Point-of-care testing with Xpert HPV for single-visit, screen-and-treat for cervical cancer prevention: a demonstration study in South Africa.

Human papillomavirus (HPV)-based screen-and-treat (SAT) is recommended but implementation presents operational challenges. We implemented HPV-SAT at a research site in Khayelitsha, South Africa, screening 3062 women aged 30-65 years (44% women living with HIV [WHIV]). All were screened using point-of-care Xpert HPV and almost all received their HPV results on the same day. HPV-positivity occurred in 41.5% of WHIV and 17.4% of women without HIV (WNoH) reducing to 26.2% in WHIV and 10.4% in WNoH applying treatment eligibility criteria based on high viral load in the channels detecting HPV16, 18, 45, 16, 18, 31, 33, 35, 52, 58. Among those eligible for treatment, 91.3% were considered suitable for ablative therapy, and 94.6% underwent thermal ablation on the same day, with no serious adverse events. Twelve months later, 39.0% of WHIV and 65.2% of WNoH treated with ablative therapy were clear of HPV. In women who were HPV-positive but ineligible for treatment, 19.1% and 12.9% had histologically-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) at 12 months. SAT programs need to weigh trade-offs between overtreatment versus delayed or no treatment for women who test positive for HPV. Treatment modalities for precancerous lesions need to be improved.

Thermal Ablation Treatment for Cervical Precancer (Cervical Intraepithelial Neoplasia Grade 2 or Higher [CIN2+]).

Cervical cancer is a leading cause of mortality for women in low- and middle-income countries (LMICs). Invasive disease can be prevented through the treatment of high-grade cervical precancer lesions. Types of treatment for cervical precancer include excisional procedures that surgically remove the affected tissue and ablation treatments which utilize extreme temperatures to destroy precancerous cells. Excision is the first-line treatment in higher income countries, but requires specialized training and equipment that make it unsuitable for low-income settings. The most common treatment globally is cryotherapy, which utilizes cryogenic gas to freeze the area. However, the need for gas presents significant procurement and logistical challenges. The World Health Organization (WHO) has recently endorsed the use of thermal ablation, a method that utilizes heat to destroy precancerous tissue. This review describes three existing thermal ablation devices and protocols for their use, including step-by-step instruction guides to perform a successful treatment with each device and observations specific to each machine.

Clinical Utility of Reflex Testing with Cancer Biomarkers to Improve Diagnostic Accuracy of Primary Human Papillomavirus Screening.

BACKGROUND: Human papillomavirus (HPV) testing is the cornerstone of cervical cancer screening, with outstanding sensitivity but only moderate specificity. We evaluated whether reflex testing for cancer biomarkers improves the sensitivity/specificity balance of screening. METHODS: Cervical samples from women in Cape Town, South Africa, ages 30-65 years, were collected and tested with Xpert HPV and with real-time PCR to detect mRNA for cyclin-dependent kinase inhibitor 2A (CDKN2A), topoisomerase 2 alpha (TOP2A), and Ki67 (MKi67). Women with histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+; 85 women without and 166 with HIV) and women with no cervical disease (331 without and 257 with HIV) were included. RESULTS: When used as reflex tests after a positive HPV result, biomarkers discriminated well between women with and without CIN2+. The inclusion of both CDKN2A and MKi67 had the best performance, with area under the curve (AUC) of 0.9171 and 0.8734 in women without and with HIV, respectively. Although excellent, these performance parameters did not improve on an approach utilizing only HPV testing with more stringent cycle threshold cutoffs and HPV genotype selection, which achieved AUC of 0.9059 and 0.8705 in women without and with HIV, respectively. CONCLUSIONS: Biomarkers can be used as triage after positive HPV results but do not outperform an approach utilizing higher viral load cutoffs on selected high-risk genotypes. IMPACT: A screening approach using HPV testing alone can be more easily implemented at the point of care.

Assessment of the implementation context in preparation for a clinical study of machine-learning algorithms to automate the classification of digital cervical images for cervical cancer screening in resource-constrained settings.

