PRECONCEPTIONAL EVALUATION
GENERAL CONSULTING
Diet
► During pregnancy, expectant mothers should be warned not to consume raw meat and dairy products and not to consume fish with high mercury content (shark and swordfish, etc.) excessively.
Maternal and paternal age
► In adolescent pregnancies; anemia, preterm labor and preeclampsia are more common.
► Both maternal and fetal mortality increases in pregnancies where the maternal age is >35. The incidence of preterm labor, spontaneous preterm labor, IUGR, fetal aneuploidy and dizygotic twinning increases due to maternal complications such as hypertension and diabetes.
Although there is a significant increase in the risk of trisomy with advanced maternal age; Monosomy-X (Turner Syndrome) is not associated with advanced maternal age.
► Although there is an increase in the risk of genetic diseases with the increase in paternal age, the incidence is very low. There is a slight increase in the risk of Down Syndrome with advanced paternal age, but there is no increase in the risk of other aneuploidies. There is no increase in the risk of IUGR and stillbirth with advanced paternal age.
Obesity
► Significant obesity causes increased maternal and fetal morbidity and mortality. It may also be associated with fetal structural anomalies (neural tube defect, cardiac anomaly).
|
Adverse
Pregnancy Outcomes in Obese Women |
||
|
Complication |
Prevalence (%) in normal weight pregnant
women (BMI-18.5-24.9) |
Prevalence (%) and Odds Ratio in Obese
(BMI 30) Pregnants |
|
gestational diabetes |
2.3 |
8.6 (4.04) |
The obstetric complication with the highest risk in obesity and pregnancy is gestational diabetes.
Assisted Reproductive Techniques
► The rate of major congenital malformations increased in pregnancies with assisted reproductive techniques and was found to be 8.3%. This risk is especially found in intracytoplasmic injection (ICSI) pregnancies.
Questioning Medical Diseases and Drug Use Diabetes Mellitus
► In the follow-up of pregestational diabetic patients, the HbA1C level and malformation rate are directly proportional, and the most important preconceptional goal is to normalize the HbA1c level. In pregestational diabetic women, HbA1C, serum creatinine, urine protein and thyroid function tests should be measured in the preconceptional period.
Epilepsy
► Being pregnant after a seizure-free year reduces the risk of epilepsy by 50-70%, and control should be sought with monotherapy, which is less teratogenic. Preconceptional high-dose folic acid (4 mg) should be started in women using antiepileptic drugs.
Other Medical Diseases and Environmental Factors
► Cardiovascular diseases, chronic hypertension, asthma, thrombophilias, renal diseases, inflammatory bowel diseases, sickle cell anemia (in risk group), thalassemias (in risk group), rheumatoid arthritis, SLE, epilepsy, depression, dermatological diseases, cancers, mercury and lead exposure should be questioned.
Questioning Infections
Infections That Need to be Screened Before Pregnancy
► Rubella (if there is no immunity, vaccinate and use effective contraception for 1 month)
► Varicella (vaccinate if not immune)
► Hepatitis B (vaccinate if not immune)
► HIV (at-risk women should be screened)
► Hepatitis C (should be screened only in high-risk cases)
► Tuberculosis (it should be screened only in high-risk cases)
► Syphilis (should be screened only in high-risk cases)
► Gonorrhea (should be screened only in high-risk cases)
► Chlamydia (should be screened only in high-risk cases)
Infections that do not need to be screened before pregnancy
► Toxoplasma
► Cytomegalovirus
► Herpes simplex virus (HSV); Only asymptomatic women with an affected partner should be screened.
Questioning Genetic Risks
• Genetic diseases are quite common and trisomies constitute about half of all chromosomal anomalies. Chromosomal anomalies are seen in approximately 50% of first trimester spontaneous abortions, 6-8% of stillbirths and early childhood deaths, and 0.4% of live births.
• Major congenital anomalies occur in 2-3% of live births. The most common cause of infant mortality is congenital defects (20%). While the most common congenital defect is cardiac anomalies, the second is neural tube defect.
• The risk of both anomalies increases in those with methylene tetrahydrofolate reductase gene polymorphism and is reduced by preconceptional folic acid supplementation. In order to prevent NTD, it is sufficient to start folic acid use before conception (400-800 µcg) and to use it in the first trimester of pregnancy. In cases with a history of NTD, using a dose of 4 mg reduces the risk.
