Prevalência de doenças durante a gravidez em uma grande amostra sul-americana não selecionada

Rev Bras Epidemiol rbepid Revista Brasileira de Epidemiologia Rev. bras. Epidemiol. 1415-790X 1980-5497 Associação Brasileira de Saúde Coletiva RESUMO Objetivo: Descrever a prevalência de doenças durante a gravidez e a associação entre a exposição fetal às doenças maternas mais prevalentes e o risco de recém-nascidos prematuros (PP) e/ou pequenos para a idade gestacional (PIG) em uma amostra não selecionada de mulheres que deram à luz em países da América do Sul. Métodos: Estudo descritivo transversal que incluiu 56.232 mães de crianças não malformadas nascidas entre 2002 e 2016, utilizando dados do Estudo Colaborativo Latino-americano de Malformações Congênitas (ECLAMC). Foram identificadas as doenças com maior número de casos observado/esperado de PP/PIG. O esperado foi obtido dos controles sem doenças. Odds ratios para variáveis de confusão de doença e eventos ao nascimento foram calculadas usando regressão logística multivariada. Resultados: Das 14 doenças mais referidas, hipertensão, infecção geniturinária, epilepsia, hipotireoidismo, diabetes e HIV/AIDS apresentaram maiores frequências de PP e/ou PIG. Idade materna nos dois extremos, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PP, enquanto idade materna avançada, primigravidez, perda fetal prévia, baixo nível socioeconômico e ascendência afro-americana foram associados a PIG. Após ajuste para as variáveis associadas, as doenças identificadas mantiveram associação com PP e todas, exceto epilepsia, com PIG. Conclusão: A descrição de uma população não selecionada de gestantes possibilitou identificar as doenças mais frequentes e seu impacto nos resultados adversos na gravidez. Seis doenças foram associadas a PP e duas a recém-nascidos PIG. Até onde sabemos, não há relatos semelhantes sobre mulheres não selecionadas intencionalmente por doenças específicas durante a gravidez em populações sul-americanas. INTRODUCTION Preterm birth (PTB), with an estimated 10.6% global rate and a 9.8% Latin-American prevalence1, and small for gestational age (SGA), with a 27% prevalence in low-middle income countries and 13% in Latin America2, are determining factors for perinatal morbi-mortality worldwide. They are also related to poor postnatal growth and diseases whose consequences may extend to late adulthood3–5, as well as with a high burden due to prolonged interventions. Fetal exposure to diseases occurring during pregnancy may increase the risk of PTB or SGA6–8. Chronic illnesses such as cardiac and respiratory diseases, cancer, and diabetes are the main causes of worldwide mortality and affect one in 20 pregnant women9. Infectious diseases during pregnancy are still common especially in developing countries10,11. Fetuses can be affected directly by the infectious agent or indirectly by maternal infection consequences, leading to congenital malformations, miscarriages, fetal death, PTB, or SGA. The impact varies according to the specific agent and exposure level, gestational age, the mother's immune status, maternal and fetal genetic susceptibility, and interaction among factors. Furthermore, persistent or recurrent infections probably explain many repetitive spontaneous preterm births12. Similarly, disorders leading to medically induced preterm deliveries, such as diabetes or hypertension, frequently persist between pregnancies. The aim of this study, in addition to a literature review, was to present the prevalence of the most frequent diseases and of PTB and SGA in a large South American sample of women who reported having been ill during gestation. While most previous studies have focused on specific diseases, we found no similar reports where women were not intentionally selected by a particular disease. METHODS The study sample comprised database registries of the Latin American Collaborative Study of Congenital Anomalies (ECLAMC), a program dedicated to the research of birth defects through a network of maternity hospitals. Data on socioeconomic and demographic characteristics, previous birth outcomes, and prenatal factors were obtained from medical records and by interviewing the mothers of malformed infants and their controls (defined as the non-malformed infant of the same sex, born at the same hospital, immediately after the malformed one) before discharge. A detailed description of ECLAMC's registry and methodology has been previously published13. In this observational, cross-sectional, hospital-based study, which only included mothers of the non-malformed control infants, birth registries from 90 maternity hospitals of 10 South American countries were used, over a total of 1,962,767 births, between 2002 and 2016. Stillborn and multiple births were excluded. From 56,232 mothers of non-malformed newborns, 16,176 (28.8%) reported having been ill during pregnancy at any gestational age, while 40,056 reported no illnesses and were used for comparison. Of the 16,176 mothers, we included 10,928 whose illnesses (a total of 16,052 occurrences) had a ≥2/1000 prevalence which was calculated as the number of mothers with each disease over the total number of mothers. The sample size was calculated for an estimated 5% prevalence error and a 95% confidence. All included illnesses were equally considered, with or without diagnostic confirmation procedures. The remaining 5,248 mothers had less prevalent or unspecified diseases, or conditions not considered as diseases such as vomiting, headache, threatened abortion, or mental retardation, and were not included in the study. Exposure Maternal diseases Fourteen diseases had the required prevalence and were included in this study: hypertension (comprising preeclampsia and gestational and chronic hypertension), anemia, asthma, diabetes, hypothyroidism, Chagas disease (endemic parasitic disease frequent in South American poor rural environment), epilepsy, obesity, urinary tract infection (including pyelonephritis), influenza, vaginal infection, toxoplasmosis, HIV/AIDS, and syphilis. Two or more coexisting illnesses were considered individually. Around half of the mothers with influenza, diabetes, and hypertension had one or more additional diseases while Chagas disease, toxoplasmosis, HIV/AIDS, and syphilis occurred as single illnesses in around 90% of cases. Confounding variables A potential confounding effect was evaluated for the following variables: Maternal age (<20 and ≥30 years); Gravidity (primigravidity and multigravidity >3); Previous fetal loss (stillbirth or miscarriage); Socioeconomic level (low and high according to a standardized scale of maternal and paternal