Introduction
Congenital syphilis (CS) is the transmission of syphilis from an infected mother to her infant at or prior to delivery. Syphilis that is untreated or treated late in gestation can lead to CS in >50% of affected pregnancies, resulting in stillbirth, neonatal death, or other morbidity, including visceral or neurologic damage in surviving infants. CS is preventable if syphilis in the mother is treated early in pregnancy with penicillin, and prenatal syphilis screening and treatment are effective interventions. Because CS is related to both community prevalence of syphilis among reproductive-aged women and prenatal intervention, CS case rates reflect a health system’s effectiveness.
Effective prevention of CS in the United States is challenging. Diagnosis remains difficult, and lack of provider awareness about CS still exists. Social determinants of health and health systems’ issues affect access to and quality of prenatal care. Many of these issues affect racial/ethnic minority women, leading to disparities in diseases, including syphilis and CS.
A previous analysis by Gust et al reviewed national case report data during 1992 through 1998, following a revision to the CS surveillance case definition that increased sensitivity to increase treatment among affected infants. The analysis of Gust et al showed declines in both overall cases of CS and cases of CS that died, with no decline in the proportion of CS cases that died. Here, we describe trends in CS infant mortality and morbidity during 1999 through 2013, and associated maternal and infant factors.
Materials and Methods
Case data for CS are reported to local and state health departments; states voluntarily transmit that data to the Centers for Disease Control and Prevention (CDC). We reviewed CS case data from all 50 states and Washington, DC, reported to CDC as of Aug. 1, 2014, for cases born during 1999 through 2013; cases were reported based on the surveillance case definition for CS used during this time period. Cases were classified by disease severity. A dead case was defined as a case of CS that died, either as a stillbirth or as a live birth that died within 12 months of delivery. A morbid case was defined as a case of CS reported as alive, with strong evidence of infection based on ≥1 of the following situations: (1) findings on darkfield microscopy or direct fluorescent antibody examination of lesions (on the infant), placenta, or umbilical cord consistent with syphilis, a reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory test, or changes on long bone radiographs consistent with syphilis; (2) physical signs or symptoms of syphilis (hepatosplenomegaly, rash, condyloma lata, snuffles, jaundice [nonviral hepatitis], pseudoparalysis, anemia, edema [nephrotic syndrome and/or malnutrition]); or (3) an elevated CSF white blood cell count (WBC) and/or CSF protein concentration absent other causes, and the case’s mother was not treated or inadequately treated for syphilis (“adequate” defined as penicillin therapy appropriate for maternal stage of infection, administered ≥30 days before delivery). A nonmorbid case was defined as a case of CS reported as alive, without the strong evidence of infection described for a morbid case (either because such tests or procedures were negative or not performed), who had a normal physical examination reported. A case of unknown morbidity was defined as a case of CS reported as alive, without the strong evidence of infection described for a morbid case (either because such tests or procedures were negative or not performed), and without a normal physical examination reported. To understand how testing (or lack of it) influenced case classification, the number of morbid and nonmorbid cases with CSF testing (CSF protein, WBC count, and/or CSF Venereal Disease Research Laboratory test) and long bone radiographic examination were calculated.
Annual rates of dead, morbid, and nonmorbid cases of CS were calculated with the annual count of dead, morbid, or nonmorbid cases of CS as the numerator and live births for the corresponding year as the denominator, using natality data matched for maternal race/ethnicity. Population denominators for 2012 (the most recent data available at time of analysis) were used to calculate rates for 2013.
Cases of CS (dead, morbid, nonmorbid, and unknown) were described by maternal and infant characteristics. Maternal characteristics analyzed were age (<25 or ≥25 years); marital status (married; single, never married; separated/divorced; or other); race/ethnicity (black, Hispanic, white, Asian/Pacific Islander, Native American/Alaska Native, or other); census region (Midwest, Northeast, South, or West); number of prenatal care visits (none, 1–4, 5–9, or ≥10 visits); trimester of first prenatal visit (first, second, or third trimester); treatment for syphilis (adequate or inadequate); and nontreponemal titer closest to delivery (≤1:4, 1:8–1:32, 1:64–1:256, or >1:256). Infant characteristics analyzed were gestational age at time of delivery (<28, 28–31, 32–36, or ≥37 weeks) and birthweight (<1500, 1500-2499, or ≥2500 g); because prematurity and low birthweight are common among stillbirths, analysis of gestational age and birthweight was limited to cases of CS that were born alive. Race/ethnicity was defined using the National Center for Health Statistics bridged-race categories, while US regions were defined using the US Census geographic regions.
