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Placental pathology in fetal growth restriction

Article  in  European journal of obstetrics, gynecology, and reproductive biology · December 2010


DOI: 10.1016/j.ejogrb.2010.11.017 · Source: PubMed

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Gynecol Obstet Invest 2010;70:219–226 Received: December 8, 2009
Accepted after revision: February 2, 2010
DOI: 10.1159/000314020
Published online: $ $ $

Preventable Maternal Risk Factors


and Association of Genital Infection
with Fetal Growth Restriction
Natalija Vedmedovska a Dace Rezeberga a Uldis Teibe b Jana Zodzika a
       

Gilbert G.G. Donders c–e   

Departments of a Obstetrics and Gynaecology, and b Biostatistics, Riga Stradins University, Riga, Latvia;
   

Departments of Obstetrics and Gynecology, c Regional Hospital Heilig Hart, Tienen, d University Hospital
   

Gasthuisberg, Leuven, and e University Hospital Citadelle Liège, Liège, Belgium


 

Key Words prevent preterm birth, but also FGR. Identifying such antici-
Intrauterine growth restriction ⴢ Bacterial vaginosis ⴢ pating factors would likely have the potential impact if de-
Preterm birth ⴢ Pre-eclampsia tected before conception, or as early as possible in gestation.
Copyright © 2010 S. Karger AG, Basel

Abstract
Introduction: Maternal risk factors may interfere with mech- Introduction
anisms regulating fetal growth. The aim of the present study
was to determine which sociodemographic and reproduc- Fetal growth restriction (FGR) occurs in 5–10% of all
tive risk factors may be related to fetal growth restriction pregnancies and is associated with significant morbidity
(FGR), with a special focus on determinants possible for pre- and mortality in the perinatal period and infancy. Com-
ventive intervention. Materials and Methods: The study pe- promise experienced in the intrauterine period has been
riod is from May 2007 until December 2009. Data about life- associated with delays in childhood motor, cognitive and
style habits were collected by use of a detailed questionnaire social development [1]. Furthermore, FGR is related to
in 65 women who attended Riga Maternity Hospital with the cardiovascular and metabolic diseases in adulthood [2].
confirmed diagnosis of intrauterine FGR of a singleton fetus, Also studies have demonstrated that at least one third of
and in 65 matched controls with normal pregnancies. Re- them never achieve normal height [3]. Inability of the fe-
sults: Being unmarried (p = 0.04), having pregnancy-related tus to achieve its genetically determined potential size
blood pressure rise (p = 0.02), current (p = 0.01) and pre-preg- may have variable pathologic pathways, many of which
nancy smoking (p = 0.01) and history of more than 3 preg- are still largely unresolved [4]. Different maternal risk
nancy failures (p = 0.04) were more frequent in women with factors are known to be involved, such as hypertensive,
FGR than controls. Surprisingly, the finding of genital infec- renal and autoimmune diseases, and the use of medica-
tion (STI) during pregnancy (p = 0.006) was also strongly as- tion and illicit drugs. Furthermore, maternal lifestyle fac-
sociated with FGR. Conclusions: Obviously, several maternal tors, like smoking and awkward dietary habits, interfere
risk factors play an important role in FGR. Besides refraining with mechanisms regulating fetal growth [5, 6]. Compli-
from smoking, screening and treating for STI may not only cations of previous pregnancies (very long and short in-

© 2010 S. Karger AG, Basel Dr. Natalija Vedmedovska


0378–7346/10/0703–0219$26.00/0 Department of Obstetrics and Gynaecology, Riga Stradins University
Fax +41 61 306 12 34 Dzirciema str. 16
E-Mail karger@karger.ch Accessible online at: LV–1013 Riga (Latvia)
www.karger.com www.karger.com/goi Tel. +371 2942 9704, Fax +371 6733 9448, E-Mail natalyved @ apollo.lv