schooling and occupation); Few prenatal visits (≤5); and Newborn ancestry (all ancestors Native American, African-American with any other ethnicity, and all ancestors Latin-European). Outcomes Newborns were classified according to their birth weight and gestational age into three growth categories: AB: adequate at birth (gestational age ≥37 weeks, birth weight ≥2500g), PTB: preterm birth (gestational age <37 weeks, birth weight >10th percentile for gestational age), and SGA: small for gestational age (any gestational age, birth weight <10th percentile for gestational age). Large for gestational age (LGA) newborns which comprised less than 5% of the total population of newborns were included in the AB category. Statistical analysis Prevalence and 95% confidence interval (95%CI) of PTB and SGA for each disease were obtained over the total number of mothers with that particular disease. The diseases with higher-than-expected PTB or SGA frequencies were identified. The expected number of cases for each disease in categories PTB and SGA was calculated based on the frequency of observed infants born to mothers without disease for each respective category. The observed/expected ratio and its 95%CI was estimated for a Poisson distribution. A multinomial logistic regression was applied to estimate the confounding effect of the included variables for each of the 14 diseases. Odds ratios (OR) and their 95%CI were obtained to identify variables associated with PTB or SGA. A logistic regression was applied to adjust the risk for PTB or SGA of diseases with significantly higher observed than expected PTB or SGA prevalence. For each disease, it included the confounding variables significantly associated both with that disease and with the adverse perinatal outcome. Ethics approval The study protocol was approved by the Ethics Committee “Centro de Educación Médica e Investigaciones Clínicas (CEMIC)” (DHHS-IRB #1745, IORG #1315). Written signed informed consents were obtained from all subjects participating in the ECLAMC program before data collection. All data were fully anonymized prior to their utilization. RESULTS The ECLAMC registry covers all South American countries except the Guyanas. From an unselected population of postpartum women, around 30% reported having suffered illnesses during pregnancy; of these, approximately 70% had had one or more of the 14 most frequent diseases. The prevalence of diseases can be found in Table 1 and the prevalence of PTB and SGA by disease is available in Table 2. Table 1 Prevalence of diseases during pregnancy in a sample of 56,232 South American women. Disease n % 95%CI No disease 40,056 71.2 70.9–71.6 Urinary infection 7,292 13.0 12.7–13.3 Influenza 2,102 3.7 3.6–3.9 Hypertension 1,766 3.1 3.0–3.3 Diabetes 903 1.6 1.5–1.7 Anemia 880 1.6 1.5–1.7 Asthma 842 1.5 1.4–1.6 Vaginal infection 657 1.2 1.1–1.3 Hypothyroidism 544 1.0 0.9–1.1 Toxoplasmosis 223 0.4 0.3–0.5 HIV/AIDS 206 0.4 0.3–0.4 Syphilis 190 0.3 0.3–0.4 Chagas disease 155 0.3 0.2–0.3 Epilepsy 154 0.3 0.2–0.3 Obesity 138 0.3 0.2–0.3 CI: confidence interval. Table 2 Prevalence of preterm birth and small for gestational age by disease in a sample of 56,232 South American women. Total PTB SGA n n % (95%CI) E O/E (95%CI) n % (95%CI) E O/E (95%CI) No disease 40,056 2,498 6.2 (6.0–6.5) -- -- 2,338 5.8 (5.6–6.1) -- -- Urinary infection 7,292 601 8.2 (7.6–8.9) 454.7 1.3 (1.2–1.4) 461 6.3 (5.8–6.9) 425.6 1.1 (1.0–1.2) Influenza 2,102 141 6.7 (5.8–7.9) 131.1 1.1 (0.9–1.3) 94 4.5 (3.6–5.4) 122.7 0.8 (0.6–0.9) Hypertension* 1,766 230 13.0 (11.4–14.7) 110.1 2.1 (1.8–2.4) 236 13.4 (11.8–15.0) 103.1 2.3 (2.0–2.6) Diabetes 903 83 9.2 (7.4–11.3) 56.3 1.5 (1.2–1.8) 29 3.2 (2.2–4.6) 52.7 0.6 (0.4–0.8) Anemia 880 46 5.2 (3.9–6.9) 54.9 0.8 (0.6–1.1) 42 4.8 (3.5–6.4) 51.4 0.8 (0.6–1.1) Asthma 842 58 6.9 (5.3–8.8) 52.5 1.1 (0.8–1.4) 47 5.6 (4.1–7.4) 49.1 1.0 (0.7–1.3) Vaginal infection 657 71 10.8 (8.5–13.4) 41.0 1.7 (1.4–2.2) 42 6.4 (4.6–8.5) 38.3 1.1 (0.8–1.5) Hypothyroidism 544 53 9.7 (7.4–12.5) 33.9 1.6 (1.2–2.0) 27 5.0 (3.3–7.1) 31.8 0.9 (0.6–1.2) Toxoplasmosis 223 10 4.5 (2.2–8.1) 13.9 0.7 (0.3–1.3) 12 5.4 (2.8–9.2) 13.0 0.9 (0.5–1.6) HIV/AIDS 206 19 9.2 (5.6–14.0) 12.8 1.5 (0.9–2.3) 25 12.1 (8.0–17.4) 12.0 2.1 (1.4–3.1) Syphilis 190 12 6.3 (3.3–10.8) 11.8 1.0 (0.5–1.8) 9 4.7 (2.2–8.8) 11.1 0.8 (0.4–1.5) Chagas disease 155 2 1.3 (0.2–4.5) 9.7 0.2 (0.0–0.7) 5 3.2 (1.1–7.4) 9.0 0.6 (0.2–1.3) Epilepsy 154 16 10.4 (6.1–16.3) 9.6 1.7 (1.0–2.7) 15 9.7 (5.6–15.6) 9.0 1.7 (1.0–2.8) Obesity 138 12 8.7 (4.6–14.7) 8.6 1.4 (0.7–2.4) 10 7.2 (3.5–12.9) 8.1 1.2 (0.6–2.3) PTB: preterm birth; SGA: small for gestational age; CI: confidence interval; E: expected value; O/E: observed/expected values. * Hypertension includes preeclampsia, and gestational and chronic hypertension. Table 3 presents the association of confounding variables with PTB and SGA in women without diseases during pregnancy and Table 4 shows the significant associations between these variables and the most frequently reported diseases. Four confounding variables showed association with PTB (maternal age <20, previous fetal loss, low socioeconomic level, and African-American ancestry), three of which (previous fetal loss, low socioeconomic level, and African-American ancestry), plus primigravidity and maternal age ≥30, were also associated with SGA. Table 3 Association of confounding variables with preterm birth and with small for gestational age in women without diseases during pregnancy. PTB SGA OR 95%CI OR 95%CI Maternal age <20 1.3 1.1–1.6 1.1 0.9–1.3 Maternal age ≥30 1.1 0.9–1.4 1.2 1.0–1.4 Primigravidity 1.1 0.9–1.3 1.5 1.3–1.8 Multigravidity 1.0 0.9–1.1 1.0 0.8–1.2 Previous fetal loss 1.4 1.2–1.7 1.4 1.2–1.7 Low socioeconomic level 1.2 1.0–1.4 1.3 1.1–1.6 High socioeconomic level 1.2 0.9–1.5 1.0 0.8–1.3 Few prenatal visits 1.1 0.9–1.3 1.1 0.9–1.3 African-American ancestry 1.6 1.2–2.3 1.7 1.3–2.2 Native ancestry 0.9 0.7–1.2 0.9 0.6–1.3 Latin-European ancestry 1.0 0.7–1.4 1.1 0.7–1.7 PTB: preterm birth; SGA: small for gestational age; OR: odds ratio; CI: confidence interval. Table 4 Significant associations between confounding variables and diseases. Disease n Confounding variables OR 95%CI Urinary infection 7,292 Primigravidity 1.2 1.0–1.3 Previous fetal loss 1.3 1.1–1.5 African-American ancestry 1.6 1.3–2.2 Influenza 2,102 Previous fetal loss 1.4 1.0–1.0 Hypertension* 1,766 Maternal age ≥30 2.4 2.0–2.9 Low socioeconomic level 1.4 1.1–1.7 Diabetes 903 Maternal age ≥30 3.8 2.6–5.4 Anemia 880 Maternal age <20 1.6 1.1–2.5 Asthma 842 Latin-European ancestry 1.8 1.1–3.1 Vaginal infection 657 Native ancestry 1.7 1.0–2.9 Hypothyroidism 544 Maternal