PRENATAL EVALUATION
Prenatal Follow-up
• Thanks to prenatal care, maternal mortality and the risk of preterm birth, stillbirth and neonatal mortality are reduced.
|
Recommended
follow-up algorithm during pregnancy |
|
|
Frequency of
follow-up |
once a month for 28 weeks |
|
To be applied
at each follow-up |
blood pressure measurement |
|
will be
applied at the first visit (weeks 0-14) |
Risk analysis for genetic, medical, obstetric and
psychosocial factors |
|
will be
applied at the second visit (weeks 15-28) |
Hematocrit or hemoglobin. |
|
To be applied
at the third visit (weeks 29-41) |
Group B streptococcal culture (rectovaginal)
(between 35-37 weeks) |
If there is an indication, tuberculosis screening can be performed with tuberculin skin test or tuberculosis blood test at any gestational week.
Screening Tests
• Every pregnant woman should be offered a screening test in the early stages of pregnancy. Although the risk of Down syndrome increases after the age of 35, 70% of Down syndrome cases are seen in pregnant women younger than 35 years of age, and maternal age alone is a bad screening test.
Screening Tests in the First Trimester (11-14 Weeks of Pregnancy)
► It is a screening test performed between 11-14 weeks of pregnancy using some markers in maternal serum and ultrasonography.
► Pregnancy-related plasma protein-A (PAPP-A) and hCG (or free 13-hCG) levels are checked in maternal serum . In addition to these serum markers, ultrasonographic fetal nuchal translucency (NT) and nasal bone measurement can be added.
Free B-hCG: Increases in Down syndrome, decreases in trisomy 18 and trisomy 13.
0 PAPP-A (pregnancy-associated plasma protein-A): It is a glycoprotein secreted by the placenta. It is released directly into the maternal serum, therefore it is not found in the amniotic fluid. Down syndrome is reduced in trisomy 18 and trisomy 13.
0 Nape thickness (NT) measurement: It is the maximum thickness of the translucent subcutaneous tissue between the skin and the soft tissue on the vertebrae in the nuchal part of the fetus. An increase in nuchal thickness indicates a disorder in lymphatic transformation. It is generally used in combination with serum markers; however, it is used as a stand-alone screening test in multiple pregnancies. In 1/3 of the chromosomal abnormalities, NT is measured as abnormal, and about half of these are Down syndrome. Apart from chromosomal aneuploidies, NT is also increased in genetic syndromes, various birth defects and especially cardiac anomalies. Therefore, chorionic villus sampling and karyotype analysis are primarily recommended for diagnosis when NT is 3 mm or more. If the karyotype analysis is normal, fetal echocardiography should be performed.
0 Nasal bone: In 2/3 of fetuses with Down syndrome, nasal bone is hypoplasic or aplasic by ultrasonography between 11-14 weeks.
|
First
trimester trisomy screening test (11-14 weeks of gestation) |
|
|
tests |
trisomy 21 |
|
hCG or free B-hCG |
Increases (2 2.0 MOM) |
|
PAPP-A |
Decreases (s 0.5 MOM) |
|
NT |
Increases (23 mm) |
|
nasal bone |
Hypoplasic/ Aplasic |
In the first trimester screening test, chorionic villus sampling and karyotype analysis should be applied as a definitive diagnostic test in patients with high risk of aneuploidy.
Screening Tests in the Second Trimester (15-21st Pregnancy Weeks)
► Between the 15th and 21st weeks of pregnancy, a triple screening test is performed by looking for alpha-fetoprotein (AFP), unconjugated estriol (uE3) and hCG (or free B-hCG) in maternal serum. In addition, quadruple screening is performed by looking at the inhibin A level.
► If the risk score obtained with these markers is 1/270 and above, karyotype analysis with amniocentesis should be applied to the patient as a diagnostic test.
0 Free (B-hCG: Levels increase in Down syndrome, decrease in trisomy 18).
Unconjugated estriol (uE3): Decreased in both Down syndrome and trisomy 18.
Inhibin A: The serum level is increased in Down syndrome.
