Nivelurile beta gonadotropinei corionice umane şi ale proteinei plasmatice A asociate sarcinii – markeri târzii de implantare şi placentaţie anormale. Comparaţie între sarcinile spontane cu feţi unici şi cele obţinute prin tehnici de reproducere uman

 Free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels – late markers of abnormal implantation and placentation. Comparison between spontaneous and IVF singleton pregnancies

First published: 23 octombrie 2020

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/ObsGin.68.3.2020.4014


Background. During the late first trimester, between 11-13 weeks of gestation, it is recommended for all pregnant women to have a screening for Down syndrome and for other chromosomal abnormalities like trisomy 13 or 18, because it estimates the potential risk and allows patients to make an informed choice about the continuation of pregnancy. The combined test analyzes three markers along with the maternal age: maternal serum beta-human chorionic gonadotropin (beta-hCG or free beta-hCG subunit), maternal serum pregnancy-associated plasma protein-A (PAPP-A) and an ultrasound measurement of nuchal translucency (NT). Objectives. To determine if there are differences regarding serum markers and pregnancy outcomes between spontaneous pregnancies and pregnancies obtained by assisted reproductive techniques (ART). Materials and method. We performed a literature review by searching MEDLINE and Cochrane databases using the keywords: beta-hCG, PAPP-A, screening, IVF, ICSI, ART, implantation. Results. Assisted reproduction techniques, such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), can alter serum markers levels and mimic the pattern associated with Down syndrome: maternal serum beta-hCG and inhibin A levels tend to be increased, while estradiol and PAPP-A levels are decreased. When comparing spontaneously conceived (SC) singleton pregnancies with in vitro fertilization/intracytoplasmic sperm injection, cohort studies confirm an increased risk of perinatal complications for the latter. The most frequent adverse outcomes are: preterm birth, intrauterine growth restriction, perinatal mortality, congenital malformations and higher risks for preeclampsia and placenta praevia. Conclusions. Overall, the risk of complications is significantly higher in ART pregnancies, but the reasons for this increase are still uncertain. The possible cause of this difference might be the increased maternal age and the particularities that occur during the implantation and placentation.

ß-hCG, PAPP-A, screening, implantation, IVF


Testul combinat de la sfârşitul trimestrului I este recomandat tuturor gravidelor, oferindu-le posibilitatea de a afla riscul fetal de trisomie 13, 18 sau 21. Acesta este un test de screening al cărui rezultat orientează – dacă este necesar – medicul specialist de medicină materno-fetală şi pacienta spre investigaţii suplimentare şi spre o decizie bine informată asupra evoluţiei sarcinii. Testul coroborează trei factori: beta gonadotropina corionică umană (beta-hCG), proteina plasmatică asociată sarcinii (PAPP-A) din sângele matern şi translucenţa nucală, măsurată ecografic. Scop. Revederea literaturii pentru a stabili dacă există corelaţii între complicaţiile perinatale şi modalitatea de obţinere a sarcinii care să poată fi decelate sub formă de riscuri în trimestrul I. Materiale şi metodă. Au fost cercetate datele din bazele MEDLINE şi Cochrane, folosind următoarele cuvinte-cheie: ß-hCG, PAPP-A, screening, implantation, IVF, ICSI, ART. Rezultate. Tehnicile de reproducere umană asistată (RUA) modifică valorile markerilor serici, mimând un tablou similar cu cel al sindromului Down: ß-hCG şi inhibina au valori crescute, în timp ce estradiolul şi PAPP-A au valori scăzute. Sarcinile obţinute prin tehnici de reproducere asistată au un risc mai mare de complicaţii: naştere prematură, restricţie de creştere intrauterină, mortalitate perinatală, anomalii congenitale şi placenta praevia. Concluzii. Riscurile asociate sarcinilor obţinute prin RUA sunt mai mari faţă de cele ale sarcinilor obţinute spontan. Acest fapt se datorează, pe de o parte, vârstei materne în general mai avansate, iar pe de altă parte, unor factori care ţin de cauzele infertilitaţii, cu defecte care apar încă din perioada de implantare şi placentaţie. 


During late first trimester, between 11-13 weeks of gestation, it is recommended for all pregnant women to have a screening for Down syndrome and for other chromosomal abnormalities like trisomy 13 or 18. The screening estimates the potential risk and allows the woman to make an informed choice about the continuation of the pregnancy and on invasive diagnostic testing with its risks.