age ≥30 2.7 1.6–4.6 Primigravidity 1.5 1.1–2.1 High socioeconomic level 1.8 1.3–2.5 Previous fetal loss 1.4 1.0–2.0 Toxoplasmosis 223 Multigravidity 2.2 1.6–3.0 Low socioeconomic level 1.5 1.2–1.9 HIV/AIDS 206 Multigravidity 2.0 1.4–2.8 Low socioeconomic level 1.5 1.0–2.3 Few prenatal visits 2.0 1.3–2.9 African-American ancestry 5.0 1.9–13.4 Syphilis 190 Low socioeconomic level 1.5 1.0–2.2 Chagas disease 155 Maternal age ≥30 1.8 1.2–2.7 Low socioeconomic level 1.7 1.2–2.7 Few prenatal visits 2.2 1.5–3.4 Native ancestry 4.5 1.6–12.6 Epilepsy 154 Maternal age ≥30 1.9 1.3–2.9 Previous fetal loss 2.3 1.5–3.5 Obesity 138 Maternal age ≥30 2.5 1.9–3.4 OR: odds ratio; CI: confidence interval. * Hypertension includes preeclampsia, and gestational and chronic hypertension. Six of the 14 diseases were significantly associated with PTB (urinary infection, hypertensive disorders, diabetes, vaginal infections, hypothyroidism, and epilepsy) and three with SGA newborns (hypertension, HIV/AIDS, and epilepsy). After adjusting for the confounding variables, all identified illnesses maintained their association with PTB and all, except epilepsy, with SGA (Table 5). Table 5 Adjusted risk for preterm birth and small for gestational age by disease. OR 95%CI ORadj 95%CI PTB Hypertension* 2.0 1.8–2.3 2.1 1.8–2.4 Vaginal infection 1.7 1.4–2.2 1.7 1.4–2.2 Epilepsy 1.7 1.1–2.7 1.7 1.0–3.0 Hypothyroidism 1.6 1.2–2.0 1.5 1.1. 2.0 Diabetes 1.5 1.2–1.8 1.4 1.1–1.8 Urinary infection 1.3 1.2–1.5 1.3 1.2–1.5 SGA Hypertension* 2.3 2.0–2.6 2.4 2.1–2.8 HIV/AIDS 2.1 1.4–3.0 1.8 1.2–2.6 Epilepsy 1.7 1.0–2.7 1.4 0.7–2.8 OR: odds ratio crude; CI: confidence interval; ORadj: adjusted odds ratio with a Poisson regression model; PTB: preterm birth; SGA: small for gestational age. * Hypertension includes preeclampsia, and gestational and chronic hypertension. DISCUSSION Women may suffer from acute and/or chronic diseases during pregnancy and fetal exposure can increase the risk of adverse outcomes; so far, literature reports on chronic diseases prevalence during pregnancy and their outcomes are discordant. For example, Kersten et al.14 reported that at least one of every five pregnant women in a sample of 5,320 subjects suffered from a chronic disease and Gogoi and Unisa15 informed that 50% of pregnant women attending a tertiary hospital from Mumbai (Maharashtra, India) had some sort of chronic disease, with anemia as the most frequent, while Jølving et al.16, using nationwide Danish data on more than 1.3 million childbirths, estimated an 8.5% chronic disease prevalence. Variables such as study design, lack of standardized diagnostic procedures, and regional differences could, among others, explain the different rates. The approximately 10% prevalence of chronic diseases in this study, is close to the values found by Jølving et al.16 and both studies identified the same most prevalent diseases (hypertension, diabetes, thyroid disorders, and epilepsy). Hypertensive disorders Around 3% of the women in our sample reported having been hypertensive during pregnancy and, in agreement with most of the literature, almost 30% of their newborns were either preterm or SGA. Their risk of having a SGA infant almost doubled that of non-hypertensive mothers. Hypertensive disorders, mainly preeclampsia, are a widely recognized cause of SGA and probably deserve no further discussion. However, differences have been described between early and late onset preeclampsia (before and after 34 gestational weeks, respectively), the former leading to SGA and the latter, often associated with maternal diabetes and obesity, too LGA infants17. On the other hand, Bramham et al.7 reported an almost three-fold PTB risk in mothers with chronic hypertension based on a meta-analysis that included more than 70,000 pregnant women from 25 countries. Similarly, in a cohort study of 7,000 mothers, and after adjusting for more than ten confounding variables, Shen et al.18 demonstrated a PTB risk almost twice as high for gestational hypertension and seven-fold for preeclampsia. However, and although hypertensive disorders, mainly preeclampsia, could per se lead to spontaneous PTB through, for example, abruption of the placenta, induced preterm delivery to avoid severe maternal complications seems to be the major cause of the reported PTB excess. It has been estimated that about one third of PTB are medically induced and that preeclampsia is its primary indication19. Using cesarean section as a proxy for induced delivery, we compared its rate between hypertensive and healthy women. It was significantly higher in the former than in the latter (56% vs. 35%) and even higher when the comparison was done between women who had delivered prematurely (68% vs. 41%). Other authors observed similar rate differences7,18. Diabetes In our sample, 1.6% of the mothers were diabetic and almost 10% of their deliveries were preterm. While some authors such as Köck et al.6 showed that spontaneous PTB was associated with diabetes, others considered that the most likely cause was medically induced PTB because of coexisting preeclampsia20. Results obtained by other authors were inconsistent21,22. On the other hand, and as universally accepted, in our sample of diabetic mothers the prevalence of SGA infants was lower than expected. Similar results were obtained by other authors who also described higher rates of large babies in women with impaired glucose tolerance3. In opposition, however, some authors hypothesized that diabetic vasculopathy leads to impaired fetal growth. Boghossian et al.23 observed an excess of SGA newborns among extremely preterm infants born to pregestational diabetic mothers (probably with diabetes types 1 or 2) when compared with those who had started using insulin during gestation (probably type 2 and gestational diabetes). While Skaznik-Wikiel et al.24 reported that the rate of SGA infants in mothers with pregestational diabetes was not higher than expected, Shefali et al.25, although with a small sample size, observed a higher frequency of LGA infants born to mothers with gestational diabetes than to non-diabetic control mothers. In our sample, no distinction could be established between different types of diabetes. However, when reviewing the medication reports, only 10% of all diabetic mothers had used insulin during gestation. On this basis we could assume a higher proportion of gestational than pregestational diabetes which might explain the lack of SGA infants born to these mothers. Hypothyroidism Hypothyroidism, which is almost ten times more frequent in women than in men, has been shown to affect 1.5–4.0% of pregnant women26,27. Its rather