Introduction: We assessed the implementation context and image quality in preparation for a clinical study evaluating the effectiveness of automated visual assessment devices within cervical cancer screening of women living without and with HIV. Methods: We developed a semi-structured questionnaire based on three Consolidated Framework for Implementation Research (CFIR) domains; intervention characteristics, inner setting, and process, in Cape Town, South Africa. Between December 1, 2020, and August 6, 2021, we evaluated two devices: MobileODT handheld colposcope; and a commercially-available cell phone (Samsung A21ST). Colposcopists visually inspected cervical images for technical adequacy. Descriptive analyses were tabulated for quantitative variables, and narrative responses were summarized in the text. Results: Two colposcopists described the devices as easy to operate, without data loss. The clinical workspace and gynecological workflow were modified to incorporate devices and manage images. Providers believed either device would likely perform better than cytology under most circumstances unless the squamocolumnar junction (SCJ) were not visible, in which case cytology was expected to be better. Image quality (N = 75) from the MobileODT device and cell phone was comparable in terms of achieving good focus (81% vs. 84%), obtaining visibility of the squamous columnar junction (88% vs. 97%), avoiding occlusion (79% vs. 87%), and detection of lesion and range of lesion includes the upper limit (63% vs. 53%) but differed in taking photographs free of glare (100% vs. 24%). Conclusion: Novel application of the CFIR early in the conduct of the clinical study, including assessment of image quality, highlight real-world factors about intervention characteristics, inner clinical setting, and workflow process that may affect both the clinical study findings and ultimate pace of translating to clinical practice. The application and augmentation of the CFIR in this study context highlighted adaptations needed for the framework to better measure factors relevant to implementing digital interventions.

Prognostic significance of BIRC7/Livin, Bcl-2, p53, Annexin V, PD-L1, DARC, MSH2 and PMS2 in colorectal cancer treated with FOLFOX chemotherapy with or without aspirin.

Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment in vivo in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7/Livin post-FOLFOX treatment compared with pre-treatment (p = 0.0001). This increase provides new insights into the prognostic role of BIRC7/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p < 0.05). Importantly, we found a significant reduction in expression of BIRC7/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments in vivo (p <0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.

Performance of Xpert HPV on Self-collected Vaginal Samples for Cervical Cancer Screening Among Women in South Africa.

OBJECTIVES: Self-sampling may increase access to cervical cancer screening in low-resource settings. Using Xpert HPV, we compared test performance of self- and clinician-collected samples in HIV-positive and HIV-negative women in South Africa. MATERIALS AND METHODS: Three hundred thirty HIV-positive and 375 HIV-negative women in the screening group and 202 HIV-negative and 200 HIV-positive women in the referral group, aged 30-65 years, participated in the study. All women self-collected a vaginal sample, and then, a cervical sample was collected by a clinician (both tested using Xpert HPV), followed by colposcopic examination and collection of histologic specimens. RESULTS: There was good agreement between self- and clinician-collected samples for detection of any high-risk human papillomavirus (HPV, κ = 0.72 [95% CI = 0.669-0.771]). Prevalence of HPV and sensitivity of the test to detect cervical intraepithelial neoplasia 2+ was similar in self- and clinician-collected samples. Specificity was lower in self-collected than in clinician-collected samples in both HIV-negative (self: 77.5% [95% CI = 72.8-81.8] vs clinician: 86.9% [95% CI = 82.9-90.2]) and HIV-positive (self: 44.0% [95% CI = 38.0-50.1] vs clinician: 59.7% [95% CI = 53.6-65.6]) women. Restricting the definition of screen-positive to 3 of 5 channels on HPV Xpert improved specificity in both HIV-negative (self: 83.2% [95% CI = 78.8-87.0] vs clinician: 89.7% [95% CI = 86.1-92.7]) and HIV-positive (self: 54.2% [95% CI = 48.1-60.2] vs clinician: 67.4% [95% CI = 61.5-72.9]) women. CONCLUSIONS: The self-collected sample had good agreement with the clinician-collected sample for the detection of HPV, and restricting the HPV types may improve the specificity in HIV-positive women.

Selecting human papillomavirus genotypes to optimize the performance of screening tests among South African women.