Analysis and results

Comparison of the first-trimester screening, using PAPP-A and β-hCG, between spontaneous and IVF singleton pregnancies

The combined test analyzes three markers along with the maternal age: maternal serum beta-human chorionic gonadotropin (beta-hCG or free beta-hCG subunit), maternal serum pregnancy-associated plasma protein-A (PAPP-A) and an ultrasound measurement of nuchal translucency (NT).

These pregnancy-associated hormones, such as hCG, the first embryonic signal molecule, progesterone or estradiol (E2), have high levels at the maternal-fetal inter­face(1,2). They influence the implantation and trophoblastic invasion.

Moreover, PAPP-A is derived from placental tro­pho­blasts and stromal cells, with high importance in placental development, causing metabolic disorders, growth restriction or even preeclampsia. Considering the fact that high levels of E2 may lead to the downregulation of E2 receptors, with results in suboptimal placental-endometrial interface, it may produce the reduction in hormones concentrations(1,2).

Assisted reproductive techniques (ART), such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), can alter serum marker levels to mimic the pattern associated with Down syndrome: maternal serum beta-hCG and inhibin A levels tend to be increased, while estradiol and PAPP-A levels are decreased(3). The results differ depending on the type of ART procedure used. A review conducted by Cavoretto et al. reported a slightly higher b-hCG in ICSI group where there was registered a difference of about 10%, but an important lower PAPP-A level in the IVF group up to an extent of about 25%, and higher values for beta-hCG, with variations among studies. On the other hand, there is no modification regarding the NT(3).

Therefore, it is recommended that clinicians should inform the laboratory about IVF and ICSI conceived pregnancies, so that the laboratory can adjust MoMs and thus reduce the need for follow-up invasive testing or secondary cell-free-DNA screening.

The variations can also occur when oocyte donation, ovulation induction, or intrauterine insemination and screening software programs are used to make appropriate adjustments, but with little changes regarding risks.

A study conducted on 1030 women, comprising 310 consecutive single IVF pregnancies and 720 naturally conceived pregnancies without any complications, made a few observations. Hormone levels were measured by standard kits and then converted to multiple of the median units (MoM). The study took into consideration demographic aspects such as maternal and paternal age, Body Mass Index (BMI), gestational history and nuchal translucency on ultrasound examination, which didn’t vary, and excluded behaviours like smoking or alcohol consumption. The result, in accordance with the previously mentioned study, showed that PAPP-A levels were lower, but free b-hCG was higher in IVF pregnancies, with no significant differences between the two groups regarding the MoM values(4). This observational study showed important levels of b-hCG in the first trimester in intracytoplasmic sperm injection pregnancies compared to naturally conceived women(5). In comparison, free b-hCG and nuchal translucency were similar in both normal and assisted reproductive technology pregnancies.

However, there are also conflicting results on the first-trimester screening in ART patients, insufficiently explained by the current literature. Some studies found no difference between these groups, while others found altered levels in ART pregnancies interpreted in the context of a multiple corpora lutea or abnormal feto-placental metabolism.

The explanation resides in the changes that occur during embryogenesis or placentation of ART conceptions(3,6). Yet, further studies are required to obtain more specific results and understand the factors that influence the first trimester.

Incidence of maternal and fetal obstetric complication in IVF versus spontaneously conceived pregnancies

Nowadays, assisted reproductive technology is no more a miracle, but a common part of medicine. In the past, a well-known high risk of adverse outcome was associated with the transfer of more embryos, in the effort to have a successful procedure.

Current guidelines recommend the practice of using single-embryo transfer to decrease the risk of adverse outcome of the future pregnancy(7-11).

When comparing spontaneously conceived (SC) singleton pregnancies with the in vitro fertilization/intracytoplasmic sperm injection, cohort studies confirm an increased risk of perinatal outcome for the second one.

The adverse pregnancy outcomes related to ART are preterm birth (PTB), fetal growth restriction, low birth weight (LBW), small for gestational age (SGA), perinatal mortality (stillbirth, neonatal death), congenital malformations, higher risk for preeclampsia, placenta praevia and placental abruption.

Overall, the risk is significantly higher in ART pregnancies, but the reasons for this increase are still uncertain. The possible causes that can explain this difference consist in maternal age, commonly increased in this situation, and particularities that occur during the placentation process.

Moreover, medications used for inducing ovulation or maintaining pregnancy in early stages, the potential for polyspermic fertilization, the delayed fertilization of the oocyte, the abnormal status at time of implantation and the manipulation of gametes and embryos may increase the risk for adverse outcome(12-14).