GOI386.indd 219 21.05.2010 14:39:56


ter-pregnancy interval, previous small for gestational age Table 1. Demographic characteristics of patients from the control
(SGA) babies, previous stillbirth) may increase the risk of and FGR groups
fetal growth restriction [7]. There is a correlation between Control FGR Statistical test
maternal characteristics and abnormal placental growth, (n = 65) (n = 65)
resulting in low placental weight and impaired fetal
growth [8]. Mean age, years 8 SD 27.184.4 28.485.4 t = 1.4
The aim of the present study was to confirm known p = 0.14
Type of residence
and discover formerly unknown socio-demographic and Urban 58 (89) 50 (77) ␹2 = 3.50
reproductive risk factors for fetal growth restriction in Rural 7 (11) 15 (23) p = 0.060
Latvia. Level of education
Basic 1 (1) 5 (8) ␹2 = 7.09
Secondary 22 (34) 19 (29) p = 0.069
Secondary/professional 4 (6) 11 (17)
Materials and Methods High/university 38 (59) 30 (46)
Marital status
Patients Unmarried 16 (25) 27 (41) ␹2 = 4.20
A prospective case-control study was performed from May Married 49 (75) 38 (59) p = 0.040
2007 to December 2009. Sixty-five women who attended Riga Ma- Employment status
ternity Hospital with the confirmed diagnosis of intrauterine Employed 56 (86) 54 (83) ␹2 = 0.24
growth restriction of singleton fetus were recruited as cases. Inclu- Unemployed 9 (14) 11 (17) p = 0.626
sion criteria were sonographically measured fetal abdominal cir-
cumference (AC) less than the 5th percentile [9] and the intention Data are given as numbers with percentages in parentheses.
to deliver in Riga Maternity Hospital. Neonates with a birth weight
above the 10th percentile for gestational age and gender were ex-
cluded from analysis. Further exclusion criteria were multiple
pregnancies, Rh immunization, known fetal chromosomal abnor-
malities and fetal malformations. After each confirmed case, the
al age was based on the last menstrual period and/or ultrasono-
next pregnant woman with a normally developed, appropriately
graphic examination in the first trimester. In case of any discrep-
growing fetus, matched for maternal and gestational age, was se-
ancy between menstrual and ultrasound dates of more than 7
lected as a control. The study was approved by the Ethical Com-
days, or if the menstrual period was irregular, the initial scans
mittee of Riga Stradins University and written informed consent
were used for the estimation and possible correction of gestation-
was obtained from all participants before inclusion into the study.
al age. In case of doubt, the fetal transcerebellar diameter at 15–
20 weeks was measured as an additional maker to improve the
Medical and Obstetric Data Collection
gestational age estimation [10]. Serial ultrasound and Doppler
A questionnaire was designed to inquire about the possible
examinations were performed, using the standard techniques
risk factors for FGR (see Appendix 1). The standard antenatal files
[11–13].
were used for collecting all data concerning medical history, sex-
ually transmitted infection (STI) screening, medication and rec-
Statistics
reational drug use, including alcohol and smoking, during preg-
Parametric statistics are presented as mean and SD. The rela-
nancy. The information about birth weight, duration of gestation
tionships between variables were assessed using ␹2, independent
at delivery, gender, Apgar score, mode of delivery, and neonatal
sample t test, Pearson’s correlation or Fisher’s exact test. Two-
health condition were obtained from standardized medical re-
tailed p ! 0.05 was considered significant. Statistical analyses
cords.
were performed using SPSS version 18.0.
Infectious Laboratory Techniques
Upon inclusion into the study, an elaborate screening for STI
and reproductive tract infections (RTI) was done according to the Results
antenatal screening program in Latvia using standardized labora-
tory procedures, including serology for antibodies (lues, HIV),
Gram smear (Trichomonas vaginalis, lactobacillary grades, dom- The demographic characteristics of the women who
inant vaginal flora, presence of leukocytes), PCR (Chlamydia tra- participated in the present study are shown in table  1.
chomatis and Neisseria gonorrhoeae), and Amsel criteria for bac- Both groups were similar in respect to age, type of resi-
terial vaginosis (BV). dence, level of education and employment status. Women
with FGR were significantly more often unmarried than
Ultrasound Results
A 2- to 5-MHz abdominal transducer (Voluson Philips, IU22) controls (p = 0.04).
with color Doppler and pulsed Doppler facilities was used. The The clinical characteristics of the women are shown in
high-pass filter was set as low as possible, at 50–70 Hz. Gestation- table 2. Both groups were similar in respect to parity and

220 Gynecol Obstet Invest 2010;70:219–226 Vedmedovska /Rezeberga /Teibe /


     

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GOI386.indd 220 21.05.2010 14:40:01