low prevalence (1%) in our sample could be due to a number of factors such as incomplete reporting because of unawareness in subclinical cases, lack of diagnosis in women without prenatal control, and preferential reporting of women whose illness was diagnosed before being pregnant, among others. Globally, and especially in developing countries, environmental iodine deficiency is the most common cause of thyroid disorders, while chronic autoimmune thyroiditis (Hashimoto's disease) is the main cause of primary hypothyroidism in iodine-sufficient areas28,29. Literature reports disagree regarding the association between clinical or subclinical hypothyroidism and adverse pregnancy outcomes. While Cleary-Goldman et al.30, among others, concluded that maternal thyroid hypofunction is not associated with a consistent pattern of adverse outcomes, in a prospective population-based study from China, involving 1,017 pregnant women, Su et al.31 showed that subclinical hypothyroidism was associated with PTB; conversely, Plowden et al.32 found no such association. Abalovich et al.33 showed that the pregnancy outcome of hypothyroid women did not depend on whether their disease was overt or subclinical, but on the received treatment. They also showed that if hypothyroid women, even with normal thyroid function, were not adequately treated, they had an increased risk of spontaneous abortion. In our sample, nearly 40% of the hypothyroid women, whose deliveries were preterm, informed having received no treatment and 26% of them reported a previous miscarriage. However, it could not be established if during that previous pregnancy these mothers had been hypothyroid and if they were medicated. Stagnaro-Green et al.34 suggested that anti-thyroid antibodies, as part of a generalized autoimmune imbalance, could be responsible for the eventually observed adverse outcomes while Kiran et al.35 found no association between thyroid antibodies and prematurity in hypothyroid women. Epilepsy With the exclusion of the teratogenic effects of antiepileptic drugs, the results on pregnancy outcomes of epileptic women reported in the literature are contradictory. Crump et al.36 found an association of epilepsy with PTB that persisted when antiepileptic drugs were used. Contrarily, other authors found that the risk of adverse outcomes increased with the use of antiepileptic drugs37,38. Reports from MacDonald et al.39, who also observed an increased PTB risk, lacked information on the use of antiepileptic medication. Kilic et al.40 found a 25% increased PTB risk in non-medicated epileptic mothers and considered that it represented early termination of pregnancy due to maternal seizures. The 0.27% prevalence observed in our study coincided with the 0.3–0.5% mentioned by MacDonald et al.39 and we found a 30% higher PTB risk in epileptic mothers while, after adjusting for confounders, no association with low birth weight was observed. Fewer mothers from the PTB and SGA groups had used antiepileptic drugs when compared with the adequate at birth group; however, the differences did not reach statistical significance because of the small number of cases. Furthermore, in our sample, half of the mothers from the PTB group had delivered through cesarean section but again the sample was too small to be conclusive about the possibility of induced deliveries. Vaginal and urinary tract infections Considering infectious diseases during pregnancy, Collier et al.41 reported a prevalence of about 64% while in our study it was around 20%. Variations in the inclusion criteria are probably involved in the difference, for example, these authors included unspecified infections and fever with and without identified infection while in our sample, only those infections specifically mentioned by the mothers were considered. In coincidence with Sever et al.42, influenza and vaginal and urinary tract infections were the most frequent self-reported diseases. It should however be taken into account that influenza is an unreliable diagnosis, often used as a general term for any unspecific cold. The most common bacterial infections during pregnancy are those of the vaginal and urinary tract, and the chorioamnionitis, as a possible complication due to bacteria ascending into the amniotic cavity, is one of the most frequent factors associated with PTB43. Leitich and Kiss44 reported PTB in approximately 10 to 15% of women suffering from bacterial vaginosis and a two-fold PTB risk based on a meta-analysis with 32 studies that included 30,518 patients. The related urinary tract infection (UTI) has also been associated with PTB although some studies have not confirmed this association45,46. In our study, the PTB prevalence of mothers with vaginal infections coincided with the published data, while 8.2% PTB prevalence observed in UTI patients was lower than the reported 15 to 32.9%45,47. African-American ancestry, often related to low socioeconomic level and less prenatal care, was a risk factor for women with UTI in our sample. This fact could suggest a lack of diagnosis of asymptomatic bacteriuria, which is a frequent UTI manifestation, and explain the difference between our results and those of published data48. On the other hand, overlapping of both infections, their coexistence, or perhaps their misdiagnoses should also be considered. Many investigators have assumed that the strong evidence supporting the association between infection and increased PTB risk implied causation43. However, in general, antibiotic therapy of genitourinary tract infections has not reduced the PTB incidence. McClure and Goldenberg49 considered the presence of abnormal vaginal flora as a simple marker of other risk factors. Results from other studies suggest interactions between genitourinary tract infections and genes linked to infectious/inflammatory/hormonal regulation processes that increase the PTB risk50,51. HIV/AIDS In our sample, HIV/AIDS was the only maternal infection associated with SGA newborns. Around 12% of infants born to mothers with HIV/AIDS were SGA and the risk of these mothers for such an outcome was significant. Wedi et al.52 reported similar results, although their sample consisted of 53,623 HIV mothers without antiretroviral therapy. We observed no differences after stratifying our sample by antiretroviral drugs treatment. Kreitchmann et al.8 have reported low birth weight or SGA and prematurity of infants born to HIV infected mothers in a study involving six South American countries. Similar results were reported by Delicio et al.53 in a Brazilian study that included antiretroviral therapy and by Xiao et al.54 in a meta-analysis of 