Human papillomavirus (HPV) testing is highly sensitive compared to cytology, with the trade-off of being less specific. We investigated whether select combinations of HPV genotypes, ascertained by Linear Array (LA) and Xpert HPV (GX), can optimize sensitivity/specificity trade-offs to detect high-grade cervical intraepithelial neoplasia (CIN2+). In a study in Cape Town, South Africa, 586 women living without and 535 living with HIV, aged 30-65 years, were recruited. Each woman underwent a pelvic exam to collect cervical samples (tested by LA and GX for 14 high-risk HPV genotypes) and underwent colposcopy with histological sampling to determine CIN2+. In multivariable logistic regression of LA results, only HPV genotypes 16, 18, 31, 33, 35, 52, 58 were significantly associated with CIN2+ (P < .05). Xpert includes these seven types along with HPV 45 within three of the test's five channels and we defined these eight types as restricted genotyping (ie 16, 18, 31, 33, 35, 45, 52, 58). Full genotyping was defined as all 14 high-risk types. Sensitivity estimates for full genotyping using LA were similar to that of restricted genotyping: 83.9% (full) vs 79.0% (restricted) in women without HIV and 93.0% (full) vs 88.9% (restricted) in women living with HIV. Specificity estimates improved for restricted vs full genotyping: 87.4% (full) vs 90.8% (restricted) in women without HIV and 63.7% (full) vs 71.4% (restricted) in women living with HIV. To optimize the performance of HPV testing for cervical cancer screening in high-burden, under-resourced settings like South Africa, only HPV 16, 18, 31, 33, 35, 45, 52, 58 could be included to define screen-positive. We recommend the inclusion of HPV45 for its known link to adenocarcinoma.

Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study.

BACKGROUND: HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. METHODS: We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. RESULTS: We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. INTERPRETATION: More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. FUNDING: Supported by the National Cancer Institute UH2/3 CA189908.

Comparing perioperative vaginal misoprostol with intraoperative pericervical hemostatic tourniquet in reducing blood loss during abdominal myomectomy: A randomized controlled trial

Objective: To compare the effectiveness of perioperative vaginal misoprostol with intraoperative pericervical hemostatic tourniquet in reducing blood loss during abdominal myomectomy. Material and Methods: A randomized controlled trial involving women with uterine leiomyoma who underwent abdominal myomectomy was conducted at a tertiary facility in Nigeria. Participants were recruited after they gave informed consent and randomized into group I (single dose 400 µg vaginal misoprostol one-hour before surgery) and group II (intraoperative pericervical hemostatic tourniquet). Eighty participants (40 in each group) were recruited. Uterine size was measured in centimeters above the pubic symphysis, and blood loss estimation involved direct volume measurement and gravimetric methods. The main outcome measures were intraoperative blood loss, blood transfusion, and recourse to hysterectomy. Ethical approval and trial registration were obtained; the data were analyzed using the SPSS software version 21.0; p<0.05 was considered significant. Results: Participants in group I had higher mean intraoperative blood loss (931.89±602.13 vs 848.40±588.85 mL, p=0.532), intra-operative blood transfusion rates (60 vs 55%; p=0.651) and mean units of blood transfused (1.30±1.20 vs 1.20±1.30; p=0.722) compared with group II. The mean uterine size (19.50±6.93 vs 20.05±6.98 cm; p=0.725) and number of fibroid nodules (11.25±7.99 vs 11.45±8.22; p=0.912) were comparable. The change in post-operative hematocrit was 2.66±2.21% vs 3.24±2.85% (p=0.315) and post-operation blood transfusion was 2.5 vs 5% (p=0.556). There was no recourse to hysterectomy in either of the study groups. While adverse effects of misoprostol occurred in 5 (12.5%) participants of group I. Conclusion: The effectiveness of perioperative vaginal misoprostol is comparable to intra-operative hemostatic pericervical tourniquet in reducing blood loss during abdominal myomectomy.

Double-blind randomized controlled trial comparing misoprostol and oxytocin for management of the third stage of labor in a Nigerian hospital.

OBJECTIVE: To compare the efficacy of oral misoprostol with that of oxytocin for active management of the third stage of labor (AMTSL). METHODS: A double-blind randomized control trial was undertaken at a center in Ilorin, Nigeria, between January and June 2013. Every other eligible patient (in the first stage of labor at term, to have a spontaneous vaginal delivery, and no/low risk of postpartum hemorrhage [PPH]) were randomly assigned with computer-generated random numbers to receive oral misoprostol (600µg) plus placebo injection or oral placebo plus oxytocin injection (1mL of 10IU) in the third stage of labor. The primary outcome was amount of blood loss during delivery. RESULTS: Mean postpartum blood loss was 325.85±164.72mL in the 100 patients given misoprostol and 303.95±163.33mL in the 100 patients given oxytocin (P=0.391). PPH (≥500mL blood loss) was recorded in 15 (15.0%) patients given misoprostol and 14 (14.0%) given oxytocin (P=0.841). Shivering, pyrexia, and diarrhea were all significantly more common in the misoprostol group (P<0.01 for all). CONCLUSION: The efficacy of oral misoprostol was similar to that of intramuscular oxytocin. Adverse effects associated with misoprostol were transient and self-limiting. Thus, oral misoprostol is efficacious and a good alternative to oxytocin for AMTSL. Pan African Clinical Trials Registry:PACTR201407000825227.