Table 2. Clinical characteristics of patients from the control and FGR groups

Control FGR Statistical test p value


(n = 65) (n = 65)

Parity
Nulliparous 35 (54) 29 (45) χ2 = 1.11 0.293
Multiparous 30 (46) 36 (55)
Mean interval between pregnancies, months 45.88x,y 45.88x,y t = 0.007 0.99
Mean gestational age at birth, weeks 8 SD 39.881.1 36.383.4 t = 7.7 <0.001
Mean birth weight, g 8 SD 3,6238515 2,0208622 t = 15.8 <0.001
Perinatal mortality 0 3 (4.5) ␹2 = 3.07 0.244
Cesarean section 6 (9) 41 (63) ␹2 = 40.82 <0.001
Apgar score below 7 at 5 min 0 2 (3) ␹2 = 2.03 0.496
Premature labor 1 (1.5) 28 (43) ␹2 = 32.36 <0.001

Data are given as numbers and percentages in parentheses.

interpregnancy interval. However, gestational age at birth

Color version available online


(p ! 0.001), birth weight (p ! 0.001) and the spontaneous 5,000 FGR
delivery rate (p ! 0.001) in the FGR group were signifi- Control
cantly lower than in controls, while the preterm delivery
4,000
rate was significantly higher (p ! 0.05). The correlation
between gestational age and birth weight is shown in fig-
ure 1. Women with FGR had lower birth weights of their
Birth weight (g)

3,000
babies at any gestational age. All cases of premature de-
livery in the study group were iatrogenic due to indicated
2,000
induced labor or cesarean section, except one.
In the FGR group, 3 perinatal deaths (4.5%) occurred
and 5-min Apgar scores below 7 were present in 2/65 (3%) 1,000
newborns, compared to no mortality or low Apgar scores
in the control group (difference not significant). Two of
0
the perinatal deaths occurred antenatally, one due to pre-
mature placental abruption, and one as a consequence of 24.0 27.0 30.0 33.0 36.0 39.0 42.0
deteriorated materno-placental flow due to pre-eclamp- Gestational age (weeks)
sia. The latter cause was also responsible for the third in-
tranatal death.
Obstetric characteristics show no differences between Fig. 1. Correlation between birth weight (g) and gestational age
(weeks).
the groups regarding most of the complications in cur-
rent or previous pregnancies (table 3). FGR women had
more pregnancy-related increase in blood pressure (pre-
eclampsia (p = 0.03) and pregnancy-induced hyperten-
sion (PIH) (p = 0.02), and they lost more pregnancies in STIs and other RTIs, in anamnesis (not significant dif-
their history (termination of pregnancy (TOP), recurrent ference) or diagnosed during current pregnancy (p =
miscarriage or stillborn, p = 0.04). 0.006), were more frequent in the FGR group than in the
Current smoking (p = 0.01) as well as pre-pregnancy controls. In the FGR group, in past history C. trachoma-
smoking (p = 0.01) were associated with FGR, but there tis was diagnosed in 2 cases, HIV in 1 case, syphilis in 2
was no difference in exposure to smoke (passive smok- cases, but during current pregnancy C. trachomatis was
ing) between both groups (table 4). diagnosed in 4 cases and BV in 4 cases. In all BV cases
vaginal culture was obtained and in all cases Ureaplasma

Maternal Risk Factors for FGR in Latvia Gynecol Obstet Invest 2010;70:219–226 221

GOI386.indd 221 21.05.2010 14:40:01


Table 3. Obstetric characteristics of patients from the control and FGR groups

Pregnancy complications FGR Control p value


(n = 65) (n = 65)