A χ 2 test for linear trend was used to determine if significant overall trends in proportions of dead or morbid cases of CS were present during 1999 through 2013. To determine if maternal or infant characteristics were associated with negative outcomes (a morbid or dead case), relative risks (RR) and 95% confidence intervals (CIs) were calculated, comparing morbid cases and dead cases as a group to nonmorbid cases. To determine if maternal or infant characteristics were associated with the most extreme negative outcome (ie, death), RR and 95% CIs were calculated, comparing dead cases to morbid cases and nonmorbid cases as a group. A sensitivity analysis was performed to explore how missing information (ie, cases classified as unknown morbidity) might affect these analyses: RR and 95% CIs were also calculated with cases of unknown morbidity reclassified as: (1) all nonmorbid cases, and (2) all morbid cases. Data were analyzed using software (SAS, Version 9.3; SAS Institute Inc, Cary, NC). CS data were collected as part of routine public health surveillance and were thus exempt from institutional review board review.
Materials and Methods
Case data for CS are reported to local and state health departments; states voluntarily transmit that data to the Centers for Disease Control and Prevention (CDC). We reviewed CS case data from all 50 states and Washington, DC, reported to CDC as of Aug. 1, 2014, for cases born during 1999 through 2013; cases were reported based on the surveillance case definition for CS used during this time period. Cases were classified by disease severity. A dead case was defined as a case of CS that died, either as a stillbirth or as a live birth that died within 12 months of delivery. A morbid case was defined as a case of CS reported as alive, with strong evidence of infection based on ≥1 of the following situations: (1) findings on darkfield microscopy or direct fluorescent antibody examination of lesions (on the infant), placenta, or umbilical cord consistent with syphilis, a reactive cerebrospinal fluid (CSF) Venereal Disease Research Laboratory test, or changes on long bone radiographs consistent with syphilis; (2) physical signs or symptoms of syphilis (hepatosplenomegaly, rash, condyloma lata, snuffles, jaundice [nonviral hepatitis], pseudoparalysis, anemia, edema [nephrotic syndrome and/or malnutrition]); or (3) an elevated CSF white blood cell count (WBC) and/or CSF protein concentration absent other causes, and the case’s mother was not treated or inadequately treated for syphilis (“adequate” defined as penicillin therapy appropriate for maternal stage of infection, administered ≥30 days before delivery). A nonmorbid case was defined as a case of CS reported as alive, without the strong evidence of infection described for a morbid case (either because such tests or procedures were negative or not performed), who had a normal physical examination reported. A case of unknown morbidity was defined as a case of CS reported as alive, without the strong evidence of infection described for a morbid case (either because such tests or procedures were negative or not performed), and without a normal physical examination reported. To understand how testing (or lack of it) influenced case classification, the number of morbid and nonmorbid cases with CSF testing (CSF protein, WBC count, and/or CSF Venereal Disease Research Laboratory test) and long bone radiographic examination were calculated.
Annual rates of dead, morbid, and nonmorbid cases of CS were calculated with the annual count of dead, morbid, or nonmorbid cases of CS as the numerator and live births for the corresponding year as the denominator, using natality data matched for maternal race/ethnicity. Population denominators for 2012 (the most recent data available at time of analysis) were used to calculate rates for 2013.