52 cohort studies. The association between immunosuppression and adverse pregnancy outcomes has been mentioned and HIV-related damage to the immune system was considered as the main cause of fetal growth restriction in pregnant HIV infected women55. Other risk factors are HIV replication and cytokine profile in the placenta affecting its function and the effect of antiretroviral drugs on systemic or local genital tract immunology or on systemic cytokines exacerbating hypertensive disorders54,56. In a study on 413 HIV-exposed but uninfected infants, Slyker et al.57 identified several confounding variables associated with PTB or SGA such as maternal genital infection and cervical HIV-1 RNA load. The authors considered that the reduction of maternal genital HIV-1 replication could be a strategy to reduce the risk of adverse neonatal outcomes. Strengths and limitations The strength of the study is the large sample size comprising data gathered by trained health professionals that allowed making inferences about the risk of perinatal adverse events in South American populations. Additionally, our sample of mothers was unselected and thereby representative of the whole population while most published studies have focused on selected samples of women with specific diseases and their impact on pregnancy outcomes. This study has some limitations. The ECLAMC program has good quality data but low territorial coverage, it is therefore inadequate to perform any regional analysis. Additionally, self-reporting implies a number of weaknesses such as memory bias when data are retrospectively obtained or lack of self-awareness of certain conditions, such as obesity considered as a disease, that leads to underreporting. Overreporting should also be considered for conditions such as influenza, a term which is often used when referring to any minor cold. Moreover, each disease was evaluated individually, for this reason, in comorbidity cases, the one actually responsible for the adverse outcome could not be identified. Some confounding variables that could act as risk factors such as a previous history of PTB, spontaneous or induced delivery, smoking, or alcohol intake were not considered, nor were socioeconomic or demographic characteristics of the regions under study. Medication as well as cesarean sections and previous abortions were not included as confounders and therefore, were not specifically analyzed. However, some findings on these variables that were not the result of a preconceived idea were obtained by reviewing the reports when relevant to support the discussion. The database housing the used registries only allowed categorical information, therefore, clinical details, for example, chronic or acute forms of diseases such as syphilis or Chagas, could not be differentiated. As a conclusion, taking into account the limitations mentioned above, the analysis of a large, unselected population of mothers in this study allowed us to evaluate the prevalence of the most frequent diseases during pregnancy and their impact on the considered outcomes in a South American population. Six diseases (urinary infection, hypertensive disorders, diabetes, vaginal infections, hypothyroidism, and epilepsy) were associated with PTB and two (hypertension and HIV/AIDS) with SGA newborns. These results may help clarify discordances found in the literature besides adding data to the scarce information available in South America. FUNDING: The research program was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-MINCyT), grant numbers PICT-2018-4275 (PI: López Camelo JS) and PICT-2018-4285 (PI: Lucas G. Gimenez), and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). The funders had no role in study design, data collection and analysis, decision to publish, nor preparation of the manuscript. ACKNOWLEDGMENTS: The authors want to thank all physicians collaborating in the ECLAMC network, and Mariana Piola and Alejandra Mariona for their technical support. REFERENCES 1 Chawanpaiboon S Vogel JP Moller AB Lumbiganon P Petzold M Hogan D Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis Lancet Glob Health 2019 7 1 e37 e46 https://doi.org/10.1016/S2214-109X(18)30451-0 1 Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health 2019; 7(1): e37-e46. https://doi.org/10.1016/S2214-109X(18)30451-0 2 Black RE Global prevalence of small for gestational age births Nestle Nutr Inst Workshop Ser 2015 81 1 7 https://doi.org/10.1159/000365790 2 Black RE. Global prevalence of small for gestational age births. Nestle Nutr Inst Workshop Ser 2015; 81: 1-7. https://doi.org/10.1159/000365790 3 Euser AM de Wit CC Finken MJJ Rijken M Wit JM Growth of preterm born children Horm Res 2008 70 6 319 328 https://doi: 10.1159/000161862 3 Euser AM, de Wit CC, Finken MJJ, Rijken M, Wit JM. Growth of preterm born children. Horm Res 2008; 70(6): 319-28. https://doi: 10.1159/000161862 4 Costello A Francis V Byrne A Puddephatt C State of the world's newborns: a report from saving newborn lives [Internet] 2001 [cited on Jun 24, 2021] Available at: https://files.eric.ed.gov/fulltext/ED458972.pdf 4 Costello A, Francis V, Byrne A, Puddephatt C. State of the world's newborns: a report from saving newborn lives [Internet]. 2001 [cited on Jun 24, 2021]. Available at: https://files.eric.ed.gov/fulltext/ED458972.pdf 5 Barker DJP The developmental origins of adult disease Eur J Epidemiol 2003 18 8 733 736 https://doi.org/10.1023/a:1025388901248 5 Barker DJP. The developmental origins of adult disease. Eur J Epidemiol 2003; 18(8): 733-6. https://doi.org/10.1023/a:1025388901248 6 Köck K Köck F Klein K Bancher-Todesca D Helmer H Diabetes mellitus and the risk of preterm birth with regard to the risk of spontaneous preterm birth J Matern Fetal Neonatal Med 2010 23 9 1004 1008 https://doi.org/10.3109/14767050903551392 6 Köck K, Köck F, Klein K, Bancher-Todesca D, Helmer H. Diabetes mellitus and the risk of preterm birth with regard to the risk of spontaneous preterm birth. J Matern Fetal Neonatal Med 2010; 23(9): 1004-8. https://doi.org/10.3109/14767050903551392 7 Bramham K Parnell B Nelson-Piercy C Seed PT Poston L Chappell LC Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis BMJ 2014 348 g2301 g2301 https://doi.org/10.1136/bmj.g2301 7 Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Chappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ 2014; 348: g2301. https://doi.org/10.1136/bmj.g2301 8 Kreitchmann R Li SX Melo VH Fernandes Coelho D Watts DH Joao E Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study BJOG 2014 121 12 1501 1508 https://doi.org/10.1111/1471-0528.12680 8 Kreitchmann R, Li SX, Melo VH, Fernandes Coelho D, Watts DH, Joao E, et al. Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study. BJOG 2014; 121(12): 1501-8. https://doi.org/10.1111/1471-0528.12680 9 Raghupathi W Raghupathi V An empirical study of chronic diseases in the United States: a visual analytics approach Int J Environ Res Public Health 2018 15 3 431 431 https://doi.org/10.3390/ijerph15030431 9 Raghupathi W, Raghupathi V. An empirical study of chronic diseases in the United States: a visual analytics approach. Int J Environ Res Public Health 2018; 15(3): 431. https://doi.org/10.3390/ijerph15030431 10 Marín R Gorostidi M Portal CG Sánchez M Sánchez E Alvarez J Long-term prognosis of hypertension in pregnancy Hypertens Pregnancy 2000 19 2 199 209 https://doi.org/10.1081/prg-100100136 10 Marín R, Gorostidi M, Portal CG, Sánchez M, Sánchez E, Alvarez J. Long-term prognosis of hypertension in pregnancy. Hypertens Pregnancy 2000; 19(2): 199-209. https://doi.org/10.1081/prg-100100136 11 Contreras-Zúñiga E Guilhermo-Arango L Zuluaga-Martínez SX Ocampo V Diabetes y embarazo Revista Colombiana de Obstetricia y Ginecología 2008 59 1 38 45 https://doi.org/10.18597/rcog.429 11 Contreras-Zúñiga E, Guilhermo-Arango L, Zuluaga-Martínez SX, Ocampo V. Diabetes y embarazo. Revista Colombiana de Obstetricia y Ginecología 2008; 59(1): 38-45. https://doi.org/10.18597/rcog.429 12 Goldenberg RL Andrews WW Faye-Petersen O Cliver S Goepfert AR Hauth JC The Alabama Preterm Birth Project: placental histology in recurrent spontaneous and indicated preterm birth Am J Obstet Gynecol 2006 195 3 792 796 https://doi.org/10.1016/j.ajog.2006.05.050 12 Goldenberg RL, Andrews WW, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC. The Alabama Preterm Birth Project: placental histology in recurrent spontaneous and indicated preterm birth. Am J Obstet Gynecol 2006; 195(3): 792-6. https://doi.org/10.1016/j.ajog.2006.05.050 13 Castilla EE Orioli IM ECLAMC: the Latin-American collaborative study of congenital malformations Community Genet 2004 7 2-3 76 94 https://doi.org/10.1159/000080776 13 Castilla EE, Orioli IM. ECLAMC: the Latin-American collaborative study of congenital malformations. Community Genet 2004; 7(2-3): 76-94. https://doi.org/10.1159/000080776 14 Kersten I Lange AE Haas JP Fusch C Lode H Hoffmann W Chronic diseases in pregnant women: prevalence and birth outcomes based on the SNiP-study BMC Pregnancy Childbirth 2014 14 75 75 https://doi.org/10.1186/1471-2393-14-75 14 Kersten I, Lange AE, Haas JP, Fusch C, Lode H, Hoffmann W, et al. Chronic diseases in pregnant women: prevalence and birth outcomes based on the SNiP-study. BMC Pregnancy Childbirth 2014; 14: 75. https://doi.org/10.1186/1471-2393-14-75 15 Gogoi M Unisa S Chronic diseases during pregnancy and birth outcome: a study based on tertiary hospital of Mumbai Women Health Open J 2017 3 2 61 68 https://dx.doi.org/10.17140/WHOJ-3-123 15 Gogoi M, Unisa S. Chronic diseases during pregnancy and birth outcome: a study based on tertiary hospital of Mumbai. Women Health Open J 2017; 3(2): 61-8. https://dx.doi.org/10.17140/WHOJ-3-123 16 Jølving LR Nielsen J Kesmodel US Nielsen RG Beck-Nielsen SS Nørgård BM Prevalence of maternal chronic diseases during pregnancy – a nationwide population based study from 1989 to 2013 Acta Obstet Gynecol Scand 2016 95 11 1295 1304 https://doi.org/10.1111/aogs.13007 16 Jølving LR, Nielsen J, Kesmodel US, Nielsen RG, Beck-Nielsen SS, Nørgård BM. Prevalence of maternal chronic diseases during pregnancy – a nationwide population based study from 1989 to 2013. Acta Obstet Gynecol Scand 2016; 95(11): 1295-304. https://doi.org/10.1111/aogs.13007 17 Lisonkova S Joseph KS Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease Am J Obstet Gynecol 2013 209 6 544.e1 544.e12 https://doi.org/10.1016/j.ajog.2013.08.019 17 Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol 2013; 209(6): 544.e1-544.e12. https://doi.org/10.1016/j.ajog.2013.08.019 18 Shen M Smith GN Rodger M White RR Walker MC Wen SW Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia PLoS One 2017 24 12 4 e0175914 https://doi.org/10.1371/journal.pone.0175914 18 Shen M, Smith GN, Rodger M, White RR, Walker MC, Wen SW. Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia. PLoS One 2017; 24;12(4): e0175914. https://doi.org/10.1371/journal.pone.0175914 19 Poon LC Shennan A Hyett JA Kapur A Hadar E Divakar H The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention Int J Gynaecol Obstet 2019 145 Suppl 1 Suppl 1 1 33 Erratum in: Int J Gynaecol Obste. 2019; 146(3): 390-1. https://doi: 10.1002/ijgo.12892 19 Poon LC, Shennan A, Hyett JA, Kapur A, Hadar E, Divakar H, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet 2019; 145 Suppl 1(Suppl 1): 1-33. Erratum in: Int J Gynaecol Obste. 2019; 146(3): 390-1. https://doi: 10.1002/ijgo.12892 20 Sibai BM Caritis S Hauth J Lindheimer M VanDorsten JP MacPherson C Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units Am J Obstet Gynecol 2000 182 2 364 369 https://doi.org/10.1016/s0002-9378(00)70225-0 20 Sibai BM, Caritis S, Hauth J, Lindheimer M, VanDorsten JP, MacPherson C, et al. Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 2000; 182(2): 364-9. https://doi.org/10.1016/s0002-9378(00)70225-0 21 Tallarigo L Giampietro O Penno G Miccoli R Gregori G Navalesi R Relation of glucose tolerance to complications of pregnancy in nondiabetic women N Engl J Med 1986 315 16 989 992 https://doi.org/10.1056/NEJM198610163151603 21 Tallarigo L, Giampietro O, Penno G, Miccoli R, Gregori G, Navalesi R. Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med 1986; 315(16): 989-92. https://doi.org/10.1056/NEJM198610163151603 22 Magee MS Walden CE Benedetti TJ Knopp RH Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity JAMA 1993 269 5 609 615 8421365 22 Magee MS, Walden CE, Benedetti TJ, Knopp RH. Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity. JAMA 1993; 269(5): 609-15. PMID: 8421365 23 Boghossian NS Hansen NI Bell EF Brumbaugh JE Stoll BJ Laptook AR Outcomes of extremely preterm infants born to insulin-dependent diabetic mothers Pediatrics 2016 137 6 e20153424 https://doi.org/10.1542/peds.2015-3424 23 Boghossian NS, Hansen NI, Bell EF, Brumbaugh JE, Stoll BJ, Laptook AR, et al. Outcomes of extremely preterm infants born to insulin-dependent diabetic mothers. Pediatrics 2016; 137(6): e20153424. https://doi.org/10.1542/peds.2015-3424 24 Skaznik-Wikiel ME Huston-Presley LP Catalano PM Diabetic vasculopathy: Is it a risk factor for IUGR? 68th Annual ADA Meeting Dallas 2008 24 Skaznik-Wikiel ME, Huston-Presley LP and Catalano PM. Diabetic vasculopathy: Is it a risk factor for IUGR? In: 68th Annual ADA Meeting. Dallas; 2008. 