Current pregnancy
Pregnancy anemia (n = 23) 9 (13.8) 14 (21.5) NS
Bleeding in early pregnancy (n = 15) 11 (16.9) 4 (6.2) NS
Threatened premature delivery (n = 9) 6 (9.2) 3 (4.6) NS
Progesterone use (n = 8) 5 (7.7) 3 (4.6) NS
Pregnancy-induced hypertension (n = 7) 7 (10.8) 0 0.02
Pre-eclampsia (n = 12) 10 (15.4) 2 (3.1) 0.03
Viral upper respiratory tract infection (n = 12) 5 (7.7) 7 (10.8) NS
Urine tract infections/AB use (n = 2) 2 (3.1) 0 NS
Without antenatal care (n = 2) 2 (3.1) 0 NS
Past history
≥3 or more miscarriages or TOP (n = 4) 4 (6.2) 0 0.04
Complications after previous deliveries (n = 2) 2 (3.1) 0 NS
SC in previous history/uterine scar (n = 1) 1 (1.5) 0 NS
Intrauterine fetal death in previous history (n = 2) 2 (3.1) 0 NS
Premature deliveries in previous history (n = 5) 3 (4.6) 2 (3.1) NS
Interval between pregnancies less than 17 months (n = 11) 7 (10.8) 4 (6.2) NS
Interval between pregnancies more than 60 months (n = 23) 11 (16.9) 12 (18.5) NS
Gynecological anomalies (congenital uterine
abnormalities, myoma, ovary cystoma) (n = 9) 7 (10.8) 2 (3.1) NS
Extrauterine pregnancy in history (n = 3) 1 (1.5) 2 (3.1) NS

Data are given as numbers, percentages and the total of that group in parentheses.

urealyticum was present. In the control group, in past his- spectrum of medical, socio-demographic and reproduc-
tory there was 1 case of syphilis and 2 of C. trachomatis tive characteristics in more detail.
infection, but no STI/RTI was diagnosed during the cur- The main weaknesses of our study are the relatively
rent pregnancy. small numbers, its case-control setup and the fact that we
There were no statistical differences in extragenital matched the control group only for gestational age at in-
morbidities between the groups (table 4), but the FGR pa- clusion. Also, we did not include the pre-pregnancy
tients used medication significantly more often (p = 0.01). weight and weight gain in our analyses, but this was be-
Most medications were taken for thyroid gland therapy cause there were no cases with malnutrition in both
(n = 2) and pituitary gland adenoma (n = 1); azithromycin groups. Due to the limited reliability in series with low
for C. trachomatis as well as antihypertensive drugs (n = numbers, multivariate analysis could not be performed.
5) were also recorded. Larger, prospective studies would probably be needed,
but are difficult to perform and expensive. Still, the strong
association between maternal characteristics and FGR in
Discussion this study could clearly direct further research.
FGR patients had the same socioeconomic and medi-
According to Latvian statistical data [14], in 2008 the cal background (age, type of residence, level of education,
prevalence in Latvia of ‘small for gestational age’ (SGA) medical history, most of the current medical problems
newborns was 12.5/1,000 term and 17.5/1,000 preterm and obstetric parameters) as controls, but were more of-
births. The prevalence of FGR and its etiologic factors ten unmarried, had experienced more pregnancy losses,
were formerly insufficiently evaluated. Therefore, we de- and delivered preterm more often than controls. As in
cided to study the association between FGR and a broad other studies [15], almost all preterm FGR pregnancies

222 Gynecol Obstet Invest 2010;70:219–226 Vedmedovska /Rezeberga /Teibe /


     

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GOI386.indd 222 21.05.2010 14:40:02