Cases of CS (dead, morbid, nonmorbid, and unknown) were described by maternal and infant characteristics. Maternal characteristics analyzed were age (<25 or ≥25 years); marital status (married; single, never married; separated/divorced; or other); race/ethnicity (black, Hispanic, white, Asian/Pacific Islander, Native American/Alaska Native, or other); census region (Midwest, Northeast, South, or West); number of prenatal care visits (none, 1–4, 5–9, or ≥10 visits); trimester of first prenatal visit (first, second, or third trimester); treatment for syphilis (adequate or inadequate); and nontreponemal titer closest to delivery (≤1:4, 1:8–1:32, 1:64–1:256, or >1:256). Infant characteristics analyzed were gestational age at time of delivery (<28, 28–31, 32–36, or ≥37 weeks) and birthweight (<1500, 1500-2499, or ≥2500 g); because prematurity and low birthweight are common among stillbirths, analysis of gestational age and birthweight was limited to cases of CS that were born alive. Race/ethnicity was defined using the National Center for Health Statistics bridged-race categories, while US regions were defined using the US Census geographic regions.
A χ 2 test for linear trend was used to determine if significant overall trends in proportions of dead or morbid cases of CS were present during 1999 through 2013. To determine if maternal or infant characteristics were associated with negative outcomes (a morbid or dead case), relative risks (RR) and 95% confidence intervals (CIs) were calculated, comparing morbid cases and dead cases as a group to nonmorbid cases. To determine if maternal or infant characteristics were associated with the most extreme negative outcome (ie, death), RR and 95% CIs were calculated, comparing dead cases to morbid cases and nonmorbid cases as a group. A sensitivity analysis was performed to explore how missing information (ie, cases classified as unknown morbidity) might affect these analyses: RR and 95% CIs were also calculated with cases of unknown morbidity reclassified as: (1) all nonmorbid cases, and (2) all morbid cases. Data were analyzed using software (SAS, Version 9.3; SAS Institute Inc, Cary, NC). CS data were collected as part of routine public health surveillance and were thus exempt from institutional review board review.
Results
During 1999 through 2013, a total of 6383 cases of CS were reported to CDC, with the highest proportions among black or Hispanic mothers; single, never-married mothers; and mothers in the South ( Table 1 ): 6.5% dead, 33.6% morbid, 53.9% nonmorbid, and 5.9% of unknown morbidity. Of the 2145 morbid cases, 1960 (91.4%) had some combination of CSF testing (CSF protein, WBC, and/or CSF Venereal Disease Research Laboratory test) and/or long bone radiographic examination, with 1197 (61.1%) having both tests performed. Of the 3443 nonmorbid cases, 511 (14.8%) had both CSF testing and long bone radiographic examination performed.
| Dead (%) | Morbid (%) | Nonmorbid (%) | Unknown (%) | Total (%) | |
|---|---|---|---|---|---|
| n = 418 | n = 2145 | n = 3443 | n = 377 | N = 6383 | |
| Maternal characteristics–demographics | |||||
| Maternal age, y | |||||
| ≥25 | 188 (45) | 1176 (55) | 1981 (58) | 222 (59) | 3567 (56) |
| ≤24 | 228 (55) | 954 (44) | 1424 (41) | 146 (39) | 2752 (43) |
| Blank | 2 (0) | 15 (1) | 38 (1) | 9 (2) | 64 (1) |