According to a worldwide study, using data from 52 cohort studies, the estimates for adverse pregnancy outcomes for ART pregnancies versus SC pregnancies were 10.9% versus 6.4% for PTB, 8.7% versus 5.8% for LBW, 7.1% versus 5.7% for SGA, 1.1% versus 0.6% regarding perinatal mortality and 5.7% versus 3.9% for congenital malformations(15).

Risk of preterm birth

The prevalence of preterm birth is distinct worldwide. The highest reported was in Asia, with 14.1%, Japan being the leading country, and the lowest was in Europe, with 9.6%(15). It seems that frozen embryo transfers are associated with a decrease in small for gestational age and LBW births, as well as with preterm births(16), suggesting that the more natural endometrial preparation is prior to transfer, the more natural placentation occurs.

Risk of fetal growth restriction

The continental difference regarding LBW showed a higher prevalence in Asia (11% in Japan) and a lower one in North America (8%). The highest prevalence of SGA was reported in Oceania (13.2%) and lowest one in North America (3.9%), while in Europe it was 5.8%. A possible limitation of the study is that it does not men­tion whe­ther the infant was conceived as a singleton or it was a multiple pregnancy that was later reduced either me­di­cally or spontaneously. There is still uncertain if LBW is influenced by ART procedures or by underlying infertility of the couple.

Risk of perinatal mortality

The highest reported perinatal mortality prevalence was found in Asia (1.6% in Japan) and Oceania (1.2%), and the lowest in North America (0.4%). The reported prevalence in Europe was about 1%. Early spontaneous loss is frequent in ART pregnancies, ultrasound examinations at early gestational age identifying spontaneous loss of at least one gestation in approximately 25% of singleton pregnancies(17). Regarding spontaneous abortion, it is reported at a rate of 16% of all pregnancies, influenced by the age of the egg provider. It is important to mention that this rate is comparable to that of SC pregnancies when using fresh fertilised eggs, but higher with thawed eggs(18).

Risk of congenital malformations

There were statistically significant differences for congenital malformation prevalence within continent groups. The highest reported congenital malformation prevalence was found in Oceania (7.3%), the second highest in Europe (6.2%), and the lowest in Asia (2.8%). The reported congenital malformation prevalence in North America was 5.1% (95% CI; 3.2-8.2)(15).

The increased risk of birth defects was observed for all major organs and systems, and on the leading place was the nervous system (2.01%). When comparing children conceived by IVF with those conceived by ICSI, there was no significant risk difference(19).

Risk of preeclampsia

Preeclampsia is a serious condition and one of the major contributors to obstetric complications such as placental abruption, fetal growth restrictions and preterm delivery. Its prevalence increases with maternal age, long intervals between births and changing of partner.

Retrospective registry studies have reported that pregnancies conceived with ART are more likely to be associated with preeclampsia (PE) and gestational hypertension.

The absence of a corpus luteum cyst in these cycles appears to be a possible underlying mechanism. Regarding PE by parity in ART pregnancies, the rates are 6% for the first, 3.3% for the second, and 4.4% for the third or higher order births(20).

When using oocyte donation, the risk for preeclampsia is double than normal, and the risk for gestational hypertension is three times higher compared to other ART procedures(21).

There is no certainty about underlying causes, but different placentation, different weight of placenta in ART pregnancies, along with increased placental inflammation and oxidative stress could be important factors to be studied.

Risk of placenta praevia

Placenta praevia is associated with multiple maternal and fetal severe outcomes, such as haemorrhage, prematurity and increased perinatal morbidity and mortality. It is reported a six-fold higher risk for ART pregnancies compared to those SC, mostly related to the reproduction technology(22).

It was also hypothetised that frozen embryo transfers are associated with decreased risk of placenta praevia and abruptio placentae, suggesting that the endometrial environment at the time of implantation plays a role in the pathogenesis of these complications.

All these increased risks in Asian countries could be related to the consanguinity rates, suggesting a relevant genetic influence.

Former investigations over ART showed that families who are using it have a higher social status, applicable to European countries.

There are differences between IVF and ICSI in singleton pregnancies. The more invasive the treatment, the more harm on the mother and her offspring. Taking into consideration the study presented before, it revealed that IVF pregnancies have higher prevalence of PTB, LBW and perinatal mortality, and a lower prevalence of congenital malformations compared to ICSI(15).


The first-trimester screening using both beta-hCG and PAPP-A is important both in spontaneously conceived and ART pregnancies to estimate the potential risks of pregnancy and the future management, according to their variations. It is well known that ART preg­nan­cies, no matter the technique used, have higher risks on pregnancy and neonatal outcome. The future patients should be carefully informed before applying for any of these procedures. 


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