Table 4. Concurrent medical problems of patients from ther con- malities were not found in placentas of babies with nor-
trol and FGR groups mal intrauterine growth [unpubl. data]. We therefore
agree with other authors that there may be a common
Concurrent medical problems FGR Control p
(n = 65) (n = 65) value ethiopathogenesis in pre-eclamptic disorders and fetal
growth restriction [25].
Illicit drug use (n = 1) 1 (1.5) 0 (0.0) NS Placental vascular disease leading to restricted fetal
Alcohol (n = 1) 1 (1.5) 0 (0.0) NS growth may also be caused by smoking during pregnan-
Smoking in current pregnancy (n = 14) 12 (18.5) 2 (3.1) 0.01 cy [26, 27]. Of interest, in our study not only current
Smoking until current pregnancy
(n = 30) 23 (35.4) 7 (10.8) 0.01 smoking, but also former smoking was related to FGR.
Extragenital pathology (n = 25) 15 (23.1) 10 (15.4) NS Furthermore, none of the smoking women with FGR had
STI/RTI (n = 8) 8 (12.3) 0 (0.0) 0.006 PIH during the current pregnancy. This is in agreement
Passive smoking (n = 35) 19 (29.2) 16 (24.6) NS with the hypothesis that maternal smoking reduces the
Use of medication for therapeutic risk of pre-eclampsia and has a mechanism of causing
reason (n = 23) 20 (30.8) 3 (4.6) 0.01
FGR which is independent of blood pressure [28–30].
Data are given as numbers, percentages and the total of that Numerous prior researches supported the association
group in parentheses. between passive smoking and fetal growth [31, 32], but
that was not supported by our findings; however, recall
bias and underreporting of the risk factor cannot be ex-
cluded.
The most striking new finding was the strong associa-
tion FGR and current STI/RTI. Although studies warn
were terminated due to medical or obstetric reasons. The that about 5–10% of the cases with FGR may be attribut-
number of cesarean sections in our study was higher than able to viral or protozoan infections in utero, its relation
in other studies [16] and may be the result of a lack of spe- to STI/RTI was not mentioned [5]. In Latvia specific tests
cific national guidelines. for toxoplasmosis, CMV and HSV are not included in the
Maternal chronic diseases may interfere with fetal routine prenatal screening program, but all cases of FGR
growth. In this study, we did not find differences in prev- were tested and appeared to be negative for these infec-
alence of renal, heart and autoimmune diseases, or asth- tions, as no stigmata of fetal infection were found during
ma or chronic hypertension between the groups. This in prenatal ultrasound or after delivery. According to the
part may be due to the general low prevalence of these results of our study, it seems that genital infections may
diseases in young women. On the other hand, the study not only be involved in the causation of preterm birth and
patients used medication for therapeutic reasons signifi- preterm rupture of the membranes [33, 34], but also of
cantly more often than controls. Over the last few years, FGR. Although not generally recognized as the cause of
the number of pregnant women who have received med- FGR, there are other data suggesting that abnormal vag-
ication has increased. Drugs and their metabolites can inal microflora, BV and mycoplasmata correlate with low
cross the placental barrier and enter the fetal circula- birth weight and FGR [35, 36]. Whether this association
tion. Several studies showed an association between FGR is linked to unrecognized, asymptomatic, chronic or re-
and anti-neoplastic medications [17], anticonvulsants current genital infection like BV, syphilis, C. trachomatis,
[18] and ␤-blockers [19]. The causal relationships with Trichomonas vaginalis or N. gonorrhea is currently un-
FGR for other medications are uncertain and, therefore, known, but a number of studies seem to suggest a clear
use of medication should always be guided by risk-benefit link between these infections and FGR and pregnancy
considerations [5]. loss, both early [37, 38] and later in pregnancy [39–41].
The association we found between pregnancy-induced Further studies are indicated to find out the relation of
hypertension or pre-eclampsia and fetal growth restric- RTIs with FGR.
tion confirms the findings of other studies [20–22] and As, in Latvia, suction-aspiration is the most common
relates to the increased likelihood of placental dysfunc- method for abortion in the first 12 gestational weeks, we
tion in women with hypertension during pregnancy [23, cannot exclude that repetitive trauma of the cervix and
24]. We recently discovered specific vascular disease-re- decidual lining of the uterine wall may have contributed
lated placental abnormalities on histological examina- to defective placental/trophoblast development in subse-
tion in the majority of FGR patients, while such abnor- quent pregnancies and pregnancy losses.

Maternal Risk Factors for FGR in Latvia Gynecol Obstet Invest 2010;70:219–226 223

GOI386.indd 223 21.05.2010 14:40:02


Given the relatively easy and straightforward possi- nancy play an important role in FGR. All possible so-
bilities to screen, detect and treat for STI before or during ciodemographic and reproductive determinants should
pregnancy, we find this association between STI and FGR be elaborated in cases with FGR, as it can enlarge our sci-
of particular interest. We feel that there is a need for fur- entific understanding of the etiology of FGR and lead to
ther studies to better understand the nature of the asso- therapeutic intervention.
ciations between genital infections and FGR, as well as
trials to discover the most effective therapeutic or pro-
Financial Disclosure
phylactic actions to prevent not only preterm birth but
also FGR. This project was supported by a grant of the Latvian Ministry
In conclusion, maternal factors with a potential for of Education and Science and European Social Fund (No.
preventive or therapeutic action before or during preg- 2009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/009).