0 Maternal serum alpha-fetoprotein (MS-AFP): Down syndrome and decreased in trisomy 18; increased in neural tube defects.
|
second
trimester trisomy screening test (15-21 weeks of gestation) |
||
|
Test |
trisomy 18 |
trisomy 21 |
|
MS-AFP |
Decreases (s 0.6 MOM) |
Decreases (s 0.7 MOM) |
|
Unconjugated estriol (uE3) |
Decreases (≤ 0.5 MOM) |
Decreases (s 0.8 MOM) |
|
hCG or free B-hCG |
Decreases (s 0.55 MOM) |
Increases (2 2.0 MOM) |
|
Inhibin-A |
- |
Increases (z 1.8 MOM) |
► MS-AFP levels are also used in neural tube defect (NTD) screening. AFP is a glycoprotein synthesized by the fetal yolk sac (vitelline sac), liver and gastrointestinal tract, and is an analogue of albumin . Until the 13th week of pregnancy, AFP rises in both fetal serum and amniotic fluid, then rapidly decreases. On the contrary, it begins to rise in maternal serum after the 12th week.
► MS-AFP level affects maternal weight, gestational week, race/ethnicity, diabetes and multiple pregnancy, and the upper limit value accepted as normal in singleton pregnancies is 2.5 MoM (multiples of median).
► The gestational age is 15-20 after confirmation. AFP (MS-AFP) levels in the maternal erum are checked between gestational weeks, and if the value is found to be 2.5 MoM and above, level II ultrasonography is applied for diagnosis and fetal anatomy is evaluated. If a neural tube defect cannot be demonstrated by ultrasonography, the risk is reduced by 95%. If a neural tube defect cannot be excluded by ultrasonography, amniocentesis can be considered for the measurement of AFP and acetylcholinesterase in amniotic fluid.
Factors affecting MS-AFP levels
Situations where it increases
• Neural tube defects
• Renal anomalies (renal agenesis, polycystic kidney)
• Multiple pregnancies (normal range would be 3.5-4.0 MoM)
• Low birth weight
• Cystic hygroma
• Esophageal and intestinal obstruction
• Urinary obstruction
• Sacrococcygeal teratoma
• Osteogenesis imperfecta
• Preeclampsia
• detachment
• Placental intervillous thrombosis
• Fetal growth restriction
• Oligohydramnios
• Abdomen anterior wall defects (omphalocele, gastroschisis)
• Pilonidal cyst
• Congenital nephrosis
• Congenital skin defects (epidermolysis bullosa)
• Cloacal exstrophy
• Placental chorioangioma
• Liver necrosis
• Fetal death
• Low maternal weight
• Maternal hepatoma, teratoma
• Underestimating the gestational age
Decreased states
• Trisomy 21 or 18
• Gestational trophoblastic diseases
• Fetal death
• Maternal diabetes
• Maternal obesity
• Overestimation of gestational age
screening with free fetal DNA (cell free DNA) in the maternal circulation (noninvasive prenatal test)
► Free fetal DNA from the maternal circulation cell is released from apoptotic placental trophoblasts rather than from true fetal cells. 9 -10. It can be detected in the maternal circulation starting from the second week and is present in the maternal plasma at a rate of 10%. However, it is generally preferred to be used after the 10th week of pregnancy. Unlike intact fetal cells, free fetal DNA is cleared in maternal blood within minutes and decreases to immeasurable levels within two hours.
► The clinical usage areas of this test;
determination of the 0 Rh genotype; It can be used to determine the fetal Rh status in cases with Rh incompatibility.
0 Determination of fetal sex; It can be used to determine maternal steroid therapy in patients at risk for X-linked disease and in fetuses at risk for congenital adrenal hyperplasia.
0 Studies are also underway to detect various single gene diseases with fetal ONA in the maternal circulation (myotonic dystrophy, achondroplasia, Huntington's disease, CAD, cystic fibrosis and thalassemia).
0 Screening for aneuploidy (Noninvasive prenatal test=NIPT}; It is recommended to be used as a screening test for trisomy 21, 18 and 13 in high-risk pregnancies as early as the 10th week of pregnancy. It is not a diagnostic test, but if the result is abnormal, the result should be confirmed with invasive diagnostic tests. Single Its sensitivity in detecting Down syndrome in pregnancies is very high, with a detection rate of 99% and a false positivity of 0.5%.As the fetal DNA fraction increases, the reliability of the test increases.
• Patients at high risk of trisomy for whom screening with maternally circulating DNA is recommended;
- Women who are 35 years or older at birth
- Presence of ultrasonographic findings that increase the risk of fetal aneuploidy
- History of trisomy 21, 18 or 13 in previous pregnancies
- Presence of a balanced translocation involving chromosome 21 or 13 in one of the parents
- Abnormal first or second trimester screening test result
• Placenta! It should be kept in mind that the results may not reflect the fetal karyotype in case of mosaicism, loss of aneuploid twin in early weeks, maternal mosaicism or maternal malignancy.