| Marital status | |||||
| Married | 41 (10) | 298 (14) | 574 (17) | 59 (16) | 972 (15) |
| Single, never married | 310 (74) | 1506 (70) | 2328 (68) | 230 (61) | 4374 (69) |
| Separated/divorced | 8 (2) | 80 (4) | 91 (3) | 11 (3) | 190 (3) |
| Other | 1 (0) | 8 (0) | 18 (1) | 7 (2) | 34 (1) |
| Unknown/missing | 58 (14) | 253 (12) | 432 (13) | 70 (19) | 813 (13) |
| Race/ethnicity | |||||
| White | 38 (9) | 262 (12) | 377 (11) | 47 (12) | 724 (11) |
| Black | 218 (52) | 1125 (52) | 1749 (51) | 211 (56) | 3303 (52) |
| Hispanic | 141 (34) | 642 (30) | 1083 (31) | 96 (25) | 1962 (31) |
| Asian/Pacific Islander | 7 (2) | 46 (2) | 95 (3) | 7 (2) | 155 (2) |
| American Indian/Alaska Native | 5 (1) | 26 (1) | 33 (1) | 3 (1) | 67 (1) |
| Other | 1 (0) | 9 (0) | 27 (1) | 4 (1) | 41 (1) |
| Unknown | 8 (2) | 35 (2) | 79 (2) | 9 (2) | 131 (2) |
| Region a | |||||
| Midwest | 75 (18) | 306 (14) | 437 (13) | 106 (28) | 924 (14) |
| Northeast | 30 (7) | 253 (12) | 394 (11) | 13 (3) | 690 (11) |
| South | 213 (51) | 1083 (50) | 1812 (53) | 207 (55) | 3315 (52) |
| West | 100 (24) | 503 (23) | 800 (23) | 51 (14) | 1454 (23) |
| Maternal characteristics–detection of maternal syphilis | |||||
| Prenatal visits, no. | |||||
| 0/No prenatal care | 199 (48) | 690 (32) | 794 (23) | 100 (27) | 1783 (28) |
| 1–4 | 84 (20) | 377 (18) | 551 (16) | 52 (14) | 1064 (17) |
| 5–9 | 39 (9) | 335 (16) | 570 (17) | 42 (11) | 986 (15) |
| ≥10 | 18 (4) | 284 (13) | 583 (17) | 37 (10) | 922 (14) |
| Unknown | 78 (19) | 459 (21) | 945 (27) | 146 (39) | 1628 (26) |
| Prenatal visits, trimester | |||||
| No prenatal care | 199 (48) | 690 (32) | 794 (23) | 100 (27) | 1783 (28) |
| First | 75 (18) | 472 (22) | 830 (24) | 63 (17) | 1440 (23) |
| Second | 68 (16) | 355 (17) | 680 (20) | 55 (15) | 1158 (18) |
| Third | 11 (3) | 253 (12) | 399 (12) | 27 (7) | 690 (11) |
| Unknown | 65 (16) | 375 (17) | 740 (21) | 132 (35) | 1312 (21) |
| Maternal characteristics–treatment and nontreponemal titers | |||||
| Treatment b | |||||
| None | 304 (73) | 1433 (67) | 1814 (53) | 255 (68) | 3844 (60) |
| Adequate | 17 (4) | 82 (4) | 684 (20) | 34 (9) | 809 (13) |
| Inadequate | 67 (16) | 630 (29) | 916 (27) | 86 (23) | 1697 (27) |
| Unknown | 30 (7) | 0 (0) | 29 (1) | 2 (1) | 33 (1) |
| Nontreponemal titer c | |||||
| ≤1:4 | 45 (11) | 553 (26) | 1273 (37) | 127 (34) | 1998 (31) |
| 1:8–1:32 | 146 (35) | 844 (39) | 1426 (41) | 144 (38) | 2560 (40) |
| 1:64–1:256 | 200 (48) | 660 (31) | 587 (17) | 78 (21) | 1525 (24) |
| >1:256 | 25 (6) | 76 (4) | 123 (4) | 21 (6) | 245 (4) |
| Unknown | 2 (0) | 12 (1) | 34 (1) | 7 (2) | 55 (1) |
| Infant characteristics | |||||
| Gestational age at birth, wk | |||||
| ≥37 | 43 (10) | 1353 (63) | 2504 (73) | 202 (54) | 4102 (64) |
| 32–36 | 103 (25) | 535 (25) | 542 (16) | 71 (19) | 1251 (20) |
| 28–31 | 114 (27) | 117 (5) | 81 (2) | 12 (3) | 324 (5) |
| <28 | 132 (32) | 37 (2) | 56 (2) | 8 (2) | 233 (4) |
| Unknown | 26 (6) | 103 (5) | 260 (8) | 84 (22) | 473 (7) |
| Birthweight, g | |||||
| ≥2500 | 45 (11) | 1408 (66) | 2592 (75) | 218 (58) | 4263 (67) |
| 1500–2499 | 111 (27) | 528 (25) | 513 (15) | 65 (17) | 1217 (19) |
| <1500 | 164 (39) | 116 (5) | 125 (4) | 18 (5) | 423 (7) |
| Unknown | 98 (23) | 93 (4) | 213 (6) | 76 (20) | 480 (8) |
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