Appendix 1. Questionnaire

Sociodemographic variables Sociodemographic variables

Age of mother, years Gynecological operations


1. no 2. yes
Type of residence: 1. urban 2. rural
(a) laparoscopy (diagnosis, year, outcome) (b) hysteroscopy (diagnosis,
Level of education: 1. basic 2. secondary 3. secondary/professional year, outcome) (c) laparatomy (diagnosis, year, outcome) (d) others
4. high/university
Obstetric history
Marital status: 1. unmarried 2. married 1. total pregnancy number
2. TOP (termination of pregnancy) ≤12 weeks of gestation for social reason
Employment status: 1. employed 2. unemployed (number, year)
Maternal BMI 3. TOP (termination of pregnancy) ≤12 weeks of gestation for medical
reason (number, year)
Maternal smoking 4. miscarriages (number, year)
1. current smoking: (a) yes (cigarettes per day) (b) no 5. stillbirth (number, year, gestational age)
2. prenatal smoking: (a) yes (cigarettes per day) (b) no 6. vaginal delivery (number, year)
3. quit smoking during pregnancy: (a) yes (when, week of gestation) 7. SC in previous history (number, year)
(b) no (c) reduce smoking (cigarettes per day) 8. extrauterine pregnancy in history (number, year)
9. interval between last and current pregnancies, months
Passive smoking (exposure to smoke)
(a) yes (b) no Complications after deliveries or after TOP (termination of pregnancy)
1. no 2. yes
Maternal alcohol use (12 ounces of regular beer (5% alcohol) equals 5 (a) manual ablation of the placenta (b) instrumental ablation of the
ounces of table wine (12% alcohol) equals 1.5 ounces of hard liquor (40% placenta or placental tissues (c) endometritis (d) others
alcohol); beer, 12 ounces, is equivalent to 1 standard drink)
(a) yes (how many drinks) (b) no Premature deliveries in previous history
1. no 2. yes (number, years, gestational age, outcome)
Maternal recreational drug use
1. current use: (a) yes (type of the substances, amount) (b) no Concurrent medical conditions
2. prenatal use: (a) yes (type of the substances, amount) (b) no 1. no 2. yes
3. quit use during pregnancy: (a) yes (when, week of gestation) (a) endocrine system diseases (thyroid gland, pituitary gland adenoma,
(b) no (c) reduce (type of the substances, amount) others)
(b) heart and vascular diseases (congenital heart defects, peripheral
Gynecological history vascular diseases, others)
1. STI/RTI in previous history: (a) yes (Trichomonas vaginalis, Chlamydia (c) kidney diseases (congenital disease, acquired kidney disease
trachomatis, Neisseria gonorrhoeae, HIV, syphilis, vaginal herpes, BV, other (inflammation, others)
----- specify) (b) no (d) respiratory diseases (chronic obstructive pulmonary disease, infectious
2. STI/RTI during current pregnancy: (a) yes (Trichomonas vaginalis, respiratory diseases, others)
Chlamydia trachomatis, Neisseria gonorrhoeae HIV, syphilis, vaginal herpes, (e) neurological disorders (back pain, cephalic disorder, compression
BV, other ----- specify) (b) no neuropathy, syndromes, others)
(f) others
Gynecological anomalies
1. no 2. yes Medication for therapeutic reason during pregnancy
(a) congenital uterine abnormalities (bicornuate or septated uterus, others) 1. no 2. yes (type, dose)
(b) myoma (c) ovary cystoma (d) others

224 Gynecol Obstet Invest 2010;70:219–226 Vedmedovska /Rezeberga /Teibe /


     

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GOI386.indd 224 21.05.2010 14:40:02


Sociodemographic variables Sociodemographic variables

Current pregnancy Viral upper respiratory tract infection


1. natural conception: (a) yes (b) no (a) gestational age (b) treatment
2. induced: (a) yes (IVF/ICSI, insemination, CC induction) (b) no
Pregnancy-induced hypertension
Antenatal care (a) gestational age (b) treatment
1. yes: (a) adequate (screening for serological and cervico-vaginal
Pre-eclampsia
infections, including serology for antibodies (lues), wet mount microscopy
(a) gestational age (b) treatment
(Trichomonas, bacterial vaginosis), cultures (gonorrhea, mycoplasmata)
and PCR (Chlamydia trachomatis) (b) intermediate (c) inadequate Others
2. no
Complications in current pregnancy
1. bleeding in early pregnancy: (a) light (b) heavy (c) treatment
2. threatened premature delivery: (a) gestational age (b) treatment
3. pregnancy anemia: (a) gestational age (b) treatment
4. urine tract infections: (a) gestational age (b) treatment

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