It is not recommended for use in multiple pregnancies.
|
Efficacy of
Screening Tests in Pregnancy in Detection of Down Syndrome |
||
|
tests |
tokens |
Detection rate (%) |
|
NT (11-14 weeks) |
NT |
64- 70 |
|
1st trimester screening test (11-14 weeks) |
NT +PAPP-A+hCG |
80-84 |
|
Quadruple screening test (weeks 15-20) |
MS-AFP +hCG + uE3 +Inhibin A |
80-82 |
|
Integrated Testing |
1.Timester test + Quad test |
94-96 |
|
Cell-free DNA screening test |
|
99 |
Obstetric ultrasonography
Ultrasonography in the First Trimester
► Components and some indications of ultrasonographic evaluation in the first trimester;
0 Determination of gestational sac diameter, localization and number
0 Identification of embryo and/or yolk sac
0 Detection of number of fetuses, amnionicity, chorionicity in multiple pregnancies
0 cardiac activity
0 Gestational age determination; measurement of head-butt distance
0 NT measurement between 11-14 weeks
0 Detection of advanced anomalies such as anencephaly
0 Investigation of the cause if there is pain, vaginal bleeding
0 Investigation of the maternal uterus and adnexal region for mass
0 As a guide in chorionic villus biopsy and embryo transfer procedures
► With transvaginal ultrasonography, the gestational sac can be seen at the 5th week, the yolk sac in the middle of the 5th week, and the embryo and cardiac activity at the 6th week.
The most accurate result in determining the gestational age up to 13 617 weeks is obtained by measuring the head-rump distance of the embryo/fetus.
Findings That Can Be Detected by Ultrasonography in the First Trimester in Down Syndrome
• NT increase
• Nasal bone hypo/aplasia
• Enlargement of the frontomaxillary angle
• Tricuspid regurgitation
• Abnormal ductus venosus blood flow (monitoring of reverse a wave)
Second and Third Trimester Ultrasonography
► Components and some indications of ultrasonographic evaluation in the second trimester;
0 Fetal cardiac activity
0 Gestational age; head circumference (HC) measurement when biparietal diameter (BPD) cannot be measured
0 Estimated fetal weight, fetal growth (IUGR-macrosomia)
0 Number of fetuses and chorionicity in multiple pregnancies
0 Amniotic fluid amount (8-24 cm) (oligohydramnios - hydramnios)
0 Placental location, proximity to the cervical canal and cord insertion site
0 Other placental anomalies
0 Pathologies related to the umbilical cord
0 Fetal anomalies (NTD, cardiac anomalies etc.); ideally 18-20. between weeks.
0 Presentation
0 Evaluation of uterine adnexa and cervix (cervical canal length)
► Many fetuses with aneuploidy are lost in utero and most of these cases have anomalies that can be detected by ultrasonography in the second trimester. On the other hand, only 25-30% of Down syndrome cases have a major anomaly that can be detected by ultrasound in the second trimester.
Findings that can be detected by ultrasonography in the second trimester in Down syndrome
Increase in nuchal fold (the finding that increases the probability of Down)
short humerus
echogenic gut
echogenic intracardiac focus
short femur
Mild dilatation of the renal pelvis
short ear
Hypoplasia or aplasia of the nasal bone
Brachycephaly or short frontal lobe
Widening at the iliac angle
Clinodactyly (hypoplasia of the middle phalanx of the 5th finger)
flat face image
Single transverse palmar line
sandal gap
single umbilical artery
Aberrant right subclavian artery
|
The relationship
between aneuploidy and defects detected by USG |
||
|
defect |
Aneuploidy Risk (%) |
Most Commonly Associated Aneuploidy |
|
cystic hygroma |
50-70 |
45 X (most common in second trimester) t21 (most
common in first trimester) t18, t13, triploidy |
|
Omphalocele |
30-50 |
t18, t13, t21, triploidy |
|
Dandy-Walker complex |
40 |
t18, t13, t21, triploidy |
|
holoprosencephaly |
30-40 |
t13, t18, t22, triploidy |
|
Duodenal atresia |
30 |
t21 |
|
cardiac defects |
10-30 |
t21, t18, t13, 45 X. 22g11.2 deletion |
|
clubfoot |
5-30 |
t18, t13 |
|
Ventriculomegaly |
5-25 |
t13, t18, t21, triploidy |
|
Nonimmune hydrops |
10-20 |
t21, t18, t13, 45X, triploidy |
|
Diaphragmatic hernia |
5-15 |
t18, t13, t21 |
|
Cleft palate/lip |
5-15 |
t18, t13 |
|
Esophageal atresia |
10 |
t18, t21 |
|
gastroschisis |
NO INCREASE |
no |
The malformation most associated with aneuploidy is Cystic Hygroma.
