring were exposed to antihypertensive medication during pregnancy, and 4391 offspring were born to women in the late-onset hypertension group. In the unexposed hypertensive group, a total of 7971 offspring were identified and 252 598 offspring in the unexposed comparison group. The majority of offspring were exposed to a β-blocker only , calcium channel blockers only , or a combination of >1 antihypertensive medication . The remainder of antihypertensive exposure was a mixture of loop diuretics , centrally acting antihypertensives , and thiazides .A significantly increased risk of emergency caesarean section was associated with untreated hypertension , exposure during pregnancy , and late-onset hypertension , compared with the unexposed comparison group (S2). When compared with the untreated hypertensive group, antihypertensive exposure during pregnancy was associated with a slight decreased risk of emergency caesarean section , while late-onset hypertension was associated with increased risk .Risk of preterm birth was significantly associated with untreated hypertension , exposure during pregnancy , and late-onset hypertension , compared with the unexposed comparison group  or >1 group of antihypertensive medications was significantly associated with increased risk of preterm birth (S3). Treatment started in any trimester was associated with increased risk of preterm birth (S3).Following adjustment for gestational age, significantly increased risk of low birthweight was associated with untreated hypertension , exposure during pregnancy , and late-onset hypertension  compared with the unexposed comparison group , followed by late-onset hypertension  and untreated hypertension  or >1 class of antihypertensive medication  at any time during pregnancy was associated with significantly increased risk of low birth weight (S4).There was an increased risk for being born small for gestational age following antihypertensive exposure during pregnancy , late-onset hypertension , and untreated hypertension  when compared with the untreated normotensive group  and throughout pregnancy  was associated with increased risk of being small for gestational age (S5). When assessing individual drug exposure during pregnancy, exposure to a β-blocker only  or >1 mediation over the pregnancy period  was associated with increased risk of being small for gestation (S5). Individual β-blockers were all associated with increased risk, with the largest increase following atenolol exposure .In this Scottish cohort of 268 711 children born between 2010 and 2014, we demonstrated increased risk of preterm birth, low and extremely low birth weight, being small for gestational age, and emergency caesarean section following exposure to any antihypertensive medication during pregnancy. However, when compared with the untreated hypertensive group, preterm birth and being small for gestational age remained significant. Furthermore, compared with the untreated hypertensive group, there was an increased risk of emergency caesarean section after late-onset hypertension, while we report a decreased risk following antihypertensive exposure during pregnancy. These findings suggests that a mix of hypertension itself, and exposure to antihypertension medication, is responsible for the observed increased risks of this study.23 the majority of these studies were of small size, had a poor study design, such as inappropriate control groups, methodologies with residual confounding, and lacked an untreated hypertensive group, leading to further possible confounding. We have reported outcomes following in utero antihypertensive exposure compared to that of an unexposed comparison group and an untreated hypertensive group, allowing us to differentiate between the risks due to underlying hypertension and medication exposure.While there is previous literature reporting an increased risk of adverse outcomes, such as preterm birth and low birth weight following in utero antihypertensive exposure,We report increased risk of preterm birth in the offspring of those exposed during pregnancy, late-onset hypertension, and in the untreated hypertension groups when compared with the unexposed comparison group. When the untreated hypertensive group was used as a comparison, this association remained for both the exposed during pregnancy and late onset hypertension groups. Our observations suggest that hypertension per se increases the risk of preterm birth and that this risk increases with medication, although the association with medication likely reflects increasing hypertension severity rather than a direct drug effect.We observed significantly increased risk of low birth weight, for all exposure groups including the untreated hypertensive group, compared with the unexposed comparison group. However, when antihypertensive exposure groups (during pregnancy and late-onset hypertension) were compared with the untreated hypertensive group, there was no increased risk of low birth weight, indicating that the risk of low birth weight is likely due to hypertension rather than medication exposure.23 have reported an increased risk of preterm birth and low birth weight associated with antihypertensive medication exposure, our results suggest that the increased risk of preterm birth and low birth weight is likely due to hypertension severity rather than medication exposure.While several studies suffering from methodological limitations24 up to 40% in women with chronic hypertension,25 and between 30% and 60% in women with preeclampsia.27 We observed an emergency caesarean rate of 14.73% in our unexposed comparison group, 30.55% in the untreated hypertension group, 28.03% in the exposed group, and 37.90% in the late-onset hypertension group, which are in line with published levels thus strengthening our group selection.In the Scottish population, the emergency caesarean rate is 15.9% for the general population,The use of Scotland-wide data sets, containing routinely collected healthcare data, permitted identification a large, nonselective cohort covering all eligible pregnancies in Scotland over a 5-year period. This approach obviated the possibility of selection or recruitment bias and provided sufficient statistical power to undertake sub-group analyses. Linkage of routinely collected healthcare data for offspring provided information on a wide range of child outcomes from birth to 30-month follow-up. Using dispensing data to determine drug exposure rather than issued prescriptions or self-reported medication use reduced the risk of reporting bias.Several assumptions were made in this study: use of an antihypertensive medication was solely for treatment of hypertension; women who did not have an ICD-10 code recorded in the Scottish Morbidity Record 02 data and who did not have antihypertensive medication dispensed were normotensive; and exposure following birth was indicative of late-onset hypertension or preeclampsia. As detailed clinical information was not available, we could not identify the severity of hypertension in affected women. While we cannot say whether hypertension was severe, we can use antihypertensive medication use as a proxy in this case, particularly if women are on >1 antihypertensive medication during pregnancy, indicating a greater need for blood pressure control. Due to the number of outcomes assessed, multiple testing was a potential issue. This was dealt with by increasing the threshold of significance and using 99% CIs. However, this poses a further limitation in that we may have missed significant results that do not meet these strict significance levels. Furthermore, due to the data-linkage cohort study design, it is not possible to guarantee coherence to medication regimes. We have attempted to limit this confounding by only using dispensed prescription data generated following the woman obtaining the medication from a pharmacy, rather than the prescription issued by a doctor.We demonstrated an increased risk of preterm birth, low birth weight, small for gestational age, and emergency caesarean section in the offspring of both treated and untreated hypertensive women. Rather than treatment with antihypertensive medication, hypertension severity may dictate the risk of preterm birth, while underlying hypertension may be the cause of low birth weight and small for gestational age.We acknowledge the support from the Farr Institute @ Scotland. The Farr Institute @ Scotland is supported by a 10-funder consortium: Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office , the Wellcome Trust, (MRC grant number MR/K007017/1). J.S. Mclay had the original concept. All authors agreed the study design. C.A. Fitton undertook data analysis and cleaning. All authors interpreted the results. C.A. Fitton and M.F.C. Steiner drafted the article, and all other authors contributed revisions. All authors reviewed and approved the final version of the manuscript. J.S. Mclay is guarantor for the study.Funding was provided by the FARR Institute at Scotland. The Farr Institute @ Scotland is supported by a 10-funder consortium: Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office , the Wellcome Trust, (MRC Grant No: MR/K007017/1).None.