Contribution of Corneal Blindness to Visual Disability among Street Blind beggars in a Local Government Area of a State in Northern Nigeria

Aim: To determine the contribution of corneal blindness to visual disability among Blind Street Beggars (bsb) with a view to draw the implications to blindness prevention programme in Sokoto North Local government area (LGA) . Materials and Methods: The cross sectional study was conducted in Sokoto North Local LGA in Sokoto State. The study was conducted over a period of six weeks between May and June; 2009. Ethical clearance was obtained from the Ethical Committee of University of Ilorin Teaching Hospital. The list of blind persons in these areas was obtained from the traditional head of the blind (Sarkin Makafi) who assisted in mobilizing the subjects. Blind subjects who consented were included in the study. Data obtained were entered and analyzed in form of frequency tables using Epi-info 2000 statistical software package . Results: A total of 202 of the registered persons were found to be blind on ophthalmic examination and were therefore included in the analysis. There were 107 (53) males and 95 (47) females with a mean age of 49 years. One hundred and sixty four (81.2) blind beggars became blind during childhood period while 38 subjects (18.8) became blind during adulthood. Trachoma corneal opacity was responsible for 12.8 of the blindness while other corneal opacity accounted for 60.8. Conclusion: Majority of the subjects had preventable blindness. We recommend a comprehensive eye care programme with a strong emphasis on health education and prompt treatment of these causes as a means of reducing the population of street blind beggars in Sokoto North LGA

Pattern of Sexually Transmitted Infections in Human Immunodeficiency Virus Positive Women Attending Antenatal Clinics in North-Central Nigeria

Background: Sexually transmitted infections (STIs) are prevalent during pregnancy and may have adverse sequalae in both mother and fetus. Interactions between these infections and human immunodeficiency virus (HIV) synergize and may cause adverse pregnancy outcomes and reverse the gains of prevention of mother to child transmission of HIV. Objectives: The objective of this study is to determine the prevalence of candidiasis; trichomoniasis; gonococcal infection; syphilis; and bacterial vaginosis in HIV pregnant women and compare with HIV negative controls. Materials and Methods: A case-control study was conducted during the period from April to December 2010 at the Department of Obstetrics/Gynecology of University of Ilorin Teaching Hospital and three Primary Health Centers in Ilorin. A total of 160 HIV positive pregnant women attending antenatal clinics were recruited; along with the same number of HIV negative matched controls. A structured proforma was used to collect information from patients; vaginal examination was performed and samples were taken from the endocervix and the posterior vaginal fornix with swab sticks. Results: STIs were recovered from 142 women; giving overall prevalence of 44.4. HIV infected women had a higher prevalence (60) compared to uninfected (28.8). The most prevalent STI was vaginal candidiasis (29.1); followed by bacterial vaginosis (9.7); and trichomoniasis (5.6). The prevalence of candidiasis; bacterial vaginosis; and trichomoniasis was higher among HIV positive pregnant women compared to HIV negative controls (P 0.05). No woman had syphilis or gonorrhea. Conclusion: The prevalence of candidiasis; bacterial vaginosis and trichomoniasis was higher in HIV infected pregnant women compared to uninfected. Routine screening of HIV infected pregnant women for these organisms is advocated

An assessment of essential maternal health services in Kwara State, Nigeria.

The objective of this study is to evaluate the levels of emergency obstetrics care (EOC) signal functions in health facilities in a developing setting with high maternal morbidity and mortality indices and to determine if there are differences between public and private health facilities in terms of availability of these signal functions. A survey of health facilities was carried out in six of the 16 Local Government Areas (LGAs) of Kwara State Nigeria. All health facilities in these LGAs including public and private health facilities offering some services to pregnant women were surveyed using an interviewer- administered, facility-assessment questionnaire adapted from the WHO/UNFPA/UNICEF international guidelines for monitoring the availability and use of obstetric services. Frequency tables, percentages and charts were used for presenting the data. Comparing public and private facilities was done using chi-square tests. A total of 258 health facilities that provide maternal health services were surveyed in this study, out of which 76 (29.5%) were private facilities and 182 (70.5%) were public sector facilities. Most of the UN indicators were not met by the health facilities in Kwara state. The availability of EOC facilities was more among the private sector and this was statistically significant. This study shows that all stakeholders involved in reducing maternal mortality have a big challenge in the areas of availability, inequity in geographical distribution of EOC facilities and poor utilisation of these EOC services by women.