► Sacrococcygeal teratoma: It is the most common neoplasm in the neonatal period and is more common in female babies. Perinatal mortality rate is around 40%. If hydrops or placentomegaly develops in the case, the loss is 100%. One of the causes of death in the postnatal period is malignant invasion. In cases, hydramnios is frequently encountered. High-output heart failure due to increased tumor vascularity or anemia due to intra-tumor hemorrhage causes hydrops in cases. In the antenatal period, masses below 7 cm can be followed ultrasonographically. For masses of 5 cm and above, the delivery method should be absolute cesarean section.
► Fetal renal pelvis dilatation: Renal pelvis dilatation is observed in 1-2% of fetuses and is temporary in 40-90% of the cases and is not associated with any anomaly. An anomaly of the urinary system can be observed in up to 1/3 of the cases, most commonly obstruction or vesicoureteral reflux at the ureteropelvic junction. In the ultrasonographic follow-up of the fetus, the measurement of the renal pelvis is made as anteroposterior diameter in the transverse plane. If the anteroposterior diameter measurement exceeds 4 mm in the second trimester and exceeds 7 mm in the third trimester, the diagnosis of renal pelvis dilatation is made. Mild pyelectasis observed in the second trimester slightly increase the risk of Down syndrome.
Prenatal Invasive Diagnostic Tests
Chorionic Villus Sampling
► Obtaining chorionic villi for cytogenetic analysis in the first trimester (10-13 weeks). The most important advantage is that direct karyotyping can be done without culturing the chorionic villus cells taken. Thus, by obtaining results in the early period, pregnancy termination can be done in earlier weeks of pregnancy.
► The most important disadvantage of this process is that more than 2% mosaicism is detected.
► The risk of discharge of amniotic fluid or infection is around 0.5%. your pregnancy
The incidence of extremity deformities or oromandibular defects increases when applied at 7 weeks of age. The fetal loss rate is similar to amniocentesis and is around 1:400; however, fetal loss rate is higher in procedures performed due to high NT.
Amniocentesis (A/S)
► The most commonly used test for genetic diagnosis is amniocentesis, and the classical application time is 15-20. are weeks of pregnancy.
► It is preferred because the risk of mosaicism is very low. The most important disadvantage of the procedure is the length of the culture phase, which lasts 7-10 days after the procedure.
► Complications of A/S are very few and occur rarely. Spotting or amniotic fluid may occur in 1-2% of cases. Chorioamnionitis risk
when less than 0.1%; fetal loss rate is around 1/500.
Fetal blood sampling (cordocentesis, percutaneous Umbilical Blood Sampling)
► It is the process of taking blood from the umbilical cord.
► Indications
0 Evaluation of fetal anemia due to alloimmunization and blood transfusion (most common indication)
0 Karyotype analysis: Results can be obtained in 24-48 hours.
0 Platelet alloimmunization
0 Fetal metabolic and hematological diseases
0 Acid-base analysis
0 Viral and bacterial cultures
0 For PCR testing in the diagnosis of infections
► Complications
0 Cord bleeding (20-30%)
0 Fetal-maternal hemorrhage (40% if crossed the placenta)
0 Fetal bradycardia (5-10%)
0 Fetal loss (1.4%)
Preimplantation genetic testing
► Preimplantation genetic diagnosis and preimplantation genetic screening are examined in two parts. For genetic analysis; polar body analysis, blastomere biopsy (3 days old and 6-8 cell embryo stage) or trophectoderm biopsy (5-6 days blastocyst stage) are used.
► Preimplantation genetic diagnosis: The aim is to place only healthy embryos intrauterinely by performing genetic analysis before implantation. Its indications include the presence of balanced translocation in the parents, single gene diseases (cystic fibrosis, thalassemia, hemophilia), fetal sex determination for X-linked diseases, detection of mutations such as BRCA-1, and detection of HLA compatibility with sibling for stem cell transplantation.
► preimplantation genetic screening: It is screening for aneuploidy before embryo transfer in couples who do not carry any known genetic abnormality.