25 Shefali AK Kavitha M Deepa R Mohan V Pregnancy outcomes in pre-gestational and gestational diabetic women in comparison to non-diabetic women--a prospective study in Asian Indian mothers (CURES-35) J Assoc Physicians India 2006 54 613 618 16941791 25 Shefali AK, Kavitha M, Deepa R, Mohan V. Pregnancy outcomes in pre-gestational and gestational diabetic women in comparison to non-diabetic women--a prospective study in Asian Indian mothers (CURES-35). J Assoc Physicians India 2006; 54: 613-8. PMID: 16941791 26 Casey BM Dashe JS Wells CE McIntire DD Byrd W Leveno KJ Subclinical hypothyroidism and pregnancy outcomes Obstet Gynecol 2005 105 2 239 245 https://doi.org/10.1097/01.AOG.0000152345.99421.2 26 Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2): 239-45. https://doi.org/10.1097/01.AOG.0000152345.99421.2 27 Cignini P Cafà EV Giorlandino C Capriglione S Spata A Dugo N Thyroid physiology and common diseases in pregnancy: review of literature J Prenat Med 2012 6 4 64 67 23272277 27 Cignini P, Cafà EV, Giorlandino C, Capriglione S, Spata A, Dugo N. Thyroid physiology and common diseases in pregnancy: review of literature. J Prenat Med 2012; 6(4): 64-7. PMID: 23272277 28 Yadav V Dabar D Goel AD Bairwa M Sood A Prasad P Prevalence of hypothyroidism in pregnant women in India: a meta-analysis of observational studies J Thyroid Res 2021 2021 5515831 5515831 https://doi.org/10.1155/2021/5515831 28 Yadav V, Dabar D, Goel AD, Bairwa M, Sood A, Prasad P, et al. Prevalence of hypothyroidism in pregnant women in India: a meta-analysis of observational studies. J Thyroid Res 2021; 2021: 5515831. https://doi.org/10.1155/2021/5515831 29 Chiovato L Magri F Carlé A Hypothyroidism in context: where we've been and where we're going Adv Ther 2019 36 Suppl 2 47 58 https://doi.org/10.1007/s12325-019-01080-8 29 Chiovato L, Magri F, Carlé A. Hypothyroidism in context: where we've been and where we're going. Adv Ther 2019; 36(Suppl 2): 47-58. https://doi.org/10.1007/s12325-019-01080-8 30 Cleary-Goldman J Malone FD Lambert-Messerlian G Sullivan L Canick J Porter TF Maternal thyroid hypofunction and pregnancy outcome Obstet Gynecol 2008 112 1 85 92 https://doi.org/10.1097/AOG.0b013e3181788dd7 30 Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112(1): 85-92. https://doi.org/10.1097/AOG.0b013e3181788dd7 31 Su PY Huang K Hao JH Xu YQ Yan SQ Li T Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China J Clin Endocrinol Metab 2011 96 10 3234 3234 https://doi.org/10.1210/jc.2011-0274 31 Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 2011; 96(10): 3234-4. https://doi.org/10.1210/jc.2011-0274 32 Plowden TC Schisterman EF Sjaarda LA Perkins NJ Silver R Radin R Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes Am J Obstet Gynecol 2017 217 6 697.e1 697.e7 https://doi.org/10.1016/j.ajog.2017.09.001 32 Plowden TC, Schisterman EF, Sjaarda LA, Perkins NJ, Silver R, Radin R, et al. Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes. Am J Obstet Gynecol 2017; 217(6): 697.e1-697.e7. https://doi.org/10.1016/j.ajog.2017.09.001 33 Abalovich M Gutierrez S Alcaraz G Maccallini G Garcia A Levalle O Overt and subclinical hypothyroidism complicating pregnancy Thyroid 2002 12 1 63 68 https://doi.org/10.1089/105072502753451986 33 Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12(1): 63-8. https://doi.org/10.1089/105072502753451986 34 Stagnaro-Green A Roman SH Cobin RH el-Harazy E Alvarez-Marfany M Davies TF Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies JAMA 1990 264 11 1422 1425 34 Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264(11): 1422-5. 35 Kiran Z Sheikh A Islam N Association of thyroid antibodies status on the outcomes of pregnant women with hypothyroidism (maternal hypothyroidism on pregnancy outcomes, MHPO-4) BMC Pregnancy Childbirth 2021 21 1 136 136 https://doi.org/10.1186/s12884-021-03594-y 35 Kiran Z, Sheikh A, Islam N. Association of thyroid antibodies status on the outcomes of pregnant women with hypothyroidism (maternal hypothyroidism on pregnancy outcomes, MHPO-4). BMC Pregnancy Childbirth 2021; 21(1): 136. https://doi.org/10.1186/s12884-021-03594-y 36 Crump C Sundquist K Winkleby MA Sundquist J Preterm birth and risk of epilepsy in Swedish adults Neurology 2011 77 14 1376 1382 https://doi.org/10.1212/WNL.0b013e318231528f 36 Crump C, Sundquist K, Winkleby MA, Sundquist J. Preterm birth and risk of epilepsy in Swedish adults. Neurology 2011; 77(14): 1376-82. https://doi.org/10.1212/WNL.0b013e318231528f 37 Artama M Gissler M Malm H Ritvanen A Drug and Pregnancy Group Effects of maternal epilepsy and antiepileptic drug use during pregnancy on perinatal health in offspring: nationwide, retrospective cohort study in Finland Drug Saf 2013 36 5 359 369 https://doi.org/10.1007/s40264-013-0052-8 37 Artama M, Gissler M, Malm H, Ritvanen A, Drug and Pregnancy Group. Effects of maternal epilepsy and antiepileptic drug use during pregnancy on perinatal health in offspring: nationwide, retrospective cohort study in Finland. Drug Saf 2013; 36(5): 359-69. https://doi.org/10.1007/s40264-013-0052-8 38 Viale L Allotey J Cheong-See F Arroyo-Manzano D Mccorry D Bagary M Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis Lancet 2015 386 10006 1845 1852 https://doi.org/10.1016/S0140-6736(15)00045-8 38 Viale L, Allotey J, Cheong-See F, Arroyo-Manzano D, Mccorry D, Bagary M, et al. Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet 2015; 386(10006): 1845-52. https://doi.org/10.1016/S0140-6736(15)00045-8 39 MacDonald SC Bateman BT McElrath TF Hernández-Díaz S Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States JAMA Neurol 2015 72 9 981 988 https://doi.org/10.1001/jamaneurol.2015.1017 39 MacDonald SC, Bateman BT, McElrath TF, Hernández-Díaz S. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol 2015; 72(9): 981-8. https://doi.org/10.1001/jamaneurol.2015.1017 40 Kilic D Pedersen H Kjaersgaard MI Parner ET Vestergaard M Sørensen MJ Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study Epilepsia 2014 55 11 1714 1721 https://doi.org/10.1111/epi.12758 40 Kilic D, Pedersen H, Kjaersgaard MI, Parner ET, Vestergaard M, Sørensen MJ, et al. Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study. Epilepsia 2014; 55(11): 1714-21. https://doi.org/10.1111/epi.12758 41 Collier SA Rasmussen SA Feldkamp ML Honein MA National Birth Defects Prevention Study. Prevalence of self-reported infection during pregnancy among control mothers in the National Birth Defects Prevention Study Birth Defects Res A Clin Mol Teratol 2009 85 3 193 120 https://doi.org/10.1002/bdra.20540 41 Collier SA, Rasmussen SA, Feldkamp ML, Honein MA;, National Birth Defects Prevention Study. Prevalence of self-reported infection during pregnancy among control mothers in the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol 2009; 85(3): 193-20. https://doi.org/10.1002/bdra.20540 42 Sever JL Ellenberg JH Ley A Edmonds D Incidence of clinical infections in a defined population of pregnant women Prog Clin Biol Res 1985 163B 317 326 39831859 42 Sever JL, Ellenberg JH, Ley A, Edmonds D. Incidence of clinical infections in a defined population of pregnant women. Prog Clin Biol Res 1985; 163B: 317-26. PMID: 39831859 43 Goldenberg RL Culhane JF Iams JD Romero R Epidemiology and causes of preterm birth Lancet 2008 371 9606 75 84 https://doi.org/10.1016/S0140-6736(08)60074-4 43 Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371(9606): 75-84. https://doi.org/10.1016/S0140-6736(08)60074-4 44 Leitich H Kiss H Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome Best Pract Res Clin Obstet Gynaecol 2007 21 3 375 390 https://doi.org/10.1016/j.bpobgyn.2006.12.005 44 Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2007; 21(3): 375-90. https://doi.org/10.1016/j.bpobgyn.2006.12.005 45 Acosta-Terriquez JE Ramos-Martínez MA Zamora-Aguilar LM Murillo-Llanes J Prevalencia de infección de vías urinarias en pacientes hospitalizadas con amenaza de parto pretérmino Ginecol Obstet Mex 2014 82 11 737 743 45 Acosta-Terriquez JE, Ramos-Martínez MA, Zamora-Aguilar LM, Murillo-Llanes J. Prevalencia de infección de vías urinarias en pacientes hospitalizadas con amenaza de parto pretérmino. Ginecol Obstet Mex 2014; 82(11): 737-43. 46 Chen YK Chen SF Li HC Lin HC No increased risk of adverse pregnancy outcomes in women with urinary tract infections: a nationwide population-based study Acta Obstet Gynecol Scand 2010 89 7 882 888 https://doi.org/10.3109/00016349.2010.486826 46 Chen YK, Chen SF, Li HC, Lin HC. No increased risk of adverse pregnancy outcomes in women with urinary tract infections: a nationwide population-based study. Acta Obstet Gynecol Scand 2010; 89(7): 882-8. https://doi.org/10.3109/00016349.2010.486826 47 Bernardo FMM Veiga ECA Quintana SM Camayo FJA Batista RFL Alves MTSSB Association of genitourinary infections and cervical length with preterm childbirth Braz J Med Biol Res 2020 54 1 e10235 https://doi.org/10.1590/1414-431X202010235 47 Bernardo FMM, Veiga ECA, Quintana SM, Camayo FJA, Batista RFL, Alves MTSSB, et al. Association of genitourinary infections and cervical length with preterm childbirth. Braz J Med Biol Res 2020; 54(1): e10235. https://doi.org/10.1590/1414-431X202010235 48 Sheffield JS Cunningham FG Urinary tract infection in women Obstet Gynecol 2005 106 5 Pt 1 1085 1089 https://doi.org/10.1097/01.AOG.0000185257.52328.a2 48 Sheffield JS, Cunningham FG. Urinary tract infection in women. Obstet Gynecol 2005; 106(5 Pt 1): 1085-9. https://doi.org/10.1097/01.AOG.0000185257.52328.a2 49 McClure EM Goldenberg RL Use of antibiotics to reduce preterm birth Lancet Glob Health 2019 7 1 e18 e19 https://doi.org/10.1016/S2214-109X(18)30543-6 49 McClure EM, Goldenberg RL. Use of antibiotics to reduce preterm birth. Lancet Glob Health 2019; 7(1): e18-e19. https://doi.org/10.1016/S2214-109X(18)30543-6 50 Macones GA Parry S Elkousy M Clothier B Ural SH Strauss JF 3rd A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth Am J Obstet Gynecol 2004 190 6 1504 1508 discussion 3A. https://doi.org/10.1016/j.ajog.2004.01.001 50 Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss 3rd JF. A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 2004; 190(6): 1504-8; discussion 3A. https://doi.org/10.1016/j.ajog.2004.01.001 51 Elias D Gimenez L Poletta F Campaña H Gili J Ratowiecki J Preterm birth and genitourinary tract infections: assessing gene-environment interaction Pediatr Res 2021 90 3 678 683 https://doi.org/10.1038/s41390-020-01200-z 51 Elias D, Gimenez L, Poletta F, Campaña H, Gili J, Ratowiecki J, et al. Preterm birth and genitourinary tract infections: assessing gene-environment interaction. Pediatr Res 2021; 90(3): 678-83. https://doi.org/10.1038/s41390-020-01200-z 52 Wedi COO Kirtley S Hopewell S Corrigan R Kennedy SH Hemelaar J Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis Lancet HIV 2016 3 1 e33 e48 https://doi.org/10.1016/S2352-3018(15)00207-6 52 Wedi COO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. Lancet HIV 2016; 3(1): e33-48. https://doi.org/10.1016/S2352-3018(15)00207-6 53 Delicio AM Lajos GJ Amaral E Cavichiolli F Polydoro M Milanez H Adverse effects in children exposed to maternal HIV and antiretroviral therapy during pregnancy in Brazil: a cohort study Reprod Health 2018 15 1 76 76 https://doi.org/10.1186/s12978-018-0513-8 53 Delicio AM, Lajos GJ, Amaral E, Cavichiolli F, Polydoro M, Milanez H. Adverse effects in children exposed to maternal HIV and antiretroviral therapy during pregnancy in Brazil: a cohort study. Reprod Health 2018; 15(1): 76. https://doi.org/10.1186/s12978-018-0513-8 54 Xiao PL Zhou YB Chen Y Yang MX Song XX Shi Y Association between maternal HIV infection and low birth weight and prematurity: a meta-analysis of cohort studies BMC Pregnancy Childbirth 2015 15 246 246 https://doi.org/10.1186/s12884-015-0684-z 54 Xiao PL, Zhou YB, Chen Y, Yang MX, Song XX, Shi Y, et al. Association between maternal HIV infection and low birth weight and prematurity: a meta-analysis of cohort studies. BMC Pregnancy Childbirth 2015; 15: 246. https://doi.org/10.1186/s12884-015-0684-z 55 Reis HLB Araujo KS Ribeiro LP Rocha DR Rosato DP Passos MRL Preterm birth and fetal growth restriction in HIV-infected Brazilian pregnant women Rev Inst Med Trop Sao Paulo 2015 57 2 111 120 https://doi.org/10.1590/S0036-46652015000200003 55 Reis HLB, Araujo KS, Ribeiro LP, Rocha DR, Rosato DP, Passos MRL, et al. Preterm birth and fetal growth restriction in HIV-infected Brazilian pregnant women. Rev Inst Med Trop Sao Paulo 2015; 57(2): 111-20. https://doi.org/10.1590/S0036-46652015000200003 56 Chen JY Ribaudo HJ Souda S Parekh N Ogwu A Lockman S Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana J Infect Dis 2012 206 11 1695 1705 https://doi.org/10.1093/infdis/jis553 56 Chen JY, Ribaudo HJ, Souda S, Parekh N, Ogwu A, Lockman S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206(11): 1695-705. https://doi.org/10.1093/infdis/jis553 57 Slyker JA Patterson J Ambler G Richardson BA Maleche-Obimbo E Bosire R Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants BMC Pregnancy Childbirth 2014 14 7 7 https://doi.org/10.1186/1471-2393-14-7 57 Slyker JA, Patterson J, Ambler G, Richardson BA, Maleche-Obimbo E, Bosire R, et al. Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants. BMC Pregnancy Childbirth 2014; 14: 7. https://doi.org/10.1186/1471-2393-14-7