Behavioral Pattern of Menopausal Nigeria Women

Context : Menopause is one area that has been shrouded in myths and taboos and the way women perceive menopause depends largely on the social belief about menopause in their society. Objective : The aims of this study are to assess how women perceived the physical changes during menopause; what the social as well as the individual adjustment practice to menopausal changes might be. Materials and Methods : Qualitative focal group study among women aged 40 years and above where eight to ten volunteers formed a group. Six sessions were held for different focal group; each lasting 1-2 h. A tape recorder and a notepad were used to record the discussions. Opinions of the women were sought on socio-cultural differences in the perception of aging; perception of menstruation; perceived causes and consequences of menopause; sexual intercourse after menopause; social support networks for menopausal women; and types of care and treatment for women in menopause. Results: The participants in the FGDs used various phrases to describe menopause in local term; while some of the participants attributed disease to be a cause of menopause; others believed that it be could be caused by witchcraft or sorcery. However; younger and old women whose menstrual flow stops prematurely seek assistance; often from traditional or spiritual healers. Conclusion: This study reveals the poor menopausal knowledge among the study group with more than half of the respondents having negative attitude towards menopause in addition to mixed feelings about religious obligation and cohabitation

Obesity in older mothers, gestational weight gain, and risk estimates for preterm phenotypes.

OBJECTIVE: To assess whether advanced maternal age modifies the relationship between maternal pregravid weight status, gestational weight gain patterns, and the occurrence of spontaneous preterm birth (SPB) and medically indicated preterm birth (MIPB). METHODS: Retrospective cohort analysis of vital statistics data from the state of Florida for the period 2004 through 2007 comprising 311,422 singleton pregnancies (two age groups: 20-24 years old or younger women and >or=35 years or older women). Mothers were classified into five clusters based on their pre-pregnancy body mass index (BMI) values: non-obese (less than 30), class I obese (30.0or=50.0). RESULTS: MIPB occurred more frequently among older than younger women [11.8% vs. 6.4%, respectively (p<0.0001)) whereas SPB occurred more frequently among younger women [11.3% vs. 10.5%, respectively (p<0.0001)). Maternal obesity increased the risk for MIPB but not for SPB. Regardless of BMI status, the risk of MIPB was elevated among older mothers, particularly among those with suboptimal (<0.23 kg/week) and supraoptimal (>0.68 kg/week) gestational weight gain. A dose-response relationship with increasing gestational weight gain was evident (p<0.01); the greatest risk for MIPB occurred among older mothers with weekly gestational weight gain in excess of 0.79 kg (OR=7.76, 95% CI=5.73-10.5). CONCLUSION: The occurrence of medically indicated preterm birth is positively associated with increased maternal pregravid body weight, older maternal age and extremes of gestational weight gain. Targeted pre- and inter-conception weight management efforts should be particularly encouraged in older mothers.

Intrauterine exposure to tobacco and risk of medically indicated and spontaneous preterm birth.

We investigated the association between prenatal smoking and the occurrence of medically indicated and spontaneous preterm delivery (<37 weeks). We performed a retrospective cohort study of singleton live births in the state of Missouri (n = 1,219,159) using maternally linked cohort data files covering the period 1989 to 2005. The main outcomes of interest were spontaneous and medically indicated preterm and very preterm birth. Logistic regression models were used to generate adjusted odds ratios and their 95% confidence intervals. There were 132,246 (10.8%) infants born preterm in the study population, of which 106,410 (80.5%) were classifiable as spontaneous preterm births and 25,836 (19.5%) were medically indicated preterm deliveries. We found elevated risks for both medically indicated and spontaneous preterm birth associated with maternal cigarette smoking during pregnancy. This heightened risk was particularly evident for medically indicated preterm birth (adjusted odds ratio [95% confidence interval] = 1.48 [1.41 to 1.55]). Women who smoke during pregnancy are at increased risk for preterm birth, and especially for medically indicated preterm delivery.